Mangiferin, a Potential Supplement to Improve Metabolic Syndrome: Current Status and Future Opportunities.

Metabolic syndrome (MetS) represents a considerable clinical and public health burden worldwide. Mangiferin (MF), a flavonoid compound present in diverse species such as mango (Mangifera indica L.), papaya (Pseudocydonia sinensis (Thouin) C. K. Schneid.), zhimu (Anemarrhena asphodeloides Bunge), and honeybush tea (Cyclopia genistoides), boasts a broad array of pharmacological effects. It holds promising uses in nutritionally and functionally targeted foods, particularly concerning MetS treatment. It is therefore pivotal to systematically investigate MF's therapeutic mechanism for MetS and its applications in food and pharmaceutical sectors. This review, with the aid of a network pharmacology approach complemented by this experimental studies, unravels possible mechanisms underlying MF's MetS treatment. Network pharmacology results suggest that MF treats MetS effectively through promoting insulin secretion, targeting obesity and inflammation, alleviating insulin resistance (IR), and mainly operating via the phosphatidylinositol 3 kinase (PI3K)/Akt, nuclear factor kappa-B (NF-[Formula: see text]B), microtubule-associated protein kinase (MAPK), and oxidative stress signaling pathways while repairing damaged insulin signaling. These insights provide a comprehensive framework to understand MF's potential mechanisms in treating MetS. These, however, warrant further experimental validation. Moreover, molecular docking techniques confirmed the plausibility of the predicted outcomes. Hereafter, these findings might form the theoretical bedrock for prospective research into MF's therapeutic potential in MetS therapy.

Cycads: A comprehensive review of its botany, traditional uses, phytochemistry, pharmacology and toxicology.

Cycads, which primarily consist of the families Cycadaceae and Zamiaceae, possess intrinsic therapeutic attributes that are prominently expressed across their morphological spectrum, including roots, leaves, flowers, and seeds. In Chinese traditional medicine, the leaves of cycads are particularly revered for their profound healing capabilities. This meticulous review engages with existing literature on cycads and presents insightful avenues for future research. Over 210 phytoconstituents have been isolated and identified from various cycad tissues, including flavonoids, azoxy metabolites, sterols, lignans, non-proteogenic amino acids, terpenoids, and other organic constituents. The contemporary pharmacological discourse highlights the antineoplastic, antimicrobial, and antidiabetic activities inherent in these ancient plants, which are of particular importance to the field of oncology. Despite the prevalent focus on crude extracts and total flavonoid content, our understanding of the nuanced pharmacodynamics of cycads lags considerably behind. The notoriety of cycads derived toxicity, notably within the context of Guam's neurological disease cluster, has precipitated an established emphasis on toxicological research within this field. As such, this critical review emphasizes nascent domains deserving of academic and clinical pursuit, whilst nested within the broader matrix of current scientific understanding. The systematic taxonomy, traditional applications, phytochemical composition, therapeutic potential, and safety profile of cycads are holistically interrogated, assimilating an indispensable repository for future scholarly inquiries. In conclusion, cycads stand as a veritable treasure trove of pharmacological virtue, displaying remarkable therapeutic prowess and holding vast promise for ongoing scientific discovery and clinical utilization.

Integrating UPLC-Q-Exactive Orbitrap/MS, network pharmacology and experimental validation to reveal the potential mechanism of Tibetan medicine Rhodiola granules in improving myocardial ischemia-reperfusion injury.

