Leonurine alleviates rheumatoid arthritis by regulating the Hippo signaling pathway.

BACKGROUND: Rheumatoid arthritis (RA) is a chronic autoimmune disease that can cause joint inflammation and damage. Leonurine (LE) is an alkaloid found in Leonurus heterophyllus. It has anti-inflammatory effects. HYPOTHESIS/PURPOSE: The molecular mechanisms by which LE acts in RA are unclear and further investigation is required. METHODS: Mice with collagen-induced arthritis (CIA), and RA-fibroblast-like synoviocytes (FLSs) isolated from them were used as in vivo and in vitro models of RA, respectively. The therapeutic effects of LE on CIA-induced joint injury were investigated by micro-computed tomography, and staining with hematoxylin and eosin and Safranin-O/Fast Green. Cell Counting Kit-8, a Transwell® chamber, enzyme-linked immunosorbent assays, RT-qPCR, and western blotting were used to investigate the effects of LE on RA-FLS viability, migratory capacity, inflammation, microRNA-21 (miR-21) levels, the Hippo signaling pathway, and the effects and intrinsic mechanisms of related proteins. Dual luciferase was used to investigate the binding of miR-21 to YOD1 deubiquitinase (YOD1) and yes-associated protein (YAP). Immunofluorescence was used to investigate the localization of YAP within the nucleus and cytoplasm. RESULTS: Treatment with LE significantly inhibited joint swelling, bone damage, synovial inflammation, and proteoglycan loss in the CIA mice. It also reduced the proliferation, cell colonization, migration/invasion, and inflammation levels of RA-FLSs, and promoted miR-21 expression in vitro. The effects of LE on RA-FLSs were enhanced by an miR-21 mimic and reversed by an miR-21 inhibitor. The dual luciferase investigation confirmed that both YOD1 and YAP are direct targets of miR-21. Treatment with LE activated the Hippo signaling pathway, and promoted the downregulation and dephosphorylation of MST1 and LATS1 in RA, while inhibiting the activation of YOD1 and YAP. Regulation of the therapeutic effects of LE by miR-21 was counteracted by YOD1 overexpression, which caused the phosphorylation of YAP and prevented its nuclear ectopic position, thereby reducing LE effect on pro-proliferation-inhibiting apoptosis target genes. CONCLUSION: LE regulates the Hippo signaling pathway through the miR-21/YOD1/YAP axis to reduce joint inflammation and bone destruction in CIA mice, thereby inhibiting the growth and inflammation of RA-FLSs. LE has potential for the treatment of RA.

Effects of mind-body exercise on physical and psychosocial well-being of stroke patients: A systematic review and network meta-analysis.

This study conducted pairwise and network meta-analysis to evaluate the effectiveness of three mind-body exercise interventions (Tai Chi, Qigong, and yoga) on physical capacity, psychological well-being, and quality of life in stroke patients. The research encompassed 30 studies involving 2107 participants and utilized the Risk of Bias 2.0 tool for quality assessment. Pairwise analysis revealed that all three mind-body exercises significantly enhanced patients' quality of life. Tai Chi demonstrated the most comprehensive improvements in balance, limb motor function, activities of daily living, and depression. Network meta-analysis indicated that Qigong was the most effective in improving balance and quality of life for post-stroke patients, followed by Tai Chi. These findings underscore the positive impact of mind-body exercises on both physical and psychosocial outcomes in stroke patients. However, further research involving rigorously designed and adequately powered trials is necessary to enhance the level of evidence in this area.

Protective effect of mussel polysaccharide on cyclophosphamide-induced intestinal oxidative stress injury via Nrf2-Keap1 signaling pathway.

