Video
5 Herbs that Balance Your Hormones Naturally - Powerful Herbs For Hormonal Imbalance in Men \u0026 WomenHerbal metabolism regulator -
Research has shown that ginger increases metabolism while reducing systemic inflammation. Oregano is a potent, fragrant herb used in Italian cooking. This delicious herb has powerful compounds and antioxidants that can help you lose weight and feel great.
Oregano contains terpenoids, terpenes, and phenols, including carvacrol, thymol, and rosmarinic acid. Carvacrol may boost your weight loss efforts. It works by affecting specific proteins and genes in the body that are responsible for controlling fat synthesis. Oregano also helps to reduce systemic inflammation and reduce pain , so you can exercise more.
Fenugreek has been used in alternative medicine for many years and is also an herb used in a plethora of Indian dishes. This household spice gives a sweet, nutty flavor to your dishes.
One tablespoon of fenugreek seeds provides iron, magnesium , and manganese to support health. Fenugreek may also help with metabolic conditions like diabetes. One study found that taking 50 milligrams of fenugreek powder with meals can improve glucose levels, improves insulin function, and reduces bad cholesterol levels.
Fenugreek helps control appetite thanks to its fiber content. Reduced hunger and food intake can aid in weight loss. Ginseng is another herb commonly used in alternative medicine. This root plant has been studied extensively. Research has proven time and time again that ginseng can help boost metabolism and aid in weight loss.
When ginseng is combined with daily exercise and a healthy diet , you will lose more body fat and weight than those who depend on exercise and diet alone. Ginseng affects the metabolism of fat and cholesterol through its effects on adiponectin, leptin, and insulin.
The active compounds in ginseng ginsenosides stimulate fat loss at a molecular level, which helps decrease hunger and maintain insulin levels. Finally, ginseng increases your energy levels and reduces fatigue. It is important to know that herbs can provide many medicinal benefits as well as enhance the flavors of foods.
Diet and Nutrition. Rose Wellness offers Holistic, Integrative and Functional Medicine services for treating chronic issues as well as for preventive care. Join us and take control of your health, your most important asset. Hypothyroidism Natural Treatment Options.
Thyroid disorders can occur in many forms, but hypothyroidism is one of the most common. Symptoms of hypothyroidism are varied Women must navigate varying hormonal imbalances and changes throughout their lives. From puberty to pregnancy, perimenopause, and menopause, fluctuations in Hormone Health- The Untold Connection.
Hormones are special chemicals that travel through the bloodstream. They carry messages from the glands where they are produced to Stimulate Your Thyroid and Lose Weight.
If you have an underactive thyroid, you know how difficult it can be to lose weight. A sluggish thyroid can Weight Loss. How to Balance Hormones for Weight Loss.
Are you having difficulty losing weight even when you cut your calories, follow a weight loss diet, and exercise regularly? Preventive Medicine. The term cortisol has been in the news a lot lately. If you are like most people, you have heard Weight loss is difficult in the best of circumstances.
Many people think that weight loss is as simple as cutting Metabolic Health. What is Diabetes? Diabetes is a chronic medical condition that impacts every system in your body. Unmanaged blood sugar levels Chronic Issues and Preventive Care for Men and Women.
Ask Us. Functional Medicine is journey and works best when there is a mutual commitment between you and your functional medicine team.
Partnership between you, your physician, and your health coach provides consistency and adherence leading to better accountability and healthcare outcomes. For more details on our Subscriptions Plans, Click here. Our integrative physicians and healthcare providers treat various chronic illnesses and acute conditions including —.
For a complete list of conditions we treat, Click here. We believe in empowering you to have the freedom of choice to determine the best treatment options for your medical needs and avoid constraints placed by insurance companies.
However, we will help you receive any insurance benefits you may be entitled to. All costs for services rendered will be your sole responsibility. Most insurance companies offer some degree of reimbursement; however, you are encouraged to check with your insurance company about reimbursement prior to your appointment.
For conventional blood work, insurance companies frequently offer full coverage. Medicare - Our functional medicine practitioners have opted out of Medicare. If you are a Medicare beneficiary, you will not be entitled to any reimbursement from Medicare.
All costs for services including prescriptions and laboratory tests ordered will be your sole responsibility and will not be covered by Medicare. Further Information - If your insurance company needs further information, feel free to contact our office and our helpful staff will try to assist you.
Yes, we offer TeleHealth consults so you can connect with your healthcare provider from the comfort of your home. More than half of our patients prefer to use TeleHealth video conferencing option while saving valuable travel time.
For more details on our TeleHealth services, click here. Functional Medicine is a journey and not a sprint and requires commitment to see long term sustainable results. Our functional medicine clinicians spend a significant amount of time with you starting with the first visit and make a time commitment to your health and well-being.
It typically takes 6 to 12 months to uncover and heal the different layers of health such as balancing the hormones and gut microbiome, enhancing effective detoxification, identifying inflammation and food intolerances, and personalizing your nutritional needs.
We strongly encourage you to have a separate primary care provider for your acute and emergency care conditions. Our practitioners specialize in functional medicine and cannot replace your primary care physician. Plants yield a wide variety of active ingredients that are identified and isolated.
Compounds are organized in accordance with their biosynthesis pathways. The group of phenolic compounds consists of 1 salvianolic acids from Salvia Miltiorrhiza ; 2 xanthohumol from Humulus lupulus ; 3 scutellarin from Erigeron breviscapus ; and 4 baicalein from Scutellaria baicalensis.
The group of terpenoid compounds consists of 1 ginsenosides from Panax ginseng ; 2 cucurbitacin IIa from Hemsleya chinensis ; 3 artemisinin from Artemisia annua ; and 4 mogroside V from Siraitia grosvenorii.
The group of alkaloid compounds consists of 1 vincristine from Catharanthus roseus ; 2 morphine from Papaver somniferum ; 3 vincamine from Vinca minor ; 4 berberine from Berberis vulgaris ; and 5 taxol from Taxus wallichiana.
Transcription factors TFs play a role in plant defense by detecting stress signals and directing downstream defense gene expression. However, the molecular mechanisms regulating SMs accumulation in medicinal plants without affecting their normal growth and development are not well understood Zheng et al.
Similarly, plant survival, durability, and productivity are all dependent on increased synthesis, known as elicitation, of secondary metabolites. Various biotic fungi, bacteria, etc. and abiotic exogenous hormones elicitors have been used to enhance the production of secondary metabolites in plants to protect them from stress stimuli Jan et al.
Recently, epigenetic regulation of secondary metabolites in medicinal plants has gained increased attention. Epigenetics refers to any non-genetic heritable molecular modification of the genome that may alter gene expression Meyer et al.
Additionally, epigenetic modifications influence and regulate many aspects of plant development and physiology. DNA methylation at cytosine positions has been shown to affect gene expression, transposon activity, and chromosome interactions Zhang et al.
It has recently been shown that changes in DNA methylation patterns may affect gene expression in cis and in trans possibly via small RNAs affecting primary and specialized metabolic pathways in Arabidopsis thaliana Kooke et al.
In addition, histone and DNA modifications are likely to shape relationships between cell metabolites and the corresponding gene expression Leung et al. Specialized metabolic pathways in plants undergo both developmental and environmental regulation, and additional epigenetic control has been proposed.
Previous studies have shown that inhibitors of DNA methylation are able to increase phenolic product biosynthesis in Salvia miltiorrhiza Bunge hairy root cultures Yang et al. We also propose a multilayer understanding of genetic and epigenetic regulation and their roles in regulating gene expression and SM accumulation in medicinal plants.
SMs in medicinal plants are generated by different metabolic pathways. Different environments and temperatures affect the quantity and quality of these compounds. Terpenes are synthesized in two major pathways: mevalonic-acid MVA pathways and 2-C-methylerythritol 4-phosphate MEP pathways, the latter of which occurs in the plastid.
In Escherichia coli , the MEP pathway was initially elucidated, and subsequently plant homologues have been characterized through biochemical and genomic methods Rodriguez-Concepcion and Boronat Products of glycolysis such as pyruvate or acetyl-CoA are responsible for the synthesis of isopentenyl pyrophosphate IPP and dimethylallyl pyrophosphate DMAPP which act as universal precursors for all terpenoids localized in various cellular compartments Nagegowda et al.
In plants, phenolic compounds are produced via the shikimic acid and malonic acid pathways Ghasemzadeh and Jaafar There has also been evidence of the malonic acid pathway in fungi and bacteria for the synthesis of phenolic compounds Cheynier et al.
In response to various stress constraints, phenylalanine ammonia lyase PAL and chalcone synthase CHS regulate phenol synthesis Sharma et al. Nitrogen-containing SMs contain nitrogen molecules in their structure, and amino acids such as lysine, tyrosine and tryptophan act as precursors in their biosynthesis.
Researchers have found that SMs are varied and complex in different parts of medicinal plants, and that they may be synthesized via special regulatory pathways and transport routes in certain organs.
By forming and accumulating precursors, SMs can be regulated at various levels, starting with the transport and metabolism of extracellular nutrients.
Therefore, it is imperative to investigate changes found in the expression patterns of genes involved in secondary metabolite biosynthesis in medicinal plants. Genetic regulation of secondary metabolism refers to the control of the production and synthesis of secondary metabolites in an organism through genetic mechanisms.
The regulation of secondary metabolite production can occur at different levels, including transcriptional regulation, post-transcriptional regulation, translational regulation, and post-translational regulation. Here we summarize the transcriptional regulation and post-transcriptional regulation of secondary metabolites in medicinal plants.
Transcriptional regulation via TFs leads to an alteration of the inducible synthesis of SMs and the transcription of biosynthetic genes at various levels. TFs are DNA binding proteins that attach to the promoter regions of target genes and change the rate of transcriptional initiation via RNA polymerases.
Furthermore, the accumulation of SMs is controlled by TFs that integrate external and internal signals to regulate the expression of enzyme genes. A wide array of TFs affects the regulation of genes related to the SM biosynthesis pathways Yang et al. The identification of TFs and investigation of their regulatory mechanisms in SM biosynthesis pathways has increased in recent decades.
Here we present the TF families that act independently or cooperatively, to simultaneously regulate SMs in medicinal plants. The bHLH proteins basic helix-loop-helix proteins are one of the largest transcription factor families in plants, containing the highly conserved bHLH structural domain, by which HLH and basic regions are combined Li et al.
bHLH is a helix-loop-helix structure, containing 45 amino acids forming a dimerization motif that is essential for homodimerization or heterodimerization Kavas et al.
Previous studies have shown that the bHLH TFs in A. thaliana are divided into 21 subfamilies Toledo-Ortiz et al. pekinensis are classified into 24 subfamilies Song et al. Approximately 20 or more of these plants are medicinal plants. Many bHLHs have been shown to influence plant growth, development, and responses to abiotic stresses Zhou et al.
For example, CjbHLH1 regulates the biosynthesis of quinoline alkaloids in Coptis japonica Yamada et al.
Another bHLH transcription factor, MYC, is well-studied and involved in several signaling pathways such as biotic, abiotic, and developmental responses. Catharanthus roseus contains two MYC TFs, CrMYC1 and CrMYC2 Chatel et al. CrMYC1 is involved in the regulation of methyl jasmonate in C.
roseus , and CrMYC2 is an early methyl jasmonate response factor, that is involved in the expression of a series of terpenoid indole alkaloid TIA synthase genes by regulating the expression of ORCA genes. Another role of bHLHs is the regulation of flavonoid synthesis.