ETHNOPHARMACOLOGY RELEVANCE: Rhodiola granules (RG) is a traditional Tibetan medicine prescription that can be used to improve the symptoms of ischemia and hypoxia in cardiovascular and cerebrovascular diseases. However, there is no report on its use to improve myocardial ischemia/reperfusion (I/R) injury, and its potential active ingredients and mechanism against myocardial ischemia/reperfusion (I/R) injury remain unclear. AIM OF THE STUDY: This study aimed to reveal the potential bioactive components and underlying pharmacological mechanisms of RG in improving myocardial I/R injury through a comprehensive strategy. MATERIALS AND METHODS: UPLC-Q-Exactive Orbitrap/MS technology was used to analyze the chemical components of RG, the potential bioactive components and targets were tracked and predicted by the SwissADME and SwissTargetPrediction databases, and the core targets were predicted through the PPI network, as well the functions and pathways were determined by GO and KEGG analysis. In addition, the molecular docking and ligation of the anterior descending coronary artery-induced rat I/R models were experimentally validated. RESULTS: A total of 37 ingredients were detected from RG, including nine flavones, ten flavonoid glycosides, one glycoside, eight organic acids, four amides, two nucleosides, one amino acid, and two other components. Among them, 15 chemical components, such as salidroside, morin, diosmetin, and gallic acid were identified as key active compounds. Ten core targets, including AKT1, VEGF, PTGS2, and STAT3, were discovered through the analysis of the PPI network constructed from 124 common potential targets. These possible targets were involved in the regulation of oxidative stress and HIF-1/VEGF/PI3K-Akt signaling pathways. Furthermore, molecular docking confirmed that the potential bioactive compounds in RG have good potential binding abilities to AKT1, VEGFA, PTGS2, STAT3, and HIF-1α proteins. Then, the animal experiments showed that RG could significantly improve the cardiac function of I/R rats, reduce the size of myocardial infarction, improve the myocardial structure, and reduce the degree of myocardial fibrosis, inflammatory cell infiltration, and myocardial cell apoptosis rate in I/R rats. In addition, we also found that RG could decrease the concentration of AGE, Ox-LDL, MDA, MPO, XOD, SDH, Ca2+, and ROS, and increase the concentration of Trx, TrxR1, SOD, T-AOC, NO, ATP, Na+k+-ATPase, Ca2+-ATPase, and CCO. Moreover, RG could significantly down-regulate the expressions of Bax, Cleaved-caspase3, HIF-1α, and PTGS2, as well up-regulate the expressions of Bcl-2, VEGFA, p-AKT1, and p-STAT3. CONCLUSION: In summary, we revealed for the first time the potential active ingredients and mechanisms of RG for myocardial I/R injury therapy through a comprehensive research strategy. RG may synergistically improve myocardial I/R injury through anti-inflammatory, regulating energy metabolism, and oxidative stress, improving I/R-induced myocardial apoptosis, which may be related to the HIF-1/VEGF/PI3K-Akt signaling pathway. Our study provides new insights into the clinical application of RG and also provides a reference for the development and mechanism research of other Tibetan medicine compound preparations.

Swertia L.: A comprehensive review of its genetic relationship, chemical compositions, pharmacological effects, toxicities, and applications.

Swertia L., as a commonly used ethnic medicine, is widely distributed in Sichuan, Yunnan, and Xizang in China. Moreover, the medicinal plants of Swertia L. have been widely used and constitute one of the most important sources of various traditional medicines in China due to their prominent activities. In this review, the information on the classification, distribution, genetic relationship, chemical composition, pharmacological effects, toxicities, and applications of the medicinal plants in Swertia L. was summarized based on the scientific literature. The results indicated that the medicinal plants of Swertia L. mainly contained chemical components including triterpenes, xanthones, and iridoids. These compounds exert pharmacological effects including ameliorating diseases related to the liver and gallbladder. They also exert antiviral and antibacterial effects and can alleviate the increase in blood glucose levels. Especially, prescriptions related to Swertia L. have been widely adopted in preclinical and clinical studies to protect against diseases affecting the liver and the gallbladder, including hepatitis, cirrhosis, and cholecystitis. In addition, it also discusses toxicity studies and future perspectives and provides a reference for their clinical development and utilization.

Ferroptosis in lung cancer: a novel pathway regulating cell death and a promising target for drug therapy.