The hard-shelled mussel (Mytilus coruscus) has been used as a traditional Chinese medicine and health food in China for centuries. Polysaccharides from mussel has been reported to have multiple biological functions, however, it remains unclear whether mussel polysaccharide (MP) exerts protective effects in intestinal functions, and the underlying mechanisms of action remain unclear. The aim of this study was to investigate the protective effects and mechanism of MP on intestinal oxidative injury in mice. In this study, 40 male BALB/C mice were used, with 30 utilized to produce an animal model of intestinal oxidative injury with intraperitoneal injection of cyclophosphamide (Cy) for four consecutive days. The protective effects of two different doses of MP (300 and 600 mg/kg) were assessed by investigating the change in body weight, visceral index, and observing colon histomorphology. Moreover, the underlying molecular mechanisms were investigated by measuring the antioxidant enzymes and related signaling molecules through ELISA, real-time PCR, and western blot methods. The results showed that MP pretreatment effectively protected the intestinal from Cy-induced injury: improved the colon tissue morphology and villus structure, increased superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH-Px) activities, and reduced malondialdehyde (MDA) content in serum and colon tissues. Meanwhile, MP also significantly increased the expression levels of SOD, GSH-Px, heme oxygenase-1 (HO-1), and nuclear factor E2-related factor 2 (Nrf2) mRNA in colon tissues. Further, western blot results showed that the expression of Nrf2 protein was significantly upregulated while kelch-like ECH-associated protein 1 (Keap1) was significantly downregulated by MP in the colonic tissues. This study indicates that MP can ameliorate Cy-induced oxidative stress injury in mice, and Nrf2-Keap1 signaling pathway may mediate these protective effects.

Kaempferol Attenuates Gouty Arthritis by Regulating the Balance of Th17/Treg Cells and Secretion of IL-17.

Kaempferol is a common flavonoid aglycone widely found in plants. It exhibits beneficial therapeutic effects in the treatment of arthritis. However, the effects of kaempferol on gouty arthritis (GA) have not been verified. This study aimed to explore the potential mechanisms by which kaempferol regulates GA by network pharmacology and experimental validation. Potential drug targets for GA were identified with a protein-protein interaction network. Then, we performed a KEGG pathway analysis to elucidate the major pathway involved in the kaempferol-mediated treatment of GA. In addition, the molecular docking was performed. A rat model of GA was constructed to verify the results of network pharmacology analysis and investigate the mechanism of kaempferol against GA. The network pharmacology study indicated that there were 275 common targets of kaempferol and GA treatment. Kaempferol exerted therapeutic effects on GA, in part, by regulating the IL-17, AGE-RAGE, p53, TNF, and FoxO signaling pathways. Molecular docking results showed that kaempferol stably docked with the core MMP9, ALB, CASP3, TNF, VEGFA, CCL2, CXCL8, AKT1, JUN, and INS. Experimental validation suggested that kaempferol eased MSU-induced mechanical allodynia, ankle edema, and inflammation. It significantly suppressed the expression of IL-1ß, IL-6, TNF-α, and TGF-ß1 and restored Th17/Treg imbalance in MSU-induced rats and IL-6-induced PBMCs. Kaempferol also affected RORγt and Foxp3 through IL-17 pathway. The present study clarifies the mechanism of kaempferol against GA and provides evidence to support its clinical use.

Mechanism underlying the action of Duanteng-Yimu Tang in regulating Treg/Th17 imbalance and anti-rheumatoid arthritis.