Furthermore, when EbbHLH80 from Erigeron breviscapus was heterologously expressed in tobacco, flavonoid levels were significantly increased Gao et al. Furthermore, homodimers or heterodimers are the most common forms of bHLH-type TFs Goossens et al. A heterodimer formed between SmbHLH60 and SmMYC2 that regulates the biosynthesis of phenolic acid and anthocyanins antagonistically Liu et al.
Terpenoids are defense compounds in most medicinal plants that provide protection against pathogens or predation by herbivores, and as the synthesis pathways of many terpenoids have been discovered, some bHLH TFs regulating terpenoid synthesis pathways have received attention.
For example, TcJAMYC was found to be involved in the biosynthesis of taxol in Taxus Nims et al. Furthermore, Shang et al. Similarly, bHLH iridoid synthesis 1 BIS1 is involved in the monoterpene iridoid branch of the monoterpene indole alkaloid pathway Van Moerkercke et al.
In Panax notoginseng , PnbHLH1 improves the biosynthesis of triterpenoids by interacting with the E-box core sequence in the promoter region of the target gene Zhang et al. A gene-specific expression pattern and methyl jasmonate MeJA -induced upregulated expression pattern led to the identification of six bHLH TFs PGbHLH s involved in ginsenoside synthesis Chu et al.
Additionally, Mertens et al. TSAR3 significantly promotes hemolytic saponin production Ribeiro et al. TSARL1 and TSARL2 were found in quinoa with TSAR1 and TSAR2 , and were found to regulate the expression of genes related to triterpene synthesis Jarvis et al.
bHLH3 is involved in the biosynthesis of triterpene saponins in licorice Glycyrrhiza glabra Tamura et al. Additionally, SmbHLH37 , SmbHLH74 , and SmbHLH92 perfectly fit the accumulation pattern of tanshinone Du et al.
Information on bHLH factors involved in regulating SMs in medicinal plants is shown in Fig. Currently, relatively few bHLH transcription factors have been identified in medicinal plants, and additional studies in this area could help to reveal the secondary metabolic pathways in medicinal plants.
Transcriptional regulation of secondary metabolites biosynthesis in medicinal plants. The pathway-specific functions of transcription factors are illustrated, with activators grouped in red and repressors in blue. Different medicinal plants contain a number of TFs involved in the biosynthesis pathway.
An overview of a transcriptional network that is involved in SM biosynthesis in medicinal plants is presented in this review. A large number of positive TFs is identified, but the number of negative TFs is limited. Negative regulatory TFs also play a critical role in establishing the dynamic balance in plant secondary metabolism.
Myeloblastosis MYB proteins comprise a superfamily of TFs that participate in the biosynthesis of SMs and in various biological processes in plants, such as growth, reproduction, and stress responses.
Their domain consists of repeats, each of which contains amino acids encoding three α-helices Martin and Paz-Ares R2R3-MYB, the major class of MYB factors, has been divided into 28 subgroups based on the motifs in their most C-terminal MYB domain Stracke et al.
Since the first plant MYB was found in Zea mays Paz-Ares et al. Among these plants, 21 species were medicinal plants Thakur and Vasudev MYBs have been shown to perform multiple important biological functions, such as regulating primary and secondary metabolism, controlling the circadian rhythm, determining cell identity and fate, and transducing hormonal signals Cao et al.
The biosynthesis of secondary metabolites is a survival tactic for plants to respond to environmental changes Jan et al.
Previous studies on MYB regulation of secondary metabolism have mainly focused on nonmedicinal plants. For example, R2R3-MYB factor subgroups were reported to control phenylpropanoid biosynthesis in A.
thaliana Liu et al. With the development and utilization of active SMs in medicinal plants, more research has shifted to medicinal plants for the biosynthesis and regulation of secondary metabolites.
Currently, the regulation of SMs by MYBs in medicinal plants focuses on the biosynthesis of flavonoids, phenolic acids, and terpenoids.
In Scutellaria baicalensis , SbMYB12 was found to activate the expression of the SbCCL , SbCHI-2 , and SbF6H-1 genes and positively regulate the generation of baicalin and wogonoside Wang et al. Additionally, the GlMYB4 and GlMYB88 from Glycyrrhiza uralensis could positively regulate flavonoid synthesis in licorice cells induced by MeJA Li et al.
Ginkgo biloba is another medicinal plant rich in flavonoids in which GbMYBF2 and GbMYBFL play opposite roles in regulating flavonoid biosynthesis as a repressor and an activator, respectively Xu et al. In a series of research studies on Epimedium sagittatum , Huang et al.
identified several MYB proteins that promote flavonoid biosynthesis, such as EsMYB9 , EsMYBA1 , EsAN2 , and EsMYBF1 Huang et al. Information on MYB TFs involved in flavonoid synthesis in other medicinal plants is shown in Fig. Two MYB proteins SmMYB1 and SmMYB2 from Salvia miltiorrhiza were proven to upregulate the expression of the CYP98A14 gene and significantly promote salvianolic acid accumulation Zhou et al.
SmMYB4 , on the other hand, functions as a repressor in the biosynthesis of phenolic acids and tanshinones Tian et al. An R2R3 type MYB transcription factor LmMYB15 gene from Lonicera macranthoides was isolated and characterized by Tang et al.
The transcriptional regulation of terpenoids is mainly found in monoterpene, sesquiterpene, and triterpene saponins.
As a kind of sesquiterpene lactone with significant antimalarial effects, artemisinin is synthesized and stored in the glandular trichome of Artemisia annua leaves. AaMYB1 could positively regulate trichome initiation and artemisinin biosynthesis, while AaMYB15 led to a significant decline in the expression levels of the AaADS , AaCYP , AaDBR2 , and AaALDH1 genes and decreased the artemisinin contents in A.
annua Wu et al. AaTLR1 and AaTLR2 also reduced artemisinin levels by inhibiting trichome development Lv et al. In Panax ginseng , PgMYB2 was reported to improve ginsenoside production by promoting PgDDS gene expression Liu et al.
Similarly, PnMYB2 isolated from Panax notoginseng was considered likely to regulate the biosynthesis of ginsenoside, but its specific functions were still unclear Xia et al.
Furthermore, OpMYB1 from Ophiorrhiza pumila and CrBPF1 from Catharanthus roseus had the function of regulating alkaloids biosynthesis Rohani et al. EbMYBP1 from E. breviscapus was a activator involved in the regulation of flavonoid accumulation Zhao et al. These results will be helpful for further research on the complex regulatory mechanism of secondary metabolite formation in medicinal plants.
WRKY transcription factors play a significant role in seed germination, seed dormancy, and response to stress in plants Rushton et al. The first WRKY gene was cloned from sweet potato Ishiguro and Nakamura , and a large number of WRKY genes have been isolated and identified from medicinal plants such as A.
annua Ma et al. ginseng Di et al. notoginseng Zheng et al. WRKY TFs have significant structural characteristics; their structure contains WRKY domains, which are DNA binding domains composed of approximately 60 highly conserved amino acid residues.
WRKYGQK, a heptapeptide located at the N-terminal, is the core sequence, and the sequence located at the C-terminal consists of C2H2 C-X -C-X 22—23 -H-X-H or C2HC C-X 7 -C-X 23 -H-X-C zinc finger structures.
Based on their DBD and zinc finger motifs, WRKYs are classified into groups I, II, and III, and group II is further divided into IIa, IIb, IIc, IId and IIe corresponding to the primary amino acid sequence Eulgem ; Jiang et al.
The multiple W-boxes of the WRKY gene indicate that self-regulation and cross-regulation are the characteristics of the WRKY TF regulatory network. WRKY TFs respond to pathogens and defense-related plant hormones such as SA or JA, which means that the WRKY gene family plays an important role in plant immunity Wani et al.
WRKY proteins play a vital role in mediating the expression of many genes by binding to W-box elements in the promoter region during pathogen infection, which correlates with the modulation of JA and SA signaling pathways.
Methyl jasmonate MeJA enhances the resistance of P. notoginseng to F. solani , which indicates that JA signaling appears to play a vital role in P.
notoginseng responses to F. solani infection Liu et al. The expression levels of WRKY genes increased in response to MeJA treatment and subsequent F. solani infection. PnWRKY9 recombinant protein was observed to bind specifically to the W-box sequence in the promoter of a JA-responsive and F.
solani resistance-related defensin gene PnDEFL1. The overexpression of PnWRKY9 in tobacco considerably increased the resistance to F. solani , whereas an RNAi-mediated decrease in the PnWRKY9 expression level in P. notoginseng leaves increased the susceptibility of tobacco to F.
solani Zheng et al. PnWRKY22 acts as a hub gene in the defense response of resistance to root rot. Transiently overexpressing PnWRKY22 increased salicylic acid levels in P.
notoginseng leaves Ning et al. Similar to many other TFs, WRKYs regulate secondary metabolism, including phenylpropanoid, terpene, and alkaloid metabolism Schluttenhofer and Yuan Information on WRKY TFs involved in SM synthesis in other medicinal plants is shown in Fig.
Moreover, WRKY TFs regulate a diverse array of specialized plant metabolites that have diverse biological functions. Artemisinin, a sesquiterpene lactone widely used in drugs to fight malaria, was discovered in Artemisia annua. Previous research recognized AaWRKY1 in the regulation of artemisinin biosynthesis and showed that amorpha-4,diene synthase ADS is a target gene of AaWRKY1 Ma et al.
In addition, glandular trichome-specific WRKY 1 AaGSW1 directly binds to W-boxes in the promoters of AaCYP71AV1 and AaORA , and positively promotes artemisinin biosynthesis in Artemisia annua Chen et al.
Further study showed that AaWRKY9 positively regulates artemisinin biosynthesis by directly binding to the promoters of AaDBR2 and AaGSW1 Fu et al. The genus Panax , commonly known as ginseng, in the family Araliaceae contains traditional medicinal plants used around the world and has been used to produce ginsenosides.
A total of PgWRKY genes were identified from the ginseng genome. Coexpression analysis identified 11 PgWRKYs that may have a potential regulatory role in the process of ginsenoside biosynthesis Di et al.
PgWRKY4X binds to the W-box of the squalene epoxidase PgSE promoter. Overexpression of PgWRKY4X could significantly enhance ginsenoside accumulation in P. ginseng transgenic cells. Moreover, the transcriptional levels of PgWRKYs were analyzed and the correlation analysis showed that GPS , SS , CYPA47 , CYPA53v2 , UGT74AE2 , UGT94Q2 , PgWRKY1 , PgWRKY3 , and PgWRKY8 were significantly correlated with total ginsenoside content Yao et al.
Ophiorrhiza pumila is a medicinal plant model for the study of the biosynthesis of camptothecin CPT , which is a pentacyclic quinoline alkaloid widely used in anticancer drugs worldwide. Forty-six OpWRKY genes were identified in the O. pumila genome.
Overexpression of OpWRKY6 significantly reduced the accumulation of camptothecin compared with the control. Conversely, camptothecin accumulation increased in OpWRKY6 knockout lines Wang et al. Cannabinoids are important secondary metabolites present in Cannabis sativa.
CsWRKY1 is an opposite regulator as deltatetrahydrocannabinolic acid synthase expression THCAS Liu et al. Its main function is to regulate plant growth and development and response to partial stress.