Lung cancer is a common malignant tumor that occurs in the human body and poses a serious threat to human health and quality of life. The existing treatment methods mainly include surgical treatment, chemotherapy, and radiotherapy. However, due to the strong metastatic characteristics of lung cancer and the emergence of related drug resistance and radiation resistance, the overall survival rate of lung cancer patients is not ideal. There is an urgent need to develop new treatment strategies or new effective drugs to treat lung cancer. Ferroptosis, a novel type of programmed cell death, is different from the traditional cell death pathways such as apoptosis, necrosis, pyroptosis and so on. It is caused by the increase of iron-dependent reactive oxygen species due to intracellular iron overload, which leads to the accumulation of lipid peroxides, thus inducing cell membrane oxidative damage, affecting the normal life process of cells, and finally promoting the process of ferroptosis. The regulation of ferroptosis is closely related to the normal physiological process of cells, and it involves iron metabolism, lipid metabolism, and the balance between oxygen-free radical reaction and lipid peroxidation. A large number of studies have confirmed that ferroptosis is a result of the combined action of the cellular oxidation/antioxidant system and cell membrane damage/repair, which has great potential application in tumor therapy. Therefore, this review aims to explore potential therapeutic targets for ferroptosis in lung cancer by clarifying the regulatory pathway of ferroptosis. Based on the study of ferroptosis, the regulation mechanism of ferroptosis in lung cancer was understood and the existing chemical drugs and natural compounds targeting ferroptosis in lung cancer were summarized, with the aim of providing new ideas for the treatment of lung cancer. In addition, it also provides the basis for the discovery and clinical application of chemical drugs and natural compounds targeting ferroptosis to effectively treat lung cancer.

Deciphering hepatocellular carcinoma pathogenesis and therapeutics: a study on anoikis, ceRNA regulatory network and traditional Chinese medicine.

Introduction: Hepatocellular carcinoma (HCC) is responsible for approximately 90% of liver malignancies and is the third most common cause of cancer-related mortality worldwide. However, the role of anoikis, a programmed cell death mechanism crucial for maintaining tissue equilibrium, is not yet fully understood in the context of HCC. Methods: Our study aimed to investigate the expression of 10 anoikis-related genes (ARGs) in HCC, including BIRC5, SFN, UBE2C, SPP1, E2F1, etc., and their significance in the disease. Results: Through Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses, we discovered that these ARGs are involved in important processes such as tissue homeostasis, ion transport, cell cycle regulation, and viral infection pathways. Furthermore, we found a significant correlation between the prognostic value of five ARGs and immune cell infiltrates. Analysis of clinical datasets revealed a strong association between BIRC5 expression and HCC pathological progression, including pathological stage, T stage, overall survival (OS), and race. By constructing a competing endogenous RNA (ceRNA) network and using molecular docking, we identified ten bioactive compounds from traditional Chinese medicine (TCM) that could potentially modulate BIRC5. Subsequent in vitro experiments confirmed the influence of platycodin D, one of the identified compounds, on key elements within the ceRNA network. Discussion: In conclusion, our study presents a novel framework for an anoikis-centered prognostic model and an immune-involved ceRNA network in HCC, revealing potential regulatory targets. These insights contribute to our understanding of HCC pathology and may lead to improved therapeutic interventions.

Identification and validation of a novel phagocytosis regulators-related signature with potential prognostic and immunotherapeutic value in patients with lung adenocarcinoma.