Background: Rheumatoid arthritis (RA) is a chronic immune disease characterised by synovitis and cartilage destruction. Currently, many patients experience poor remission after new antirheumatic drug treatments. Duanteng-Yimu Tang (DTYMT), a traditional Chinese medicine, is effective in the treatment of RA. In this research, we designed to investigate the anti-RA effects of DTYMT and explore its potential mechanisms. Methods: Network pharmacology was adopted to explore the main pathways of DTYMT in patients with RA. Collagen-induced arthritis models of male DBA/1 mice were established, and their histopathological changes were observed by hematoxylin-eosin staining and micro-CT. qRT-PCR was performed to detect the expression of Foxp3 and RORγt in the serum and synovial tissue and IL-17, IL-1ß, TNF-α, and IL-10 mRNA in vivo. The proliferation and invasion of synovial cells were analyzed using Cell Counting Kit-8 and transwell assays, respectively. The ratio of T helper 17 (Th17) to regulatory T (Treg) cells was analyzed by flow cytometry. Results: Network pharmacology analysis revealed that Th17 cell differentiation may be the key pathway of DTYMT in RA. DTYMT ameliorated joint damage, inhibited RORγt expression, and increased Foxp3 expression in CIA mice. DTYMT significantly decreased IL-1ß, IL-17, and TNF-α mRNA levels, and increased IL-10 mRNA levels in IL-6-induced cells. Additionally, DTYMT inhibited Th17 cell differentiation and promoted Treg cell production, thus improving the Treg/Th17 imbalance. DTYMT also inhibited the proliferation, migration, and invasion of RA fibroblast-like synovial cells. Conclusions: These results indicate that DTYMT could regulate the Treg/Th17 cell balance, which is a possible mechanism of DTYMT in treating RA.

Shikonin and cisplatin synergistically overcome cisplatin resistance of ovarian cancer by inducing ferroptosis via upregulation of HMOX1 to promote Fe2+ accumulation.

BACKGROUND: Cisplatin-based chemotherapy often results in ovarian cancer (OC) chemical resistance and treatment failure. The combination of natural compounds with platinum-based agents is a new strategy for overcoming cisplatin resistance. At present, the synergistic effects and mechanism of combination of shikonin and cisplatin to overcome cisplatin resistance in OC are still unknown. PURPOSE: This study was to evaluate the synergistic effects of shikonin and cisplatin on cisplatin-resistant OC cells and to assess the underlying molecular basis for these effects. METHODS: Cell counting kit-8 assay, colony-formation assay, proteomic analysis, reactive oxygen species (ROS) detection, lipid peroxidation (LPO) detection, Fe2+ detection, western blot, and quantitative real-time reverse transcription PCR (qRT-PCR) were performed to evaluate the effects of shikonin and cisplatin on cisplatin-resistant OC cells. Underlying mechanisms of action were investigated in vitro using small molecule inhibitors and siRNA. In vivo, the effect of shikonin and cisplatin combination on tumor growth in BALB/c nude mice was evaluated, with tumor immunohistochemical (IHC) staining performed to detect ferroptosis-related proteins. RESULTS: In vitro, shikonin and cisplatin were shown to synergistically reduce the viability of cisplatin-resistant OC cells. Proteomic results demonstrated that the combination of the two drugs induced a ferroptotic process, as evidenced by increased levels of ROS, LPO, and Fe2+, with downregulation of glutathione peroxidase 4 (GPX4). Heme oxygenase 1 (HMOX1) inhibition and siRNA interference attenuated the combined effect of the two drugs on cell viability. Accumulation of Fe2+ was attenuated by siRNA interference of HMOX1. In vivo, combination treatment significantly inhibited the growth of subcutaneous tumors in BALB/c nude mice and increased the expression of ferroptosis-related proteins in tumor tissue. CONCLUSION: We report for the first time that the co-treatment of shikonin and cisplatin overcomes cisplatin resistance in OC through ferroptosis. Mechanistic analysis reveals the co-treatment induces ferroptosis through upregulation of HMOX1 that promotes Fe2+ accumulation.

Combinations of Tibetan tea and medicine food homology herbs: A new strategy for obesity prevention.