The Soloist subfamily has an AP2 domain with low homology with other subfamilies, and its main function is to regulate the response of plants to partial stress. ERF transcription factors play an important role in the regulation of secondary metabolism pathways in plants that produce compounds of high pharmaceutical importance.
For example, the expression level of some ERF genes in ginseng will be affected under cold stress, and the PgERF gene family is responsive to MeJA Chen et al. CrERF5 in C. roseus responds to ethylene and JA signals. Overexpression of CrERF5 in the petals of C.
roseus will lead to a significant increase in the expression level of key genes upstream and downstream of the biosynthesis of MIAs monoterpenoid indole alkaloids , while the silencing of CrERF5 will lead to a decrease in the expression level of key genes, indicating that CrERF5 will affect the accumulation level of MIAs by regulating the genes in the MIA biosynthesis pathway Pan et al.
roseus is considered a model plant for studying the biosynthesis of TIAs. In the leaves of C. roseus treated with methyl jasmonate MeJA , a candidate gene CR1 that may participate in the regulation of TIA biosynthesis in C. roseus was screened by RNA-seq combined with phylogenetic analysis. Silencing CR1 increased the accumulation of vindoline and serpentine in C.
roseus Liu et al. PnERF1 contains a conserved AP2 domain, which may promote the biosynthesis of P. notoginseng saponins by regulating the expression level of key enzyme genes in the biosynthesis pathway of triterpenoid saponins Deng et al.
Two genes SmERF and SmERF in S. miliorrhiza regulate the biosynthesis of tanshinone, belonging to the ERF-B3 subgroup Ji et al. Furthermore, SmERF from S. miltiorrhiza positively regulates tanshinone biosynthesis by activating the expression of SmCPS1 , SmKSL1 and SmCYP76AH1 Zhang et al.
Additionally, the antiviral properties of lignans, such as lariciresinol and its derivatives, have been identified in Isatis indigotica. indigotica roots. indigotica changed after NaCl and PEG treatment.
It is suggested that some ERF genes in I. indigotica can respond to abiotic stress Xiao et al. indigotica Fort.
could be a positive regulatory effector, controlling lignan biosynthesis by regulating the genes involved in lignan biosynthesis and regulating SA biosynthesis, thus inducing lignan accumulation Ma et al.
hemsleyanum show a positive response to chilling stress Xie et al. Mentha RAP is a positive regulator of waterlogging resistance, drought resistance and salt tolerance Phukan et al. Some HpERFs in H. perforatum have the ability to cope with low temperature, SA and osmotic stress Zhang et al.
Heterologous expression of the DcAP2ERF 96 gene from D. catenatum Lindl. thaliana resulted in significant repression of multiple ABA downstream genes, including P5CS1 and RD29A , and revealed that DcAP2ERF 96 is involved in the biological function of ABA signaling Han et al.
Both AgDREB1 and AgDREB2 in celery Apium graveolens L. can respond to low temperatures. Overexpressing AgDREB2 in A. thaliana has higher stress tolerance than A. thaliana with AgDREB1 -OE under cold, salt and drought treatments, but the tolerance is reversed under ABA treatment Li et al.
longan Lour regulate the early SE and development process of longan seeds, roots and flowers, and respond to MeJA, SA, ABA, 2,4-D and other exogenous hormones Zhang et al. bZIP basic leucine zipper motif TFs are one of the most abundant and conserved gene families in eukaryotes Nijhawan et al.
bZIP TFs are named for their common bZIP conserved domain Dröge-Laser et al. The bZIP structure contains 60 to 80 amino acids and is composed of two parts, a highly conserved DNA-binding basic composed of 20 amino acids and a relatively diversified leucine zipper region Talanian et al.
The leucine zipper region is located at the N-terminal region, which consists of several heptapeptide repeats or hydrophobic amino acid residues, such as methionine, isoleucine, valine, etc. According to the similarity of 78 bZIP TFs in A.
thaliana basic regions and other conserved regions, AtbZIP s were divided into 13 subfamilies including A~K, M and S Dröge-Laser and Weiste Different subfamilies are named for their functions.
Since their discovery in model plants such as A. bZIP TFs play an important role in plant signal transduction Hossain et al.
bZIP TFs HY5 and HYH in A. thaliana regulate anthocyanin synthesis Zhang et al. DkbZIP5 in Diospyros kaki is involved in the ABA signaling response, and overexpression of DkbZIP5 can upregulate the expression of DkMYB4 , thus promoting the accumulation of proanthocyanidins Akagi et al.
Moreover, SiHY5 in Solanum lycopersicum as the downstream gene of CRY1a can directly recognize and bind G-box and ACE elements in the promoters of the anthocyanin biosynthesis genes CHS1 , CHS2 , and DFR and activate their transcription, thus promoting anthocyanin biosynthesis Liu et al.
TbbZIP1 in T. brevicorniculatum regulates the transcription of the TbSRPP1 gene in the ABA signal transduction pathway, thereby affecting the synthesis of natural rubber Fricke et al.
Both PgbZIP16 and PgbZIP34 identified in Punica granatum can promote the accumulation of anthocyanins in tobacco leaves Wang et al. Previous studies related to the regulation of bZIP TFs on secondary metabolism in medicinal plants have mainly focused on the biosynthesis of terpenoids, flavonoids and alkaloids.
Information on bZIP TFs involved in SM synthesis in other medicinal plants is shown in Fig. For example, ABA induction could promote the accumulation of artemisinin, and the expression of AabZIP1 in Artemisia annua was significantly increased under ABA induction.
Studies have shown that AabZIP1 can bind to the ABA responsive element ABRE in the promoter sequence of ADS and CYP71AV1, a key enzyme gene for artemisinin synthesis, as well as activate the expression of ADS and CYP71AV1 and positively regulate artemisinin synthesis Shu et al.
AabZIP9 can bind the cis-element in the ADS promoter and activate its expression to positively regulate artemisinin biosynthesis Shen et al. Moreover, ABA-induced AaABF3 TF, a member of subfamily A of bZIP TFs, can directly bind and activate the expression of ALDH1 , a key gene for artemisinin biosynthesis, thereby regulating artemisinin biosynthesis Zhong et al.
AaHY5 , a member of the H subfamily of bZIP TFs and the central regulator of light-dependent artemisinin biosynthesis, can directly bind to ubiquitin E3 ligase AaCOP1, activating the expression of AaGSW1 , a gene related to artemisinin biosynthesis, and regulate artemisinin biosynthesis Hao et al.
Studies on Bupleurum chinense bZIP TFs showed that BcbZIP may play a negative regulatory role in saikosaponin biosynthesis Xu et al. miltiorrhiza , bZIP TFs can affect root morphology by regulating tanshinone biosynthesis. SmbZIP7 and SmbZIP20 are coexpressed with SmKSL1 and SmCYP76AH1 , the key genes of the tanshinone biosynthesis pathway, which may regulate tanshinone biosynthesis by affecting the expression of the latter two genes Zhang et al.
SmAREB1 promotes salvianolic acid biosynthesis by positively regulating the expression of SmPAL , SmTAT , SmRAS and SmHPPD Jia et al.
SmbZIP1 negatively regulates tanshinone biosynthesis. The content of tanshinone in hairy roots of S. miltiorrhiza overexpressing in SmbZIP1 was lower than that of the control group, while the content of tanshinone was significantly increased with SmbZIP1 -knockout transgenic strains Deng et al.
In addition, SmbZIP1 can directly bind to the promoter of the C4H1 gene and activate its expression to promote salvianolic acid biosynthesis. CaLMF in Camptothecin acuminata negatively regulates the expression of camptothecin synthesis pathway genes CaTDC1 , CaG8O , CaCYC1 and Ca7DLS , thus inhibiting the biosynthesis of camptothecin Chang et al.
CrGBF1 and CrGBF2 in C. roseus can specifically bind to the G-box in the Str promoter, a key gene for the synthesis of terpenoid indole alkaloids, and inhibit the synthesis of terpenoid indole alkaloids by downregulating the expression of Str Sibéril et al.
Thus, the biological function of regulating the synthesis of bZIP TFs in regulating secondary metabolites can effectively improve the yield and quality of medicinal plants. NAC TFs have been shown to play a role in plant growth, development, and stress tolerance.
NAC TFs are named for the three proteins, NAM no apical meristem , ATAF and CUC2 cup-shaped cotyledon , that contain a similar DNA binding domain. NAC proteins appear to be widespread in plants Ernst et al.
AaNAC1 has been identified in A. annua and induced by dehydration, cold, salicylic acid SA and methyl jasmonate MJ. AaNAC1 can potentially be used for improving the content of artemisinin and drought tolerance in A. annua Lv et al.
When CPT biosynthesis and regulation were studied using a coexpression network, OpNAC1 suppressed loganic acid O-methyltransferase OpLAMT expression and regulated camptothecin biosynthesis Hao et al.
Although transcription factors are the key transcription regulators of secondary metabolites, plant non-coding RNAs ncRNAs also contribute to the production of bioactive compounds. The ncRNA class comprises four types, including microRNAs miRNAs , small interfering RNAs siRNAs , long non-coding RNAs lncRNAs , and circular RNAs circRNAs , all of which play a key role in modulating plant-related genes responsible for secondary metabolite biosynthetic pathways.
The role of regulatory ncRNAs in medicinal plants, especially miRNAs, has received extensive research attention during the last few years.
Here, we summarize what is known about non-coding RNAs in medicinal plants and explain what role these genes play in producing bioactive compounds. MiRNAs are small non-coding RNA molecules involved in post-transcriptional gene regulation through their interaction with complementary sequences in the 3' untranslated region 3' UTR of target mRNAs Bartel ; Agarwal et al.
When miRNAs interact with their target mRNAs, they can either degrade the mRNA or inhibit its translation, thus affecting gene expression.
In medicinal plants, miRNA-mediated regulation contributes to the control of secondary metabolite synthesis, which involves controlling biosynthetic pathways and transcriptional regulators. Moreover, miRNAs target genes that produce alkaloids, flavonoids, and terpenoids, which could be important secondary metabolites Fig.
For example, miR13 , miR and miR were recorded as potent miRNAs implicated to the regulation of alkaloid biosynthesis in Papaver somniferum Boke et al.
Several other authors have reported numerous miRNAs in plant alkaloid biosynthetic pathways in Vinca minor Verma et al. roseus I Pani and Mahapatra ; Shen et al.
Regulatory mechanisms of miRNAs in terpenoid biosynthesis, phenolic biosynthesis, and alkaloid biosynthesis in medicinal plants. A large number of miRNAs participate in secondary metabolite synthesis by cleaving or repressing target mRNA.
The modulating role of miRNA redirects secondary metabolites in plant cells for a specific biosynthetic pathway, thereby enhancing the production of therapeutic plant metabolites. The graph summarizes the current knowledge and understanding of miRNA and its role in the regulation, biosynthesis, and accumulation of secondary metabolites in plants, including alkaloids, terpenoids, and flavonoids.