Background: Lung adenocarcinoma (LUAD) is a malignant tumor that seriously affects the prognosis of patients. Tumor-associated macrophages (TAMs) play a vital role in the tumor microenvironment and can be used as a potential target for tumor therapy, and phagocytosis regulators (PRs) are particularly important in this process. However, the PRs-related signature that can predict the potential prognostic and immunotherapeutic value in patients with LUAD has not been discovered. Methods: In this study, we mainly analyzed the effect of phagocytosis regulators on the prognosis of LUAD, and based on multiple screening analyses including differential analysis, univariate Cox analysis, and Lasso analysis, we constructed a prognostic risk model consisting of five genes. To verify the stability of the model, survival analysis and ROC curve verification were carried out through multiple data sets. In addition, we also combined many factors, such as immune infiltrating cells, clinical grouping characteristics, immune examination sites, pro-inflammatory factors, and other factors as well as in vitro cell experiments and clinical tissue samples for further validation analysis. Results: After identifying 29 differentially expressed PRs in LUAD samples, we further constructed a prognostic model consisting of five prognostic signatures (FURIN, KIF23, SASH3, GNPNAT1, and ITGAL). Further survival analysis tests, ROC verification, as well as univariate and multivariate Cox regression analysis showed that the risk score of the model could well predict the prognosis of LUAD patients and could be used as an independent prognostic factor. In addition, we further found that these phagocytic regulators-related signatures were closely related to the immune microenvironment and immunotherapy in LUAD patients, and could well predict the efficacy of immunotherapy in patients. In vitro cell experiments and Immunohistochemistry of clinical tissues showed that the expressions of FURIN, KIF23, SASH3, GNPNAT1 and ITGAL in normal lung cells/tissues and LUAD cells/tissues were consistent with bioinformatics results, and 3 of them had significant differences. Conclusion: Our study identified a novel PRs-related signature that has potential application value in predicting the prognosis of LUAD patients and predicting the efficacy of immunotherapy. This provides a new basis for the prognosis assessment of LUAD patients and provides a novel target for immunotherapy of LUAD patients.

An In Vitro Dissolution Determination of Multi-Index Components in Tibetan Medicine Rhodiola Granules.

The composition of the Tibetan medicine Rhodiola granules (RG) is complex, and the overall quality of RG is difficult to determine. Therefore, establishing a method to determine the multi-component in vitro dissolution of RG is of great significance for quality control. This study uses the second paddle method of the fourth general rule 0931 from the Chinese Pharmacopoeia (2020 edition), compliant with apparatus 2 of the United States Pharmacopeia (USP). The dissolution apparatus was set to a rotation speed of 100 rpm with ultrapure water as the dissolution medium. A sample volume of 1 mL was collected at each timepoint. Furthermore, the cumulative dissolution of gallic acid, salidroside, and ethyl gallic acid in RG at different time points was determined by high-performance liquid chromatography (HPLC). Finally, the dissolution curves were drawn, and the curves were fitted to the GompertzMod, the Gompertz, the Logistic, and the Weibull equations. The results showed that the cumulative dissolution of gallic acid in RG was over 80% at 1 min, the cumulative dissolution of salidroside and ethyl gallic acid was over 65% at 5 min, and the cumulative dissolution of each index component decreased after 30 min. The curve fitting demonstrated that the GompertzMod equation was the best-fitting model for each index component of RG. In conclusion, the dissolution test method described in this protocol is simple, accurate, and reliable. It can characterize the dissolution behavior of the index components in RG in vitro, which provides a methodological reference for quality control of RG and quality evaluation of other ethnic compounds.

Natural polyphenols: a potential prevention and treatment strategy for metabolic syndrome.

Metabolic syndrome (MS) is the term for a combination of hypertension, dyslipidemia, insulin resistance, and central obesity as factors leading to cardiovascular and metabolic disease. Epidemiological investigation has shown that polyphenol intake is negatively correlated with the incidence of MS. Natural polyphenols are widely found in cocoa beans, tea, vegetables, fruits, and some Chinese herbal medicines; they are a class of plant compounds containing a variety of phenolic structural units, which are potent antioxidants and anti-inflammatory agents in plants. Polyphenols are composed of flavonoids (such as flavanols, anthocyanidins, anthocyanins, isoflavones, etc.) and non-flavonoids (such as phenolic acids, stilbenes, and lignans). Modern pharmacological studies have proved that polyphenols can reduce blood pressure, improve lipid metabolism, lower blood glucose, and reduce body weight, thereby preventing and improving MS. Due to the unique characteristics and potential development and application value of polyphenols, this review summarizes some natural polyphenols that could treat MS, including their chemical properties, plant sources, and pharmacological action against MS, to provide a basis for the further study of polyphenols in MS.