Obesity has become a significant global public health problem. Functional drinks have been an essential direction for obesity prevention research. The present study investigated the preventive effect and safety of winter melon and lotus leaf Tibetan tea (WLTT, a compound tea drink based on Ya'an Tibetan Tea and medicine food homology herbs) on obesity. The rats' hypercaloric high-fat diet (HFD) obesity model was established to evaluate obesity prevention and explored the mechanism through intestinal flora regulation. The results showed that in obese rats with the intervention of WLTT (400, 800, and 1600 mg/kg BW), the body weight, fat accumulation, adipocyte cell size, serum lipid levels, and antioxidant enzyme activity (SOD, GSH-Px, and MDA) were progressively improved. 16S rRNA high-throughput sequencing showed that WLTT could improve intestinal flora disorders due to HFD, which significantly reversed the relative abundance of Firmicutes and the F/B ratio associated with an HFD, and significantly upregulated the relative abundance of Verrucomicrobia. At the genus level, the downregulation of the relative abundance of Akkermansia and unclassified_Lachnospiraceae groups, and the upregulation of the relative abundance of Romboutsia, Ruminococcus, Corynebacteriume, and Saccharibacteria_genera_incertae_sedis groups brought about by the HFD were significantly reversed. The results of the above experiments were compared favorably with those of a parallel experiment with Bi -Sheng -Yuan slimming tea (BSY, a functional drink based on green tea and medicine food homology herbs). Overall, the findings have provided that WLTT can prevent obesity owing to an HFD by regulating intestinal flora and has a good safety profile, and combinations of Tibetan tea and medicine food homology herbs could be a new option for obesity prevention.

New opportunities and challenges of natural products research: When target identification meets single-cell multiomics.

Natural products, and especially the active ingredients found in traditional Chinese medicine (TCM), have a thousand-year-long history of clinical use and a strong theoretical basis in TCM. As such, traditional remedies provide shortcuts for the development of original new drugs in China, and increasing numbers of natural products are showing great therapeutic potential in various diseases. This paper reviews the molecular mechanisms of action of natural products from different sources used in the treatment of inflammatory diseases and cancer, introduces the methods and newly emerging technologies used to identify and validate the targets of natural active ingredients, enumerates the expansive list of TCM used to treat inflammatory diseases and cancer, and summarizes the patterns of action of emerging technologies such as single-cell multiomics, network pharmacology, and artificial intelligence in the pharmacological studies of natural products to provide insights for the development of innovative natural product-based drugs. Our hope is that we can make use of advances in target identification and single-cell multiomics to obtain a deeper understanding of actions of mechanisms of natural products that will allow innovation and revitalization of TCM and its swift industrialization and internationalization.

Upregulation of hypothalamic POMC neurons after biliary diversion in GK rats.

Background: Bile acids are important signaling molecules that might activate hypothalamic neurons. This study aimed to investigate possible changes in hypothalamic pro-opiomelanocortin (POMC) neurons after biliary diversion in diabetic rats. Methods: Ten GK rats were randomly divided into the biliary diversion (BD) and sham groups. The glucose metabolism, hypothalamic POMC expression, serum bile acid profiles, and ileal bile acid-specific receptors of the two groups were analyzed. Results: Biliary diversion improved blood glucose (P = 0.001) and glucose tolerance (P = 0.001). RNA-Seq of the hypothalamus showed significantly upregulated expression of the POMC gene (log2-fold change = 4.1, P < 0.001), which also showed increased expression at the protein (P = 0.030) and mRNA (P = 0.004) levels. The POMC-derived neuropeptide α-melanocyte stimulating hormone (α-MSH) was also increased in the hypothalamus (2.21 ± 0.11 ng/g, P = 0.006). In addition, increased taurocholic acid (TCA) (108.05 ± 20.62 ng/mL, P = 0.003) and taurodeoxycholic acid (TDCA) (45.58 ± 2.74 ng/mL, P < 0.001) were found in the BD group and induced the enhanced secretion of fibroblast growth factor-15 (FGF15, 74.28 ± 3.44 pg/ml, P = 0.001) by activating farnesoid X receptor (FXR) that was over-expressed in the ileum. Conclusions: Hypothalamic POMC neurons were upregulated after BD, and the increased TCA, TDCA, and the downstream gut-derived hormone FGF15 might activate POMC neurons.