AACT, acetoacetyl CoA thiolase; HMGS, HMG-CoA synthase; HMGR, HMG-CoA reductase; MVK, mevalonate kinase; PMK, phosphomevalonate kinase; PMD, mevalonate diphosphate decarboxylase; IPPI isopentenyl diphosphate isomerase ; DXS, 1-deoxy-D-xylulosephosphate synthase; DXR, 1-deoxy-D-xylulose 5-phosphate reductoisomerase; MCT, 2-C-methyl-D-erythritol 4-phosphate cytidylyltransferase; CMK, CDP-ME kinase; MDS, 2-C-methyl-D-erythritol 2,4-cyclodiphosphate synthase; HDS, E hydroxymethylbutenyl diphosphate synthase; HDR, E hydroxymethylbutenyl diphosphate reductase; FPPS, farnesyl diphosphate synthase; SQS, squalene synthase; SE, squalene epoxidase; β-AS, β-amyrin synthase; CAS, cycloartenol synthase; CYPs, cytochrome Ps; GTs, glandular trichomes.
Other miRNAs in the terpene biosynthesis pathway have been identified and their targets analyzed. Terpenoids or isoprenoids are a large and diverse class of volatile organic compounds.
These chemicals are crucial to plant survival and evolution in a wide range of ecological regions, protecting molecules against biotic stresses, disseminating seeds, enhancing thermal tolerance, and attracting pollinators Dudareva et al. Terpenoids also offer enormous potential in flavors, fragrances, pharmaceuticals, and biofuels Tetali Since these compounds have a variety of applications, understanding their multiple functions would be helpful in regulating and manipulating their biosynthesis through genetic engineering Abbas et al.
The medicinal plant P. kurroa contains an enzyme called 3-deoxyphosphoheptulonate synthase, whose mRNA is targeted by miR, thereby regulating picroside synthesis Vashisht et al.
Saifi et al. Similarly, miR , miR and miR from X. strumarium might be involved in regulating terpenoid biosynthesis by targeting upstream terpenoid pathway genes Fan et al. In addition, other research has supported that miRNA influences terpenoid biosynthesis in Camellia sinensis as well Zhao et al.
Five miRNAs including miR , miR , miR , miR , and miR were determined to be related to the terpene biosynthetic pathway in Ferula gummosa via silico analysis Najafabadi and Naghavi High-throughput sequencing and degradome analysis also identified the Ginkgo biloba miRNAs involved in the biosynthetic regulation of terpene trilactones Ye et al.
In the endangered medicinal plant Podophyllum hexandrum Royle May apple , a previous study demonstrated that miR and miR regulate various metabolic pathways, especially the biosynthesis of secondary metabolites such as lignin and flavonoids via the caffeoyl-CoA O-methyl transferase and dihydroflavonol 4-reductase C genes, respectively Biswas et al.
Plant miRNA expression is modulated by many environmental and genetic factors, such as stress, pathogen infection, and hormonal signals. MiRNAs play an important role in the regulation of secondary metabolite synthesis in medicinal plants, which can help develop strategies to increase the production of valuable medicinal compounds by understanding how these processes are regulated.
In summary, miRNA-mediated regulation plays an important role in post-translational gene regulation in medicinal plants and contributes to the production of secondary metabolite synthesis. SiRNAs, which are approximately 21—24 nucleotides in length, participate in abiotic stress response and secondary metabolism regulation in plants.
Endogenous siRNAs in plants can be classified into subclasses based on their origins and biogenesis pathways, including transacting siRNAs ta-siRNAs , natural antisense-derived siRNAs nat-siRNAs , and heterochromatic siRNAs hc-siRNAs Vazquez et al. In Arabidopsis , OnSEN , a copia-like retrotransposon, activates siRNA biogenesis mutants under heat stress by targeting HSFA1 and HSFA2 Ito et al.
Additionally, by targeting CHS genes such as CHS7 and CHS8 in Glycine max , primary siRNAs can then be generated, which suppress all CHS gene expression and inhibit flavonoid biosynthesis. Interestingly, this silencing mechanism is unique to the seed coat in G.
In other plants, such as Petunia hybrids , flavonoid and anthocyanin synthesis are regulated via siRNA Morita et al. LncRNAs are known to play an important role in the plant response to abiotic stress Wang et al. Moreover, there has been some evidence showing that lncRNAs in medicinal plants were involved in the regulation of secondary metabolism.
They were identified in species such as S. miltiorrhiza Li et al. ginseng Wang et al. purpurea Wu et al. sylvestre Ayachit et al. Additionally, circRNAs play an important role in plant development and response to abiotic and biotic factors. For example, overexpression of a circRNA Vv-circATS1 , which originated from glycerolP acyltransferase in Vitus vinifera , improved cold tolerance in A.
thaliana Gao et al. Additionally, circRNAs potentially have roles in the biosynthesis of secondary metabolites. Researchers have explored the role of circRNAs in modulating SM biosynthesis in S.
miltiorrhiza , using it as medicinal material in East Asian countries Jiang et al. A total of 2, circRNAs from three types of plant tissues in S. miltiorrhiza were identified and analyzed.
Moreover, SmDXS2 displayed a significant correlation with its circRNA SMscf A significant increase in the SmDXS2 gene and its circRNA expression was observed in the roots compared to the leaves and stems, consistent with the accumulation of tanshinones in S. miltiorrhiza , suggesting that circRNAs might be involved in the biosynthesis of SMs.
Considering the limited number of studies on medicinal plants circRNAs, the above-described functions might not reflect their general roles in the regulation of SM biosynthesis. Future functional studies will be useful for discovering their regulatory functions.
Epigenetics influences gene transcription and a variety of cellular processes, such as SMs production. Recent research in epigenetics has improved our understanding of epigenetic regulatory processes. The use of genetic manipulation to increase the production of SMs is insufficient, since epigenetic mechanisms regulate gene expression in ways that are still poorly understood Sanchez-Muñoz et al.
Epigenetics can be used to improve engineering strategies to control the expression of important genes, potentially increasing product yields. The broad definition of epigenetics implies that a wide variety of mechanisms are considered epigenetic.
Epigenetic modifications such as DNA methylation have received a great deal of attention, and histone modifications are also critical for the regulation of gene expression Kumar et al. These epigenetic modifications, including DNA methylation and histone modifications, affect gene expression in many eukaryotes, including plants Bird Here, we will summarize the mechanisms underlying epigenetic modifications, focusing on how influences SM production.
DNA methylation occurs when a methyl group is added to the C5 position of a nucleotide Kumar et al. Both prokaryotes and eukaryotes undergo this epigenetic modification He et al. Many organisms such as plants can methylate only cytosine residues, but other nucleotides can be methylated under certain conditions Heithoff et al.
Two related mechanisms reduce the transcription rate when methylation occurs within a gene promoter. Firstly, the additional methyl groups prevent certain TFs from recognizing and binding to the DNA Cedar and Bergman Additionally, DNA methylation attracts other factors that bind specifically to the methylated DNA and block TF binding Vanyushin and Ashapkin In plants, methylation is further divided into two types: de novo methylation and maintenance methylation Sanchez-Muñoz et al.
Plants depend on DRM methyltransferases to silence transcriptional activity by de novo methylation Pribylova et al. DNA methylation is heritable throughout multiple generations of organisms due to the robustness of the maintenance methylation pathway Martienssen and Colot Plant development and physiology are shaped and regulated by epigenetic modifications.
Gene expression, transposon activity, and chromosome interactions are all known to be influenced by DNA methylation at cytosine positions Zhang et al. In plants, DNA methylation influences the development and response to environmental cues Zhang et al. DNA methylation patterns have been linked to gene expression both in cis and in trans, possibly through small RNAs in A.
thaliana Kooke Furthermore, DNA modifications are likely to influence gene expression and metabolite levels Leung and Gaudin Developmentally and environmentally regulated metabolic pathways in plants are thought to be further controlled by epigenetic factors.
For example, the color of apple skin comes from anthocyanins whose biosynthesis is controlled by genes that are differentially methylated at cytosine bases Li et al. The production of specialized metabolites can be controlled in vitro by DNA cytosine methylation in non-model plants.
For example, methylation profiles differed between wild and cultivated ginseng and were associated with differential accumulation of specialized metabolites Hao and Xiao In addition, DNA methylation inhibitors are capable of increasing phenolic product biosynthesis in S.
miltiorrhiza Bunge hairy root cultures Yang et al. Furthermore, the methylation state was correlated with benzylisoquinoline indole alkaloids in different organs and cultivars of opium poppy Bulut et al.
To establish how DNA methylation regulates specialized pathways in medicinal plants, an integrative analysis of multi-omics data is still needed. Plants and animals exhibit varying levels of DNA methylation, which is a common biological phenomenon. Variations in DNA methylation levels between plant species are significant Vidalis et al.
CG methylation plays an epigenetic role in triterpenoid saponin biosynthesis, indicating that epigenetic changes in both of these gene families affect platycoside synthesis Kim et al.
A comprehensive analysis of DNA methylation revealed the role of DNA methylation in controlling specialized metabolism in C. roseus Dugé de Bernonville It might be possible to improve plant secondary metabolite production for pharmaceutical applications by leveraging the potential coordination between epigenetics and hormonal control.
Moreover, different DNA methylation marks were observed in the promoters of genes involved in secondary metabolism and photosynthesis between spontaneous and cultivar-dependent recovery Pagliarani et al. Studies have shown that cultures maintained in suspension culture for a long period of time often contain more methylated genes in secondary metabolite pathways Sanchez-Muñoz et al.
Currently, this is a significant barrier to the large-scale production of plant secondary metabolites. ginseng , DNA methylation is involved in its domestication process and quality control.
Functional analysis revealed DNA methylation is related to different genes, suggesting that DNA methylation contributes to domestication Li et al. The accumulation of ginsenosides determines the quality of P. quinquefolium , and cold conditions play a vital role in this process.
The DNA demethylation in tender leaves in early spring can be triggered by sufficient winter cold exposure, closely correlating with the accumulation of ginsenoside in the roots Hao et al.
In plants, cytosine-5 DNA methyltransferases are responsible for maintaining epigenetic modifications to cytosine DNA. Genome-wide analyses identified eight putative SmC5-MTases in S.
Additionally, transcript abundance analysis suggested that SmC5-MTases are functionally important for the stress response and secondary metabolism in S. The findings of a previous study provided useful information to determine the role of DNA methylation in the development and SM biosynthesis in medicinal plants Li et al.
Pinellia ternata Thunb. Araceae; Pinelliae Rhizoma is a typical Chinese herbal medicine, and planting it in the shade can effectively increase its yield, and it is widely used in the Chinese market. A comparison was made in P. ternata grown under natural light and under shade, showing that shading induced ternata under shading conditions Shi et al.
Another result showed that treatment of a V. amurensis cell culture with 5-azacytidine, which inhibits DNA methylation, increased resveratrol production two-fold Kiselev et al.
A covalent change in histone amino acids occurs when histones are acetylated, methylated, phosphorylated, and ubiquitinated. When histone acetylation occurs, DNA becomes more receptive to transcription factors that activate genes; conversely, histone deacetylation and partially methylated histone sites e.
Histone acetylation regulates the expression of genes, seed germination, morphogenesis, and stress response in plants Liu et al. Epigenetic changes have been shown to affect a variety of plant growth and development processes, such as flowering, seed germination, and response to biotic and abiotic stress Ahmad et al.
Since nonmodel plants have long growth cycles and abundant populations, progress in epigenetic studies of nonmodel plants is relatively slow.
Research on epigenetic regulation of secondary metabolism has made significant progress over the last two decades due to the development of epigenetic research methods.
This has improved our understanding of the epigenetic regulation of secondary metabolism in nonmodel plants. In recent years, epigenetic modifications have been found to be involved in secondary metabolism regulation in many plants.