Network analysis combined with pharmacological evaluation strategy to reveal the mechanism of Tibetan medicine Wuwei Shexiang pills in treating rheumatoid arthritis.

Tibetan medicine is an important part of traditional Chinese medicine and a significant representative of ethnic medicine in China. Tibetan medicine is gradually recognized by the world for its unique curative effects. Wuwei Shexiang pills (WPW) has been widely used to treat "Zhenbu" disease (Also known as rheumatoid arthritis) in Tibetan medicine, however, its potential bioactive ingredients and mechanism for RA treatment remain unclear. In this study, we used a combination of gas chromatography-mass spectrometry (GC-MS), ultra-performance liquid chromatography coupled with quadrupole time-of-fight mass spectrometry (UPLC-Q-TOF/MS), network analysis and experimental validation to elucidate the potential pharmacodynamic substances and mechanisms of WPW in the treatment of rheumatoid arthritis (RA). The results showed that songoramine, cheilanthifoline, saussureanine C, acoric acid, arjunolic acid, peraksine, ellagic acid, arjungenin and other 11 components may be the main activities of WPW in the treatment of RA. PIK3CA, AKT, MAPK, IL-6, TNF, MMP1, MMP3, and CDK1 are considered as core targets. PI3K-AKT, MAPK, apoptosis, cell cycle, and other signaling pathways may be the key pathways for WPW to play a role in the treatment of RA. Furthermore, we validated the underlying molecular mechanism of WPW predicted by network analysis and demonstrated its possible mechanism through in vivo animal experiments. It was found that WPW could significantly improve the degree of paw swelling, and reduce ankle joint diameter and arthritis index. Further histomorphological analysis showed that WPW could reduce the degree of synovial tissue inflammation and ankle joint cartilage damage. Meanwhile, WPW could down-regulate the levels of IL-6, IL-1ß, and IL-17, and increase the levels of IL-10 and IL-4 in the serum of AA rats. TUNEL staining confirmed that WPW could significantly promote the apoptosis of synovial cells. Moreover, the immunohistochemical results showed that WPW decreased the expression of PI3K, AKT, MAPK, MMP1, MMP3, CDK1, and Bcl-2, as well as increased the expression of Bax protein. In conclusion, we successfully combined GC-MS, UPLC-Q-TOF/MS, network analysis, and experimental validation strategies to elucidate the inhibition of inflammation by WPW in AA model rats via PI3K/AKT, MAPK, cell cycle and apoptotic pathways process. This not only provides new evidence for the study of potential pharmacodynamic substances and the mechanism of WPW in the treatment of RA, but also provides ideas for the study of other Tibetan medicine compound preparations.

A Comprehensive Review on the Chemical Properties, Plant Sources, Pharmacological Activities, Pharmacokinetic and Toxicological Characteristics of Tetrahydropalmatine.

Tetrahydropalmatine (THP), a tetrahydroproberine isoquinoline alkaloid, is widely present in some botanical drugs, such as Stephania epigaea H.S. Lo (Menispermaceae; Radix stephaniae epigaeae), Corydalis yanhusuo (Y.H.Chou & Chun C.Hsu) W.T. Wang ex Z.Y. Su and C.Y. Wu (Papaveraceae; Corydalis rhizoma), and Phellodendron chinense C.K.Schneid (Berberidaceae; Phellodendri chinensis cortex). THP has attracted considerable attention because of its diverse pharmacological activities. In this review, the chemical properties, plant sources, pharmacological activities, pharmacokinetic and toxicological characteristics of THP were systematically summarized for the first time. The results indicated that THP mainly existed in Papaveraceae and Menispermaceae families. Its pharmacological activities include anti-addiction, anti-inflammatory, analgesic, neuroprotective, and antitumor effects. Pharmacokinetic studies showed that THP was inadequately absorbed in the intestine and had rapid clearance and low bioavailability in vivo, as well as self-microemulsifying drug delivery systems, which could increase the absorption level and absorption rate of THP and improve its bioavailability. In addition, THP may have potential cardiac and neurological toxicity, but toxicity studies of THP are limited, especially its long-duration and acute toxicity tests. In summary, THP, as a natural alkaloid, has application prospects and potential development value, which is promising to be a novel drug for the treatment of pain, inflammation, and other related diseases. Further research on its potential target, molecular mechanism, toxicity, and oral utilization should need to be strengthened in the future.