Triptolide improves chondrocyte proliferation and secretion via down-regulation of miR-221 in synovial cell exosomes.

BACKGROUND: Rheumatoid arthritis (RA), the most common type of inflammatory arthritis, can cause bone damage and disability. Triptolide, a prominent treatment for RA, has satisfactory anti-inflammatory effects. However, the mechanism of action of triptolide in RA remains unknown. PURPOSE: This study aimed to explore the molecular mechanisms underlying triptolide-mediated improvements in RA and identify the miRNA pathway responsible for these effects. METHODS: We identified various dysregulated miRNAs associated with RA by mining previously described microarray data and verified and screened these candidates using RT-qPCR. Hematoxylin-eosin staining was then applied to identify pathological changes in the affected joints, and cell counting kit-8 analysis and flow cytometry were employed to examine cell proliferation and apoptosis, respectively. Extracted exosomes were verified using transmission electron microscopy. RESULTS: Our results revealed that the legs of rats with collagen-induced arthritis presented with obvious swelling and bone damage, a high degree of inflammatory cell infiltration into the synovium, and structural changes to the cartilage. Data mining identified 39 dysregulated miRNAs in these tissues, and RT-qPCR further refined these observations to highlight miR-221 as a potential RA biomarker. Subsequent evaluations revealed that fibroblast-like synovial (FLS) cells secrete Exs carrying dysregulated miR-221 in vitro. These Exs mediate miR-221 levels, inflammation, and TLR4/MyD88 signaling via their fusion with chondrocytes, leading to changes in chondrocyte growth and metabolic factor levels. Additionally, the addition of triptolide impaired miR-221 expression, cell proliferation, inflammatory factors, and the protein levels of TLR4/MyD88 in RA-FLS and promoted the apoptosis of FLS. The therapeutic effect of triptolide on miR-221 Exs was reversed by miR-221 inhibitor in both normal and RA FLS. CONCLUSION: Our research shows that effective treatment with triptolide is mediated by its regulation of growth and secretory functions of chondrocytes via the inhibition of miR-221 secretion by FLS, providing a new target and natural medicinal candidate for future RA treatments.

Study on the effect and mechanism of quercetin in treating gout arthritis.

Quercetin is widely found in natural plants, especially Chinese herbal plants. It has been used to treat arthritis in China for thousands of years. However, the effects and mechanisms of quercetin in the treatment of gout arthritis (GA) remain unclear. We aimed to verify the treatment of GA with quercetin and investigate the underlying mechanism. A combination of network pharmacology and experiments was used to reveal the mechanism of quercetin in the treatment of GA. Potential targets of quercetin and gout were identified. Then, the protein-protein interaction network for the common targets between quercetin and gout was constructed and the core targets were identified. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses for the common targets were performed to elucidate the pharmacological functions and mechanisms associated with quercetin treatment in GA. Finally, a monosodium urate-induced GA rat model was used to validate the predicted mechanisms in network pharmacology. Seventy-two common targets were identified. KEGG analysis revealed that treatment of GA with quercetin predominantly involved the interleukin (IL)-17, tumor necrosis factor (TNF), mitogen-activated protein kinase, and phosphoinositide 3-kinase-Akt signaling pathways. In an experimental validation, quercetin attenuated ankle joint inflammation-induced bone destruction and histological lesions. It also diminished the expression of IL-6, IL-17A, and IL-17F in the IL-17 pathway, and regulated the release of RAR-related orphan receptor gamma t,IL-17E, IL-1ß, IL-6, TNF-α, Foxp3, and transforming growth factor-beta 1. The collective findings implicate quercetin as a valuable alternative drug for the treatment of GA.

Drosophila melanogaster diabetes models and its usage in the research of anti-diabetes management with traditional Chinese medicines.