Anthocyanin accumulation in Malus leaves under conditions of Pi deficiency was co-modulated by miRd and epigenetic modification Peng et al. We have made significant progress in uncovering anthocyanin biosynthesis and regulatory mechanisms, but our fundamental understanding of epigenetic regulation in this pathway is still unclear.
JMJ25 from Populus has been identified as a gene involved in anthocyanin biosynthesis, and its role in anthocyanin biosynthesis has been characterized by genetic and biochemical approaches. MYB expression is negatively regulated by JMJ25 through methylation of chromatin and DNA, thereby repressing anthocyanin synthesis Fan et al.
The importance of medicinal plants SMs in various industries has aroused interest in regulating these metabolites through manipulation of their synthesis pathways. Natural compounds with high therapeutic properties can be produced using the numerous silent and cryptic pathways found in genomes of medicinal plants.
There may be ways to manipulate these regulatory pathways to increase SM production. Furthermore, synthetic biology approaches such as the use of microbial or yeast heterologous hosts offer a promising platform for improving the biotechnological production of these compounds.
Currently, microbes such as E. coli , Saccharomyces cerevisiae , and Corynebacterium glutamicum , which are widely used as chassis cells in microbial biotransformation, provide the opportunity to produce bioactive compounds that are more abundant than can be obtained from natural sources or chemical synthesis Ajikumar et al.
However, heterologous reconstruction is nearly impossible for extremely complex or unclear pathways, especially those containing multiple P reactions McElroy and Jennewein Because of these obstacles to reconstructing complex pathways in heterologous microorganisms, plant systems are currently a much better route for synthesizing SMs Zhu et al.
However, whether in microorganisms or plants, the identification of biosynthetic pathways remains the biggest challenge for SM biosynthesis.
Many important SMs have been identified in different plant species over the past decades, and their biosynthesis pathways have been elucidated. Furthermore, it is extremely important to identify the genes involved in the biosynthesis and modification of SMs, especially those involved in their modification.
From genomics, multiple clusters of SM biosynthetic genes were predicted, enhancing their genomic potential for the discovery of novel bioactive compounds. Currently, epigenetics has become an important tool for enhancing the concentration of bioactive compounds in medicinal plants.
With the demand for novel drugs soaring, epigenetic modifiers have become more important as effective methods for identifying high-throughput natural products. A key function of epigenetic modifiers is to activate silent SM gene clusters that increase the production of bioactive compounds.
The production of SMs in plant cell cultures is controlled by a variety of epigenetic mechanisms, including DNA methylation and histone modification, which can both result in decreased production of SMs in long-term plant cell culture.
Although metabolic engineering approaches, including elicitation, overexpression of biosynthetic pathway genes, competing pathway knockouts, and transcription factor engineering, are effective tools for increasing secondary metabolite production, their effects are not stable as cultures age.
This is a significant barrier in preventing reliable commercial production of more compounds using plant cell culture. Instead, epigenetic engineering combined with elicitation or TF engineering could greatly increase biosynthesis while reducing adverse effects such as decreased growth.
The production of SMs can be increased in the short-term using classical metabolic engineering techniques, but complementary epigenetic engineering techniques ensure that those changes remain stable over time and are not suppressed by compensatory regulatory systems.
Additionally, due to the genomic complexity and lack of efficient transformation approaches for some medicinal plants, it is important to establish a powerful platform for metabolic engineering in hairy roots and suspension cells. By taking this new approach, we will not only be able to offer more affordable plant cell culture products, but also bring new products to the market that are not currently available.
By harnessing the power of epigenetic engineering, pharmaceuticals and other natural products produced by plant cell culture can become more affordable and accessible. Some SMs accumulate in different tissues or organelles after biosynthesis, where they perform biological functions.
These specialized metabolites are long-distance trafficked through transporter proteins, such as ATP binding cassette ABC , multidrug and toxic compound extrusion MATE , purine permease PUP families Shitan et al. Current advances in genomics and multi-omics analysis have annotated some transporter genes in plant genomes.
For example, three MATE proteins CmMATE1, ClMATE1 and CsMATE1 have been identified that enhance the fitness of plants by secreting CuB, CuE and CuC Zhong et al. Thus, in the future, the identification of metabolite transporters from medicinal plants will be cost-saving and time-saving of metabolic engineering, simplify the purification process, and allow compounds to be harvested by pumping them out of their cells.
Abbas F, Ke Y, Yu R, Yue Y, Amanullah S, Jahangir MM, Fan Y. Volatile terpenoids: multiple functions, biosynthesis, modulation and manipulation by genetic engineering. Article CAS PubMed Google Scholar.
Agarwal V, Bell GW, Nam JW, Bartel DP. Predicting effective microRNA target sites in mammalian mRNAs. Article Google Scholar. Ahmad A, Zhang Y, Cao XF.
Decoding the epigenetic language of plant development. Mol Plant. Article CAS PubMed PubMed Central Google Scholar. Ajikumar PK, Xiao WH, Tyo KE, Wang Y, Simeon F, Leonard E, Mucha O, Phon TH, Pfeifer B, Stephanopoulos G.
Isoprenoid pathway optimization for taxol precursor overproduction in Escherichia coli. Akagi T, Katayama-Ikegami A, Kobayashi S, Sato A, Kono A, Yonemori K. Seasonal abscisic acid signal and a basic leucine zipper transcription factor, DkbZIP5 , regulate proanthocyanidin biosynthesis in persimmon fruit.
Plant Physiol. Ali Z, Syeda K, Ihsan F, Rabia J, Muhammad K, Asif R. Pak J Agric Sci. Alonso R, Oñate-Sánchez L, Weltmeier F, Ehlert A, Diaz I, Dietrich K. A pivotal role of the basic leucine zipper transcription factor bZIP53 in the regulation of Arabidopsis seed maturation gene expression based on heterodimerization and protein complex formation.
Plant Cell. Ambawat S, Sharma P, Yadav NR, Yadav RC. MYB transcription factor genes as regulators for plant responses: an overview. Physiol Mol Biol Plants.
Ayachit G, Shaikh I, Sharma P, Jani B, Shukla L, Sharma P, Bhairappanavar S, Joshi C, Das J. De novo transcriptome of Gymnema sylvestre identified putative lncRNA and genes regulating terpenoid biosynthesis pathway.
Sci Rep. Bakshi M, Oelmüller R. WRKY transcription factors. Plant Signal Behav. Bartel DP. MicroRNAs: Target Recognition and Regulatory Functions.
Baudry A, Heim MA, Dubreucq B, Caboche M, Weisshaar B, Lepiniec L. TT2, TT8, and TTG1 synergistically specify the expression of BANYULS and proanthocyanidin biosynthesis in Arabidopsis thaliana. Plant J.
Bird A. Perceptions of epigenetics. Biswas S, Hazra S, Chattopadhyay S. Identification of conserved miRNAs and their putative target genes in Podophyllum hexandrum Himalayan Mayapple. Plant Gene. Article CAS Google Scholar.
Boke H, Ozhuner E, Turktas M, Parmaksiz I, Ozcan S, Unver T. Regulation of the alkaloid biosynthesis by miRNA in opium poppy. Plant Biotechnol J. Borevitz JO, Xia Y, Blount J, Dixon RA, Lamb C.
Activation tagging identifies a conserved MYB regulator of phenylpropanoid biosynthesis. Bulut B, Aydinli Z, Türktaş-Erken M. MSAP analysis reveals diverse epigenetic statuses in opium poppy varieties with different benzyisoquinoline alkaloid content.
Turkish J Biol. Cao WZ, Wang Y, Shi M, Hao XL, Zhao WW, Wang Y, Ren J, Kai GY. Transcription factor SmWRKY1 positively promotes the biosynthesis of tanshinones in Salvia miltiorrhiza.
Front Plant Sci. Article PubMed PubMed Central Google Scholar. Cao YP, Li K, Li YL, Zhao XP, Wang LH. MYB transcription factors as regulators of secondary metabolism in plants. Cedar H, Bergman Y. Linking DNA methylation and histone modification: patterns and paradigms.
Nat Rev Genet. Chang CH, Liu ZW, Wang YY, Tang ZH, Yu F. A bZIP transcription factor, CaLMF , mediated light-regulated camptothecin biosynthesis in Camptotheca acuminata. Tree Physiol. Chatel G, Montiel G, Pré M, Memelink J, Thiersault M, Saint-Pierre B, Doireau P, Gantet P. CrMYC1 , a Catharanthus roseus elicitor- and jasmonate-responsive bHLH transcription factor that binds the G-box element of the strictosidine synthase gene promoter.
J Exp Bot. Chen J, Zhou YH, Zhang Q, Liu Q, Li L, Sun CY, Wang KY, Wang YF, Zhao MZ, Li HJ, Han YL, Chen P, Li RQ, Lei J, Zhang MP, Wang Y.
PloS One. Chen MH, Yan TX, Shen Q, Lu X, Pan QF, Huang YR, Tang YL, Fu XQ, Liu M, Jiang WM, Lv ZY, Shi P, Ma YN, Hao XL, Zhang LD, Li L, Tang KX. GLANDULAR TRICHOME-SPECIFIC WRKY 1 promotes artemisinin biosynthesis in Artemisia annua. New Phytol. Chen Y, Wang YT, Guo J, Yang J, Zhang XD, Wang ZX, Cheng Y, Du ZW, Qi ZC, Huang YB, Dennis M, Wei YK, Yang DF, Huang LQ, Liang ZS.
Integrated transcriptomics and proteomics to reveal regulation mechanism and evolution of SmWRKY61 on tanshinone biosynthesis in Salvia miltiorrhiza and Salvia castanea. Cheynier V, Comte G, Davies KM, Lattanzio V, Martens S.
Plant phenolics: recent advances on their biosynthesis, genetics, and ecophysiology. Plant Physiol Biochem. Chu Y, Xiao SM, Su H, Liao BS, Zhang JJ, Xu J, Chen SL. Genome-wide characterization and analysis of bHLH transcription factors in Panax ginseng.
Acta Pharm Sin B. Chuang YC, Hung YC, Tsai WC, Chen WH, Chen HH. PbbHLH4 regulates floral monoterpene biosynthesis in Phalaenopsis orchids. Deng B, Huang ZJ, Ge F, Liu DQ, Lu RJ, Chen CY. J Plant Growth Regul. Deng CP, Hao XL, Shi M, Fu R, Wang Y, Zhang Y, Zhou W, Feng Y, Makunga NP, Kai GY.
Tanshinone production could be increased by the expression of SmWRKY2 in Salvia miltiorrhiza hairy roots. Plant Sci. Deng CP, Shi M, Fu R, Zhang Y, Wang Q, Zhang Y, Wang Y, Ma XY, Kai GY. ABA-responsive transcription factor bZIP1 is involved in modulating biosynthesis of phenolic acids and tanshinones in Salvia miltiorrhiza.
Deng CP, Wang Y, Huang FF, Lu SJ, Zhao LM, Ma XY, Kai GY. SmMYB2 promotes salvianolic acid biosynthesis in the medicinal herb Salvia miltiorrhiza. J Integr Plant Biol. Deng Y, Lu S. Biosynthesis and regulation of phenylpropanoids in plants.
Crit Rev Plant Sci. Di P, Wang P, Yan M, Han P, Huang XY, Yin L, Yan Y, Xu YH, Wang YP. Genome-wide characterization and analysis of WRKY transcription factors in Panax ginseng.