Investigation of the mechanism of Isobavachalcone in treating rheumatoid arthritis through a combination strategy of network pharmacology and experimental verification.

ETHNOPHARMACOLOGY RELEVANCE: Isobavachalcone (IBC) is a natural chalcone compound widely distributed in traditional Chinese medicine Psoralea corylifolia L., and Tibetan medicine Abelmoschus manihot (L.) Medik. Etc.. Among them, Psoralea corylifolia has the effect of tonifying the kidney and strengthening Yang, and it is recorded in the Medicinal theory that it can be used in managing rheumatism and arthralgia. In addition, It has been included in many prescriptions in traditional Chinese medicine as the main herb for managing rheumatoid arthritis (RA). Similarly, Abelmoschus manihot is a common Tibetan medicinal herb and is a common medicinal material in Tibetan medicine and reported in ancient medicinal books such as Jing Zhu Ben Cao and Si Bu Yi Dian to possess the effect of Ganhuangshui and thus can be used in treating Huangshui diseases (such as RA). Previous research has demonstrated IBC to possess numerous biological activities, including anti-cancer, anti-inflammatory, antibacterial and immunomodulatory. Nevertheless, its efficacy and potential mechanism in treating rheumatoid arthritis are yet to be investigated. AIM OF THE STUDY: This study aimed at investigating the therapeutic efficacy and mechanism of IBC in treating RA through a combined strategy of network pharmacology, in vitro, and in vivo evaluation. MATERIALS AND METHODS: The Swiss Target Prediction and GeneCards databases were consulted to predict the potential targets of IBC and RA. Additionally, the potential targets for IBC in treating RA were predicted by consulting databases such as String, Cytoscape, MCODE, and Cytohubba. R software was utilized for enrichment analysis of GO and KEGG pathways, followed by in vitro experimentation using cell lines and in vivo experimentation using animals to explore the potential mechanism of IBC in RA treatment. RESULTS: By integrating the results of network pharmacological analysis, 17 genes were found to be strongly associated with RA, such as TNF, MAPK13, EGFR, PTGS2, MMP3, etc. The enrichment analysis indicated that IBC possessed tremendous therapeutic efficacy in managing RA through PI3K-AKT, rheumatoid arthritis, and TNF signaling pathways. The in vitro experimentation indicated that IBC inhibited the proliferation, migration, and invasion, and promoted apoptosis and inhibition of inflammation of MH7A cell lines stimulated with TNF-α. The IBC might also have an increasing effect on the intracellular ROS and reducing effect on the mitochondrial membrane potential. The western blotting results indicated that IBC markedly inhibited the expression of p-PI3K, p-AKT, p-JAK1, p-STAT3 and SOCS3 proteins in TNF-α stimulated MH7A cells. Furthermore, we found that IBC also significantly reduced paw swelling and arthritis severity in CIA model rats through in vivo animal studies. CONCLUSIONS: In short, this study explored the effect of IBC by combining network pharmacology prediction with in vitro and in vivo experimentation. The results indicated that IBC exerts its anti-rheumatoid arthritis effect by regulating cell proliferation and survival via PI3K/AKT and JAK/STAT signaling pathways. This may open a new horizon and provide a theoretical foundation for further development and utilization of IBC in RA management.