The prevalence of diabetes mellitus (DM) is increasing rapidly worldwide, but the underlying molecular mechanisms of disease development have not been elucidated, and the current popular anti-diabetic approaches still have non-negligible limitations. In the last decades, several different DM models were established on the classic model animal, the fruit fly (Drosophila melanogaster), which provided a convenient way to study the mechanisms underlying diabetes and to discover and evaluate new anti-diabetic compounds. In this article, we introduce the Drosophila Diabetes model from three aspects, including signal pathways, established methods, and pharmacodynamic evaluations. As a highlight, the progress in the treatments and experimental studies of diabetes with Traditional Chinese Medicine (TCM) based on the Drosophila Diabetes model is reviewed. We believe that the values of TCMs are underrated in DM management, and the Drosophila Diabetes models can provide a much more efficient tool to explore its values of it.

Single-cell transcriptomics reveals the natural product Shi-Bi-Man promotes hair regeneration by activating the FGF pathway in dermal papilla cells.

BACKGROUND: Finasteride and minoxidil are two commonly used drugs for the treatment of hair loss. However, these two drugs have certain side effects. Thus, the further elucidation of treatments for hair loss, including those using Chinese herbal medicine, remains important clinically. Shi-Bi-Man (SBM) is a hair health supplement that darkens hair and contains ginseng radix, tea polyphenols, polygonum multiflorum, radix angelicae sinensis, aloe, linseed, and green tea extract. PURPOSE: This study aimed to find potential effective monomer components to promote hair regeneration from SBM and to explore the mechanism of SBM to promote hair regeneration. METHODS: Supplementation with the intragastric administration or smear administration of SBM in artificially shaved C57BL/6 mice, observe its hair growth. UPLC/MS and UPLC/LTQ-Orbitrap-MS detect the main components in SBM and the main monomers contained in the skin after smearing, respectively. A network pharmacology study on the main components of SBM and single-cell RNA sequencing was performed to explore the role of SBM for hair regeneration. RESULTS: SBM significantly induced hair growth compared with a control treatment. TSG and EGCG were the main monomers in the skin after SBM smearing. The results of single-cell sequencing revealed that after SBM treatment, the number of hair follicle stem cells (HFSCs) and dermal papilla cells (DPCs) increased significantly. Cell interactions and volcano dots show that the interaction of the FGF signaling pathway was significantly enhanced, in which Fgf7 expression was especially upregulated in DPCs. In addition, the Wnt signaling pathway also had a partially enhanced effect on the interactions between various cells in the skin. The network pharmacology study showed that the promotion of the FGF and Wnt pathways by SBM was also enriched in alopecia diseases. CONCLUSION: We report that SBM has a potential effect on the promotion of hair growth by mainly activating the FGF signaling pathway. The use of SBM may be a novel therapeutic option for hair loss.

The role of selenium in severe fever with thrombocytopenia syndrome: an integrative analysis of surveillance data and clinical data.

OBJECTIVES: Selenium deficiency can be associated with increased susceptibility to some viral infections and even more severe diseases. In this study, we aimed to examine whether this association applies to severe fever with thrombocytopenia syndrome (SFTS). METHOD: An observational study was conducted based on the data of 13,305 human SFTS cases reported in mainland China from 2010 to 2020. The associations among incidence, case fatality rate of SFTS, and crop selenium concentration at the county level were explored. The selenium level in a cohort of patients with SFTS was tested, and its relationship with clinical outcomes was evaluated. RESULTS: The association between selenium-deficient crops and the incidence rate of SFTS was confirmed by multivariate Poisson analysis, with an estimated incidence rate ratio (IRR, 95% confidence interval [CI]) of 4.549 (4.215-4.916) for moderate selenium-deficient counties and 16.002 (14.706-17.431) for severe selenium-deficient counties. In addition, a higher mortality rate was also observed in severe selenium-deficient counties with an IRR of 1.409 (95% CI: 1.061-1.909). A clinical study on 120 patients with SFTS showed an association between serum selenium deficiency and severe SFTS (odds ratio, OR: 2.94; 95% CI: 1.00-8.67) or fatal SFTS (OR: 7.55; 95% CI: 1.14-50.16). CONCLUSION: Selenium deficiency is associated with increased susceptibility to SFTS and poor clinical outcomes.