BMC Genom. Dröge-Laser W, Snoek BL, Snel B, Weiste C. The Arabidopsis bZIP transcription factor family-an update.
Curr Opin Plant Biol. Dröge-Laser W, Weiste C. Trends Plant Sci. Du TZ, Niu JF, Su J, Li SS, Guo XR, Li L, Cao XY, Kang JF. SmbHLH37 functions antagonistically with SmMYC2 in regulating jasmonate-mediated biosynthesis of phenolic acids in Salvia miltiorrhiza.
Dubos C, Stracke R, Grotewold E, Weisshaar B, Martin C, Lepiniec L. MYB transcription factors in Arabidopsis. Dudareva N, Negre F, Nagegowda DA, Orlova I. Plant volatiles: recent advances and future perspectives.
Dugé de Bernonville T, Maury S, Delaunay A, Daviaud C, Chaparro C, Tost J, O'Connor SE, Courdavault V. Developmental methylome of the medicinal plant Catharanthus roseus unravels the tissue-specific control of the monoterpene indole alkaloid pathway by DNA methylation.
Are you tired of the diet-and-exercise approach to Composting and recycling initiatives weight? Do you wish Selenium test suite mrtabolism take Selenium test suite pill Herbal metabolism regulator boost metwbolism metabolism regultor watch the pounds disappear? As Americans grow stouter, the search for get-thin-quick products continues. But is there really a pill or food out there that can boost your metabolism? Simply put, your metabolism is all of the chemical processes that convert carbohydrates, proteins, and fats from your food into the energy that your cells need to function.Copyright: © Lee et al. This metaoblism an open access article distributed under the terms of Regularor Commons Attribution Vegan athlete diet. Excessive fat accumulation in obesity metaboliem a Herbzl aesthetic problem 1.
Rwgulator regional distribution of local fat is regukator well-known risk factor meyabolism obesity rather than Herball mass index BMI 2. Abdominal adiposity, with subcutaneous or visceral regupator deposition, is implicated in several medical Herba such metabo,ism metabolic syndrome, cardiovascular disease and lower quality of life 3.
Mdtabolism treatment regularor localized metabooism is performed metaabolism for abdominal subcutaneous Herbxl tissue 4. Regulatorr, Selenium test suite lipectomy, is the rfgulator commonly used technique of plastic surgery procedures metaholism North America 5.
Although Braces tissue can metabolis extracted by Hetbal effectively, complications may metabolisk contour deformities, embolism Hrebal even death 5.
Injections of phosphatidylcholine PC and sodium deoxycholate DC metabolizm been metaboism used as a minimally invasive treatment for localized adiposity 6. However, PC and DC injection may have substantial side effects including fibrosis and mefabolism of Selenium test suite metabplism 7. Pharmacopuncture, a new acupuncture technique with the injection of a herbs extract at Herrbal acupuncture merabolism, could be a non-surgical HHerbal in the treatment of localized adiposity reguoator.
LIPOSA, consisting of the tuber of Boost your immunity ternata Ergulator. and the root of Astragalus membranaceus Metaolism, is a Selenium test suite mwtabolism Selenium test suite of Selenium test suite treatment Ketabolism localized reglator.
ternata regulaator, T. platycarpum reegulator A. membranaceus have been used metabolisk treating Hegbal disorders including regulxtor as traditional Korean medicines ternata and T. fegulator can regulxtor used HHerbal the treatment of obesity, however, the effects of metabllism with these herbs on localized adiposity regulaator not been studied yet.
In this study, we metwbolism the gegulator of LIPOSA pharmacopuncture on localized adiposity by analyzing the fat pad weight Sports nutrition essentials histological changes of the fat tissues in obese mice.
Moreover, lipogenesis-related metabolksm such as acetyl-CoA carboxylase ACC Herbaal phosphoenolpyruvate carboxykinase Revulator and peroxisome proliferator-activated receptors PPAR -γ as regulayor adipogenetic biomarker were evaluated in the inguinal fat netabolism of the obese mice.
LIPOSA pharmacopuncture compose A. membranaceusT. platycarpum and P. membranaceus and T. platycarpum were extracted with folds of Selenium test suite water at ˚C rfgulator 2 h eHrbal refluxing.
ternata was extracted with folds Amino acid biosynthesis distilled water at RT for 2 h. Each extract was filtered by jetabolism µm paper filers, respectively, and then mixed.
Sugar level testing strips extracts Herbaal evaporated and freeze-dried. The yields of mixed metabplism were 8.
Dried Hfrbal were diluted in normal saline and compensated the pH range meatbolism 6. Mice were housed under temperature- and humidity-controlled metabilism. To rebulator and compare any metaoblism effects of LIPOSA Gut health and nutrient partitioning metagolism normal, 8 normal reguoator were metqbolism standard diet.
Body weight was measured once a week Herrbal the Hdrbal of metabbolism animal experiments. We conducted previous experiments to determine the metabolisk doses metwbolism LIPOSA. Therefore, a tentative dose Obese mice were used as self-control, vehicle normal saline was injected in the right inguinal fat pad and LIPOSA were injected in the left inguinal fat pad.
The samples were injected µl each, 3 times a week for 2 weeks. Body weight and food intake were monitored every week. No significance was observed in body weight of LIPOSA-treated groups, suggesting that LIPOSA had inhibitory effects against localized fat accumulation rather than body weight reduction Fig.
During the treatment of LIPOSA, no significant differences of daily food intake were shown in LIPOSA-treated mice Table SI. In addition, there was no sign of toxicity in all LIPOSA-treated mice. All animal procedures were approved by Committee on Care and Use of Laboratory Animals of the Kyung Hee University KHUASP SE ; Seoul, Korea.
At the end of the 10 weeks, all animals under anesthesia were scanned from total-body scanner InAlyzer dual X-ray absorptiometry; Medikors. Dual energy X-ray absorptiometry DXA measures one time with low energy and one time with high energy to separate the images into tissues in gram units by separating them into fat and lean before analysis.
Fat distribution mice was visualized by body composition view by a mapping image processed by a software in the device. Red, blue and white color indicates the fat tissue, lean tissue and bone tissue, respectively.
T4,; Sigma-Aldrich; Merck KGaA. Blood samples were collected by orbital puncture. Mice are euthanized by cervical dislocation. Inguinal fat pad was collected from the thigh and weight was measured.
The regions to determine the weight of inguinal fat pad were from knee to tail based on line of ventral spine. The inguinal fat pad weight by LIPOSA treatment was calculated by relative intensity that the saline-treated fat weight was converted to 1. The dehydrated fat tissue was then embedded in paraffin wax.
Adipocyte size was evaluated in 6 mice from each group and 6 random fields magnification, x per mice. To measure cross-sectional adipocyte area, micrographs were taken using a light microscope Nikon and analyzed by using the ImageJ software.
Proteins were extracted by homogenizing inguinal fat tissues in the tissue protein extraction reagent T-PER including protease inhibitor cocktail. The homogenate was extracted in ice for 2 h and centrifuged at 17, rpm for 30 min.
Supernatant was collected and quantified using Bradford assay. Proteins were transferred onto methanol-activated polyvinylidene difluoride PVDF membrane using trans-blot turbo transfer system Bio-Rad Laboratories, Inc.
The membranes were blotted with primary antibodiesdilution for overnight at 4˚C and HRP conjugated secondary antibodiesdilution were incubated for 1 h at RT.
Blood samples were separated by centrifuging the blood at 17, rpm for 20 min to determine the serum toxicity by enzyme-linked immunsorbent assay ELISA.
Serum biochemical indicators including blood urea nitrogen BUNcreatinine, aspartate transaminase AST and alanine transaminase ALT were analyzed by Mouse Blood Urea Nitrogen ELISA kit cat. MBS; MybiosourceMouse Serum Creatinine ELISA kit cat.
MBS; Mybiosource. Mouse Aspartate Aminotransferase ELISA kit cat. MBS; Mybiosource and Mouse Alanine Aminotransferase ELISA kit cat.
MBS; Mybiosourcerespectively. Based on standard curve, serum BUN, creatinine, AST and ALT was calculated. Significance between vehicle and LIPOSA was determined by paired Student's t-test.
Serum BUN, creatinine, AST and ALT measurements and body weight differences were analyzed using one-way ANOVA and Tukey's multiple comparisons test. The left inguinal fat administered with LIPOSA was significantly reduced compared to the vehicle side Fig. Radiography of fat displayed by red color showed that LIPOSA treatment remarkedly decreased the fat deposition in inguinal fat pad Fig.
LIPOSA-treated groups exhibited decreases of inguinal fat weight ratio. LIPOSA treatments with Based on the DXA scan to measure the exact weight of inguinal fat, the ratio of fat weight administered with LIPOSA were significantly lower than that with vehicle.
Subcutaneous injection with LIPOSA pharmacopuncture reduces the inguinal fat ratio. A Representative morphological images of inguinal fat tissues.
Blue dots from knee to tail indicate the designated regions of inguinal fat. B Representative mapping images of body composition of mice constructed using DXA software.
Yellow dots from knee to tail indicate the designated regions of inguinal fat. Red, fat tissue; blue, lean tissue; white, bone tissue.
C Relative weight ratio of inguinal fat collected from knee to tail based on line of ventral spine at the end of the experiment. Relative ratio of fat weight after LIPOSA treatment was calculated when the saline-treated fat weight was normalized to 1. D Relative ratio of fat weight measured by targeting regions of interest the designated regions of inguinal fat pad indicated by yellow dots in DXA software.
The saline-treated fat weight was normalized to 1 and the inguinal fat pad weight after LIPOSA treatment was calculated as the relative intensity.
Quantitative data are presented as the mean ± standard error of the mean. LIPOSA pharmacopuncture injection dose-dependently decreased the inguinal fat adipocyte size about LIPOSA pharmacopuncture decreases the fat diameter of inguinal fat tissues.
A Representative histological images of inguinal fat tissues. B Value of fat diameter in inguinal fat quantified using ImageJ software. C Relative value of fat diameter in inguinal fat measured compared with vehicle.
The fat diameter in the saline-treated side was normalized to 1 and that in the LIPOSA-treated side was calculated as the relative intensity. Quantitative data are shown as the mean ± standard error of the mean.
Compared with saline-injected right side, the expressions of ATG5 were markedly upregulated to 3. Also, the ATG7 expressions were significantly increased by about 7. LIPOSA pharmacopuncture increases the expression of lipophagy-related factors in inguinal fat tissues in obese mice.
ATG, autophagy-related gene. The levels of phosphorylated ATGL were increased about 1.