A network pharmacology approach to predict potential targets and mechanisms of "Ramulus Cinnamomi (cassiae) - Paeonia lactiflora" herb pair in the treatment of chronic pain with comorbid anxiety and depression.

BACKGROUND: Traditional Chinese medicine (TCM) prescriptions have multiple bioactive properties. "Gui Zhi-Shao Yao" herb pair is widely used to treat chronic pain (CP), as well as anxiety and depression. However, its related targets and underlying mechanisms have not been deciphered. METHODS: In this study, the network pharmacology method was used to explore the bioactive components and targets of "Gui Zhi-Shao Yao" herb pair and further elucidate its potential biological mechanisms of action in the treatment of CP with comorbid anxiety disorder (AD) and mental depression (MD). RESULTS: Following a series of analyses, we identified 15 active compounds, hitting 130 potential targets. After the intersections the targets of this herb pair and CP, AD and MD - sorted by the value of degree - nine targets were identified as the vital ones: Akt1, IL6, TNF, PTGS2, JUN, CASP3, MAPK8, PPARγ and NOS3. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis results demonstrated 11 pathways, such as AGE-RAGE signalling pathway, IL-17 signalling pathway, TNF signalling pathway, which primarily participate in the pathological processes. CONCLUSIONS: This study preliminarily predicted and verified the pharmacological and molecular mechanisms of "Gui Zhi-Shao Yao" herb pair for treating CP with comorbid AD and MD from a holistic perspective. In vivo and in vitro experiments will be required to further investigate the mechanisms.KEY MESSAGEA network pharmacology approach was applied to identify key targets and molecular mechanisms.Nine targets were regarded as the vital targets for chronic pain with comorbid anxiety and depression.Predicted 11 pathways were the potential therapy targets and pharmacological mechanism of "Gui Zhi-Shao Yao" herb pair.

Advances in ameliorating inflammatory diseases and cancers by andrographolide: Pharmacokinetics, pharmacodynamics, and perspective.

Andrographolide, a well-known natural lactone having a range of pharmacological actions in traditional Chinese medicine. It has long been used to cure a variety of ailments. In this review, we cover the pharmacokinetics and pharmacological activity of andrographolide which supports its further clinical application in cancers and inflammatory diseases. Growing evidence shows a good therapeutic effect in inflammatory diseases, including liver diseases, joint diseases, respiratory system diseases, nervous system diseases, heart diseases, inflammatory bowel diseases, and inflammatory skin diseases. As a result, the effects of andrographolide on immune cells and the processes that underpin them are discussed. The preclinical use of andrographolide to different organs in response to malignancies such as colorectal, liver, gastric, breast, prostate, lung, and oral cancers has also been reviewed. In addition, several clinical trials of andrographolide in inflammatory diseases and cancers have been summarized. This review highlights recent advances in ameliorating inflammatory diseases as well as cancers by andrographolide and its analogs, providing a new perspective for subsequent research of this traditional natural product.

Effects and mechanisms of natural plant active compounds for the treatment of osteoclast-mediated bone destructive diseases.