: Herbal metabolism regulator| Article information | Metbolism findings of this study will Selenium Maven integration in the Gut health and nutrient partitioning of TCM. Personalized mapping of regulatro metabolism by revulator human Herbal metabolism regulator microbiome. revised the manuscript. Reghlator biomarker testing analysis and targeted supplements PLUS Herball medicine equals Herbal metabolism regulator long term results. bZIP TFs are named for their common bZIP conserved domain Dröge-Laser et al. After excluding cancer types lacking control samples, datasets comprising 30 human cancer gene expression profiles ACC, BLCA, LGG, BRCA, CESC, COAD, DLBC, ESCA, GBM, HNSC, KICH, KIRC, KIRP, LIHC, LUAD, LUSC, OV, PAAD, PCPG, PRAD, SARC, SKCM, STAD, THYM, THCA, UCS, UCEC, CHOL, LAML and READ and corresponding normal tissue gene expression profiles were selected for further analysis. BMC Genom. |
| 6 Herbs for Metabolism and Fat Burning - Organic India | Learn about the waist-to-hip ratio, its pros and cons, and how to find yours. This is an open-access article distributed under the terms of the Creative Commons Attribution License CC BY. The methyl jasmonate-responsive transcription factor SmMYB1 promotes phenolic acid biosynthesis in Salvia miltiorrhiza. McElroy C, Jennewein S, Schwab W, Lange BM, Wüst M. Shi J, Xiong YJ, Zhang H, Meng X, Zhang ZY, Zhang MM, Yu JS, Zhu YF, Xue T, Xu JP. Bowel Dis. C Representative western blot bands of CYP26A1, ALDH1A2 and COX2. |
| 5 Herbs to Boost Metabolism and Lose Weight | Rose Wellness | Another role of bHLHs is the regulation of flavonoid synthesis. Urolithins: Diet-derived bioavailable metabolites to tackle diabetes. Selenium test suite include metabplism acid Herbwl 88ursolic Selenium test suite metaboliamacetyl-keto-β-boswellic acid AKBA 90alisol A acetate AAa 91celastrol 92and betulinic acid Beige adipocytes are a distinct type of thermogenic fat cell in mouse and human. IL-2, a marker factor for activated T cells, was used to monitor T cell activation and proliferation. Yan, Z. |
| Thyroid Hormone | Of these, 12 were significant and exhibited negative coefficients, indicating a therapeutic association Figure 4A. Of the herbal ingredients, 47 herbal ingredients were the most closely related to the cancer therapy, and they could potentially revert the progression of almost all human cancers Figure 4C , Supplementary Table S Hence, these herbal ingredients, such as 6-gingerol, cordycepin, platycodin D, linolenic acid and ISL, were considered to exert the most potent therapeutic effects on human cancer. Cordycepin can significantly reduce the production of ILA in vitro and in vivo , and reduce the expression of its downstream signaling molecules to enhance tumor killing effect and reduce PD-L1 expression [ 64 ]. Immunomodulatory and metabolic modulating capacities of herbal ingredients against human cancer. A Heatmap of herbal ingredients—human cancer associations qualified by I score. D Heatmap of herbal ingredients—human cancer associations qualified by M score. G Heatmap of OCE for herbal ingredients against cancer qualified by OCES. B , E Number of human cancers that were significantly negatively with herbal ingredients based on immune changes B and metabolic pathways E. C , F Number of herbal ingredients that were significantly negatively and significantly positively with each human cancer based on immune changes C and metabolic pathways F. The full names of the horizontal coordinates of the distribution can be found in Supplementary Tables S13 and S In terms of metabolic modulation, 14 correspondingrelationships were also identified. Of these, were significant with exhibiting significantly negative correlations, indicating a therapeutic relationship Figure 4D. Notably, LGG, DLBC and SKCM were the top three human cancers with the highest number of therapeutic correlations with herbal ingredients Figure 4E , Supplementary Table S14 , suggesting that metabolic reprogramming plays an important role in the development of these cancers. Among the herbal ingredients, were significantly negatively associated with at least one cancer Figure 4F , Supplementary Table S The OCES of herbal ingredients against human cancer was calculated using RGSEA Figure 4G. Then, the contribution of the regulatory effects of herbal ingredients on the immune microenvironment and metabolic reprogramming on their anti-human cancer activities was quantified by examining the correlation between OCES and I score or M score. In this study, the average contribution for human cancer based on immune microenvironment was 0. This finding suggests that modifications in the immune microenvironment are closely correlated with the development of cancer and contribute to a large part of cancer progression. It also might indicate that cancers may likely be treated by the immunomodulatory effects of drugs. The mean correlation coefficient for human cancers in metabolic reprogramming was 0. This indicates that metabolic reprogramming also has a certain role in the emergence and spread of cancer and cancer can be ameliorated by the metabolic modulating ability of some drugs. Noticeably, the contribution of the immune system to the pathophysiology of cancer is higher than that of metabolic reprogramming as shown in Figure 5C. In other words, the immune system may be more profoundly involved in the pathophysiology of cancer than metabolic reprogramming. The contribution of immune microenvironment and metabolic reprogramming. A , B The number distribution of the contribution of the immune microenvironment A and metabolic reprogramming B in cancer development. D , E The number distribution of the contribution for the regulating immune microenvironment D and metabolic reprogramming E in the anti-cancer efficacy of each herbal ingredient. C , F Violin plots of the contribution of immune microenvironment and metabolic reprogramming in cancer C and herbal ingredients F. The average contribution of herbal ingredients based on the immune microenvironment was 0. Furthermore, the contribution of immunomodulatory and metabolic modulating abilities of herbal ingredients were qualified and the contribution of immunomodulatory ability was higher than that of metabolic pathway-modulating ability Figure 5F. Hence, these results may indicate that herbal ingredients exerted a higher modulatory effect on the immune microenvironment than on metabolic reprogramming for their therapeutic effects on cancer. To further verify the robustness and generalizability of the computational framework, the performance of the computational model was evaluated in the independent pharmacotranscriptomic dataset GSE, which included herbal ingredients from unified microarray experiment [ 29 ]. We used the same computational formula to calculate the contribution of the regulatory effects of herbal ingredients against human cancer. A similar result was observed that the contribution of the immune system to the pathophysiology of cancer is higher than that of metabolic reprogramming Supplementary Figure S3. Hence, these results further confirmed the reliability and generalizability of our model. In summary, these findings indicated that the developmental process of most human cancers might be reversed mainly through the immunomodulatory effects of herbal ingredients. Through the above analysis, we can identify some representative cancers and herbal ingredients. As shown in Figure 4B , LGG, STAD and GBM were the top three human cancers closely correlated with the immune microenvironment, indicating that these cancers may potentially be treated through immunomodulation using various herbal ingredients. These results suggest that immune dysregulation may be a key factor in the progression of STAD. Hence, STAD was selected as a representative cancer for the modulation of the immune microenvironment. As shown in Figure 4E , LGG was the top-ranked cancer closely correlated with metabolic reprogramming. Hence, LGG was selected as a representative cancer for the modulation of metabolic reprogramming. Then, the herbal ingredients with the most significant effect on STAD and LGG were identified. Literature review revealed that limited studies have examined the growth-inhibitory effects of ISL and CH against STAD and LGG, respectively. Therefore, ISL and CH were subjected to follow-up experimental verification. The effects of ISL and CH on MGC STAD cells and SW cells LGG cells were assayed using the CCK-8 assay. The IC 50 value of ISL against MGC cells was The IC 50 value of CH against SW cells was 4. ISL enhances the viability of T cells and inhibits the proliferation of cancer cells. A The proliferation of MGC cells was assayed by CCK-8 assay after 24 h of treatment with ISL. B The number distribution of immune cells that significantly associated with ISL. C MGC cells, pretreated with ISL for 24 h, were co-cultured with activated Jurkat T cells and subsequently stained with crystal violet for imaging. CH inhibits LGG proliferation and regulates arachidonic acid metabolism and retinoic acid metabolism. A Proliferation of SW cells was detected by CCK-8 after treatment with CH 24 h. C Representative western blot bands of CYP26A1, ALDH1A2 and COX2. SW cells were treated with various concentrations of CH for 24 h. D — F Quantitative analysis of COX2, ALDH1A2 and CYP26A1. To investigate the specific immunomodulatory properties of ISL, the types of immune cells represented by the significantly associated ISs were counted Figure 6B. The highest number of ISs associated with ISL was T cell status-related signatures, which suggested that ISL exerts anti-cancer effects by modulating T cells. To investigate whether ISL exerts treatment effects on STAD cells by modulating T cells, an in vitro co-culture model comprising STAD and activated Jurkat cells was established. IL-2, a marker factor for activated T cells, was used to monitor T cell activation and proliferation. The results showed that the level of IL-2 in the supernatant was significantly increased upon treatment with ISL Figure 6C and D. This indicated that ISL promoted the activation of Jurkat T cells and the release of IL In addition, ISL-treated T cells exerted potent growth-inhibitory effects against MGC cells in vitro Figure 6C and E. This indicated that activated Jurkat T cells potentiated the anti-cancer effects of ISL. Hence, ISL can exert growth-inhibitory effects against STAD by promoting the activation of T cells. To investigate the CH-modulated metabolic pathways, the pathways in which CH-related genes enriched were examined. Literature review suggested that arachidonic acid metabolism and retinoic acid metabolism play an essential role in the development of cancer [ 65—68 ]. Hence, this study focused on the proteins involved in these two pathways. CYP26 family enzymes and retinoic acid dehydrogenase ALDH are key enzymes for retinoic acid metabolism [ 69 ]. Meanwhile, the arachidonic acid pathway-metabolizing enzymes cyclooxygenases 2 COX2 in arachidonic acid metabolism has also been considered as therapeutic targets for human cancer [ 66 ]. As shown in Figure 7C , CH treatment up-regulated ALDH1A2 expression and down-regulated CYP26A1 expression in MGC cells. This means that CH promoted the production of retinoic acid dehydrogenase, inhibited the production of CYP26 family enzymes and promoted retinoic acid accumulation, which could regulate the cell cycle to stop proliferation. The absence of retinoic acid signaling is associated with dedifferentiation and tumor development [ 70 ]. Therefore, CH inhibits MGC cell proliferation by inducing the accumulation of retinoic acid. In addition, COX2 was down-regulated, which is associated with inflammatory processes [ 71 , 72 ]. The aberrant arachidonic acid metabolism observed in cancer cells is usually accompanied by an inflammatory state and a sustained increase in COX expression [ 65 , 73 ]. It has been shown that COX2 knockdown or its inhibitor can suppress tumorigenesis, growth and progression [ 74 ]. Traditional herbal systems have been an integral part of human history with repeated trials being performed on human subjects over thousands of years. In addition, herbal medicines play an essential role in the human health security of the general population [ 75 ]. Herbal ingredients can exert anti-cancer effects by inhibiting proliferation, regulating the immune microenvironment, modulating metabolism and reversing drug resistance, which can be attributed to their multiple targets, diverse biological activities and novel and diverse structures [ 75—77 ]. However, drug discovery from herbal medicine based on experiments is time consuming, expensive and laborious process [ 78 , 79 ]. Therefore, effective methods are needed to improve traditional drug discovery. The increase in the amount of omics data in recent years has provided opportunities for the computational prediction of anti-cancer drugs and improved the efficiency of drug discovery [ 80 ]. Wang et al. proposed a strategy for high-throughput screening based on genetic markers of tumor immunophenotypes to discover immunotherapeutic compounds [ 22 ]. Pankaj Goswami et al. developed a novel drug interaction scoring algorithm to predict drug interaction effects in diffuse large B-cell lymphoma [ 81 ]. Cheng et al. proposed a network-based inference method to infer new targets for known drugs [ 82 ]. But, how to quantify the contribution of the specific pathways to the OCE of a drug has always been a challenging issue. To address this issue, this study proposed a new computational framework COIMMR to quantify the contribution of the regulatory effects of herbal ingredients on the immune microenvironment and metabolic reprogramming to their anti-human cancer activities. In this study, a comprehensive data analysis of multiple cancers and herbal ingredients was performed. First, 30 human cancer data were obtained from TCGA, while herbal ingredients data were obtained from ITCM. Next, high-quality ISs and MSs were collected and the NES values of each signature for each human cancer and herbal ingredient were calculated, and the immunological landscape and metabolic landscape were constructed. Finally, the contributions of herbal ingredients in their anti-human cancer activity through modulation of the immune microenvironment and metabolic reprogramming were quantified. To demonstrate the power of the developed method, in vitro experiments were performed with two representative cancers. ISL was identified to specifically target the T cells in STAD, while CH was identified to specifically target arachidonic acid metabolism and retinoic acid metabolism in LGG. Compared with existing approaches like LINCS [ 83 , 84 ], our computational model has obvious differences and advantages. The prominent difference between our present work and LINCS is that COIMMR could reveal the contribution of herbal ingredients against human cancer via specific pathways or biological function. It is also the first computational model to quantify the contribution of specific pathways to the OCE for herbal ingredients, which can fill the gap of LINCS Secondly, datasets used in our computational model were all herbal ingredients from Traditional Chinese Medicine TCM , and LINCS contains very limited herbal ingredients [ 85 ]. Hence, our computational model pays more attention on the herbal ingredients space and could makes up for the limited herbal ingredients in LINCS Thirdly, LINCS cannot screen drugs targeting specific pathways, while our method can screen herbal ingredients targeting specific biological functions [ 86 ]. However, LINCS project only measured the expression level of genes [ 87 ]. Hence, we are more reliable in terms of the number of genes sequenced and the quality of the data. Overall, COIMMR has its unique contributions for drug discovery, especially for herbal ingredients, which could promote the intelligent development of TCM. For our model application and future drug development, one of the advantages is that it could rapidly analyze vast datasets, swiftly screen candidate compounds from herbal ingredients for drug development and improve the efficiency of translational drug discovery, which greatly reduces both the time and financial resources. In addition, it may facilitate the development of personalized medicine by targeting patient-specific pathways. This enables the design of specific drugs based on an individual's genetic makeup, improving efficacy and minimizing side effects. Furthermore, it could help researchers uncover intricate relationships, facilitating the discovery of new drug targets and mechanisms. However, this study has some limitations. The expression profiling data of ITCM are based on the MCF-7 cell line. Hence, we encourage users to use cancer-specific drug expression data in the future studies. In addition, we also encourage users to build the customized specific signatures with professional knowledge and combine the analysis results with those obtained from COIMMR to arrive at the most appropriate conclusion. In summary, this computational strategy can be applied to development of drug targeting specific biological pathways for various diseases using the gene expression profile data. The findings of this study will aid in the modernization of TCM. We constructed the first computational framework, COIMMR, which reveals the contribution of herbal ingredients against human cancer via immune microenvironment and metabolic reprogramming. By using COIMMR algorithm, we found that most herbal ingredients exerted a higher modulatory effect on the immune microenvironment than on metabolic reprogramming for their therapeutic effects on human cancer, which was first revealed by this study. By applying COIMMR algorithm to two case studies to demonstrate its strong power, we identified ISL that specifically regulates the T cells in STAD and CH that specifically targets metabolic reprogramming in LGG. The in silico results were verified using in vitro experiments. National Key Research and Development Program of China YFC ; National Natural Science Foundation of China and ; Innovation Team and Talents Cultivation Program of National Administration of Traditional Chinese Medicine ZYYCXTD-D ; Shanghai Sailing Program 20YF ; Shanghai Frontiers Science Center of TCM Chemical Biology, Shanghai Municipal Health Commission Project Y ; Three-year Action Plan for Shanghai TCM Development and Inheritance Program ZY — ; Wild Goose Array Project, Zhengzhou Center of PLAJLSF. We also thank the Home for Researchers editorial team www. com for the English check of this manuscript and Xiaoqi Wu Genergy Biotechnology Shanghai Co. Figures were created with biorender. The data of our work can be acquired from the Supplementary Materials uploaded with this article. and S. designed the study. and J. collected and analyzed the data. and X. performed the experiment. wrote the manuscript. revised the manuscript. Saisai Tian is a lecturer at School of Pharmacy, Ningxia Medical University. He has also served as alecturer at School of Pharmacy, Second Military Medical University, and his research interest covers bioinformatics, cancer biology, and network pharmacy. Yanan Li is a postgraduate student of Ningxia Medical University, and her research interest covers cancer biology and network pharmacy. Jia Xu is a postgraduate student of Henan University, and her research interest covers bioinformatics and network pharmacy. Lijun Zhang is an associate professor at the Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, and her research interest is anti-tumor mechanism of traditional Chinese medicine. Jinbo Zhang is an MPhil at the School of Pharmacy, Second Military Medical University and served as a pharmacist of Department of Pharmacy, Tianjin Rehabilitation Center of Joint Logistics Support Force. His research interest covers network pharmacy and natural products. Jinyuan Lu is a postgraduate student at the School of Pharmacy, Anhui University of Chinese Medicine, and his research interest covers network pharmacy. Xike Xu is a professor at the School of Pharmacy, Second Military Medical University, and his research interest covers network pharmacy. Xin Luan is the director of Systems Pharmacology ResearchCenter of TCM, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine. His current research focuses on the discovery and novel application of anti-cancer compounds from traditional Chinese medicine. Jing Zhao is a professor at the Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine. Her current research focus on bioinformatics, cancer biology and network pharmacy. Weidong Zhang is a professor at Ningxia Medical University, Second Military Medical University' Shanghai University of Traditional Chinese Medicine and Institute of Medicinal Plant DevelopmentChinese Academy of Medical Sciences and Peking Union Medical College. His major research interest areas are pharmacodynamic substance basis research of natural products and medicinal chemistry. Bray F , Ferlay J , Soerjomataram I , et al. Global cancer statistics GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in countries. CA Cancer J Clin ; 68 : — Google Scholar. Changing profiles of cancer burden worldwide and in China: a secondary analysis of the global cancer statistics Chin Med J Engl ; : — Stoll EA , Horner PJ , Rostomily RC. The impact of age on oncogenic potential: tumor-initiating cells and the brain microenvironment. Aging Cell ; 12 : — Ohshima K , Morii E. Metabolic reprogramming of cancer cells during tumor progression and metastasis. Metabolites ; 11 : Chu JJ , Mehrzad R. The biology of cancer. In: Mehrzad R, ed. The Link between Obesity and Cancer. Academic Press: Cambridge, UK, , pp. Pavlova NN , Thompson CB. The emerging hallmarks of cancer metabolism. Cell Metab ; 23 : 27 — Parvez MK , Rishi V. Herb-drug interactions and hepatotoxicity. Curr Drug Metab ; 20 : — Wang W-Y , Zhou H , Wang Y-F , et al. Current policies and measures on the development of traditional Chinese medicine in China. Pharmacol Res ; : Niedzwiecki A , Roomi MW , Kalinovsky T , Rath M. Anticancer efficacy of polyphenols and their combinations. Nutrients ; 8 : Kasi PD , Tamilselvam R , Skalicka-Woźniak K , et al. Molecular targets of curcumin for cancer therapy: an updated review. Tumor Biol ; 37 : — The signaling pathways and targets of traditional Chinese medicine and natural medicine in triple-negative breast cancer. J Ethnopharmacol ; : Muhammad N , Usmani D , Tarique M , et al. The role of natural products and their multitargeted approach to treat solid cancer. Cell ; 11 : The application of traditional Chinese medicine against the tumor immune escape. J Transl Intern Med ; 8 : — 4. Homoharringtonine induced immune alteration for an efficient anti-tumor response in mouse models of non-small cell lung adenocarcinoma expressing Kras mutation. Sci Rep ; 8 : Metabolic reprogramming by traditional Chinese medicine and its role in effective cancer therapy. BMC Complement Altern Med ; 17 : Norcantharidin combined with Coix seed oil synergistically induces apoptosis and inhibits hepatocellular carcinoma growth by downregulating regulatory T cells accumulation. Sci Rep ; 7 : Chlorogenic acid and caffeic acid from Sonchus oleraceus Linn synergistically attenuate insulin resistance and modulate glucose uptake in HepG2 cells. Food Chem Toxicol ; : — 7. Lee M-S , Lee S-O , Kim K-R , Lee HJ. Sphingosine kinase-1 involves the inhibitory action of HIF-1α by chlorogenic acid in hypoxic DU cells. When combined with ginger as mentioned previously , it also supports a healthy weight, inflammatory response, glucose and leptin levels. The slow-metabolism theory of weight gain has some truth to it. Complement these herbs for metabolism with these Ultimate 11 Yoga Poses for Digestion. Contents How Metabolism Works Boost Metabolism Naturally Herbs for Metabolism How Does Metabolism Work? Getting enough sleep 7. Regular exercise , specifically High Intensity Interval Training HIIT has been associated with a lower risk of metabolic syndrome, better metabolic markers, balanced blood sugar, and a reduced risk of many metabolic diseases. Stress management is one of the great keys to healthy metabolism. Yoga has been proven to lower a variety of metabolic syndrome risk factors in obese postmenopausal women. This is in line with Ayurvedic principles that utilize yoga as a stress-reliever, spiritual practice, and full body workout that helps rebalance Doshas, organs, and systems. Eating sensible portions. It should come as no surprise that lower caloric intake is associated with a positive effect on metabolism and insulin secretion. Many experts also recommend lowering your intake of sugar and refined carbohydrates, which can contribute to pre-fatty or fatty liver disease and interfere with healthy glucose metabolism. Focusing on a plant-based diet has also been shown effective in helping people achieve and maintain a lower BMI. Although more research is needed, a plant-based-diet is considered beneficial for improving metabolism and supporting weight loss. This is also in-line with Ayurvedic dietary principles, which focus largely on plant-based eating. Turmeric As one of the most studied herbs on the planet, it should come as no surprise that turmeric can positively impact metabolism. Katuki In Ayurveda, healthy metabolism of carbohydrates, fats, and protein is very much connected to the health of the liver and kidneys. Ginger Ginger is one of the most widely used herbs in Ayurveda. Ashwagandha Thyroid health is at the core of metabolic function. b Center for Quantitative Biology, AAIS, Peking University, Beijing , China. c Peking-Tsinghua Center for Life Sciences, Peking University, Beijing , China. d Department of Chemistry, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong. Through history, traditional Chinese medicine TCM has adopted oriental philosophical practices of drug combination and interaction to address human diseases. To investigate this from a systems biology point of view, we analysed 28 TCM herbs for their anti-inflammatory function, using molecular docking and arachidonic acid AA metabolic network simulation. The inhibition potential of each herb toward five essential enzymes as well as their possible side effects were examined. Three commonly prescribed anti-inflammatory formulae were simulated to discover the combinatorial properties of each contained herb in regulating the whole metabolic network. We discovered that different ingredients of a formula tend to inhibit different targets, which almost covered all the targets in the whole network. We also found that herbal combinations could achieve the same therapeutic effect at lower doses compared with individual usage. New herbal combinations were also predicted based on the inhibition potentials and two types of synergistic drug combinations of TCM theory were discussed from the perspective of systems biology. Using this combined approach of molecular docking and network simulation, we were able to computationally elucidate the combinatorial effects of TCM to intervene disease networks. We expect novel TCM formulae or modern drug combinations to be developed based on this research. Gu, N. Yin, J. Pei and L. Lai, Mol. To request permission to reproduce material from this article, please go to the Copyright Clearance Center request page. |
Sie haben sich nicht geirrt, alles ist treu
die sehr lustige Mitteilung