Bone-destructive diseases, caused by overdifferentiation of osteoclasts, reduce bone mass and quality, and disrupt bone microstructure, thereby causes osteoporosis, Paget's disease, osteolytic bone metastases, and rheumatoid arthritis. Osteoclasts, the only multinucleated cells with bone resorption function, are derived from haematopoietic progenitors of the monocyte/macrophage lineage. The regulation of osteoclast differentiation is considered an effective target for the treatment of bone-destructive diseases. Natural plant-derived products have received increasing attention in recent years due to their good safety profile, the preference of natural compounds over synthetic drugs, and their potential therapeutic and preventive activity against osteoclast-mediated bone-destructive diseases. In this study, we reviewed the research progress of the potential antiosteoclast active compounds extracted from medicinal plants and their molecular mechanisms. Active compounds from natural plants that inhibit osteoclast differentiation and functions include flavonoids, terpenoids, quinones, glucosides, polyphenols, alkaloids, coumarins, lignans, and limonoids. They inhibit bone destruction by downregulating the expression of osteoclast-specific marker genes (CTSK, MMP-9, TRAP, OSCAR, DC-STAMP, V-ATPase d2, and integrin av3) and transcription factors (c-Fos, NFATc1, and c-Src), prevent the effects of local factors (ROS, LPS, and NO), and suppress the activation of various signalling pathways (MAPK, NF-κB, Akt, and Ca2+). Therefore, osteoclast-targeting natural products are of great value in the prevention and treatment of bone destructive diseases.

Tianma Gouteng Decoction regulates oxidative stress and inflammation in AngII-induced hypertensive mice via transcription factor EB to exert anti-hypertension effect.

Hypertension is one of the important causes of cardiovascular diseases, and the imbalance of vascular homeostasis caused by oxidative stress and endothelial inflammation occurs throughout hypertension pathogenesis. Therefore, inhibiting oxidative stress and endothelial inflammation is important for treating hypertension. Tianma Gouteng Decoction (TGD) is a Chinese herbal medicine that is commonly used to treat hypertension in China, and demonstrates clinically effective antihypertensive effects. However, its blood pressure reduction mechanism remains unclear. In this study, we further determined the antihypertensive effects of TGD and revealed its underlying mechanism. We established an AngII-induced hypertension mice model, which was treated with TGD for six weeks. We monitored blood pressure, heart rate, and body weight every week. After six weeks, we detected changes in the structure and function of the heart, the structure of blood vessels, and vasomotor factors. We also detected the expression of oxidative stress and inflammation-related genes. We found that TGD can significantly reduce blood pressure, improve cardiac structure and function, and reverse vascular remodeling, which could be due to the inhibition of oxidative stress and inflammation. We also found that the effect of inhibiting oxidative stress and inflammation could be related to the up-regulation of transcription factor EB (TFEB) expression by TGD. Therefore, we used AAV9 to knock down TFEB and observe the role of TFEB in TGD's antihypertensive and cardiovascular protection properties. We found that after TFEB knockdown, the protective effect of TGD on blood pressure and cardiovascular remodeling in AngII-induced hypertensive mice was inhibited, and that it was unable to inhibit oxidative stress and inflammation. Therefore, our study demonstrated for the first time that TGD could exert anti-oxidative stress and anti-inflammatory effects through TFEB and reverse the cardiovascular remodeling caused by hypertension.

Network differentiation: A computational method of pathogenesis diagnosis in traditional Chinese medicine based on systems science.

Resembling the role of disease diagnosis in Western medicine, pathogenesis (also called Bing Ji) diagnosis is one of the utmost important tasks in traditional Chinese medicine (TCM). In TCM theory, pathogenesis is a complex system composed of a group of interrelated factors, which is highly consistent with the character of systems science (SS). In this paper, we introduce a heuristic definition called pathogenesis network (PN) to represent pathogenesis in the form of the directed graph. Accordingly, a computational method of pathogenesis diagnosis, called network differentiation (ND), is proposed by integrating the holism principle in SS. ND consists of three stages. The first stage is to generate all possible diagnoses by Cartesian Product operated on specified prior knowledge corresponding to the input symptoms. The second stage is to screen the validated diagnoses by holism principle. The third stage is to pick out the clinical diagnosis by physician-computer interaction. Some theorems are stated and proved for the further optimization of ND in this paper. We conducted simulation experiments on 100 clinical cases. The experimental results show that our proposed method has an excellent capability to fit the holistic thinking in the process of physician inference.