Genus Physalis L.: A review of resources and cultivation, chemical composition, pharmacological effects and applications.

ETHNOPHARMACOLOGICAL RELEVANCE: The genus Physalis L. (Solanaceae) is commonly used in the treatment of dermatitis, leprosy, bronchitis, pneumonia, hepatitis and rheumatism in China and other Asian countries. AIM OF THE REVIEW: This article reviews the resources, cultivation, phytochemistry, pharmacological properties, and applications of Physalis L., and proposes further research strategies to enhance its therapeutic potential in treating various human diseases. MATERIALS AND METHODS: We conducted a systematic search of electronic databases, including CNKI, SciFinder and PubMed, using the term "Physalis L." to collect information on the resources, phytochemistry, pharmacological activities, and applications of Physalis L. in China during the past ten years (2013.1-2023.1). RESULTS: So far, a variety of chemical constituents have been isolated and identified from Physalis L. mainly including steroids, flavonoids, and so on. Various pharmacological activities were evaluated by studying different extracts of Physalis L., these activities include anti-inflammatory, antibacterial, antioxidant, antiviral, antineoplastic, and other aspects. CONCLUSION: Physalis L. occupies an important position in the traditional medical system. It is cost-effective and is a significant plant with therapeutic applications in modern medicine. However, further in-depth studies are needed to determine the medical use of this plant resources and cultivation, chemical composition, pharmacological effects and applications.

Anemarrhena asphodeloides Bunge total saponins ameliorate diabetic cardiomyopathy by modifying the PI3K/AKT/HIF-1α pathway to restore glycolytic metabolism.

ETHNOPHARMACOLOGICAL RELEVANCE: Based on the theory of traditional Chinese medicine (TCM), diabetic cardiomyopathy (DCM) belongs to the category of "Xiaoke disease" according to the symptoms, and "stasis-heat" is the main pathogenesis of DCM. The Chinese medicine Anemarrhena asphodeloides Bunge (AAB), as a representative of heat-clearing and engendering fluid, is often used clinically in the treatment of DCM. Anemarrhena asphodeloides Bunge total saponins (RATS) are the main bioactive components of AAB, the modern pharmacologic effects of RATS are anti-inflammatory, hypoglycemic, and cardioprotective. However, the potential protective mechanisms of RATS against DCM remain largely undiscovered. AIM OF THE STUDY: The primary goal of this study was to explore the effect of RATS on DCM and its mechanism of action. MATERIALS AND METHODS: Streptozotocin and a high-fat diet were used to induce DCM in rats. UHPLC/Q-TOF-MS was used to determine the chemical components of RATS. The degenerative alterations and apoptotic cells in the heart were assessed by HE staining and TUNEL. Network pharmacology was used to anticipate the probable targets and important pathways of RATS. The alterations in metabolites and main metabolic pathways in heart tissue were discovered using 1 H-NMR metabolomics. Ultimately, immunohistochemistry was used to find critical pathway protein expression. RESULTS: First of all, UHPLC/Q-TOF-MS analysis showed that RATS contained 11 active ingredients. In animal experiments, we found that RATS lowered blood glucose and lipid levels in DCM rats, and alleviated cardiac pathological damage, and decreased cardiomyocyte apoptosis. Furthermore, the study found that RATS effectively reduced inflammatory factor release and the level of oxidative stress. Mechanistically, RATS downregulated the expression levels of PI3K, AKT, HIF-1α, LDHA, and GLUT4 proteins. Additionally, glycolysis was discovered to be a crucial pathway for RATS in the therapy of DCM. CONCLUSIONS: Our findings suggest that the protective effect of RATS on DCM may be attributed to the inhibition of the PI3K/AKT/HIF-1α pathway and the correction of glycolytic metabolism.

Application of hyaluronic acid-based nanoparticles for cancer combination therapy.

Cancer is a significant public health problem in the world. The treatment methods include surgery, chemotherapy, phototherapy, and immunotherapy. Due to their respective limitations, the treatment effect is often unsatisfactory, laying hidden dangers for metastasis and recurrence. Since their exceptional biocompatibility and excellent targeting capabilities, hyaluronic acid-based biomaterials have generated great interest as drug delivery methods for tumor therapy. Moreover, modified HA can self-assemble into hydrogels or nanoparticles (NPs) for precise drug administration. This article summarizes the application of HA-based NPs in combination therapy. Ultimately, it is anticipated that this research will offer guidance for creating various HA-based NPs utilized in numerous cancer therapies.

Co2P nanowire arrays anchored on a 3D porous reduced graphene oxide matrix embedded in nickel foam for a high-efficiency hydrogen evolution reaction.

Regulating the structural and interfacial properties of transition metal phosphides (TMPs) by coupling carbon-based materials with large surface areas to enhance hydrogen evolution reaction (HER) performance presents significant progress for water splitting technology. Herein, we constructed a composite substrate of a three-dimensional porous graphene oxide matrix (3D-GO) embedded in nickel foam (NF) to grow a Co2P electrocatalyst. Well-defined gladiolus-like Co2P nanowire arrays tightly anchored on the substrate show enhanced electrochemical characteristics for the hydrogen evolution reaction (HER) based on the promoting roles of 3D porous reduced GO (3D-rGO) derived from 3D-GO, which promotes the dispersion of active components, improves the rate of electron transfer, and facilitates the transport of water molecules. As a result, the obtained Co2P@3D-rGO/NF electrode exhibits superior HER activity in 1.0 M KOH media, achieving overpotentials of 36.5 and 264.7 mV at current densities of 10 and 100 mA cm-2, respectively. The electrode also has a low Tafel slope of 55.5 mV dec-1, a large electrochemical surface area, and small charge-transfer resistance, further revealing its mechanism of high intrinsic activity. Moreover, the electrode exhibits excellent HER stability and durability without surface morphology and chemical state changes.

Advances in traditional Chinese medicine for the treatment of chronic obstructive pulmonary disease.

ETHNOPHARMACOLOGICAL RELEVANCE: Chronic obstructive pulmonary disease (COPD) is the third leading cause of death globally and thus imposes heavy economic burden on patients, their families, and society. Furthermore, COPD seriously affects the quality of life of patients. The concept of "overall regulation" of traditional Chinese medicine (TCM) plays an important role in the prevention and treatment of COPD. AIM OF THE STUDY: The objective of this review is to summarize the TCM theories, experimental methods, TCM extracts, active TCM ingredients, and TCM formulas for the treatment of COPD and reveal the effects and mechanisms of TCM treatments on COPD. MATERIALS AND METHODS: This article reviewed literature on TCM-based treatments for COPD reported from 2016 to 2021. Relevant scientific studies were obtained from databases that included PubMed, China National Knowledge Infrastructure, Web of Science, Google Scholar, The Plant List, ScienceDirect, and SciFinder. RESULTS: This review summarized TCM-based theory, experimental methods, active ingredients, and potential toxicities, the effects of TCM extracts and formulations, and their mechanisms for the treatment of COPD. Most investigators have used in vivo models of cigarette smoke combined with lipopolysaccharide induction in rats and in vitro models of cigarette smoke extract induction. The active ingredients of TCM used for the treatment of COPD in relevant studies were triterpenoids, flavonoids, phenolics, quinones, glycosides, and alkaloids. TCMs commonly used in the treatment of COPD include antipyretic drugs, tonic medicines, anticough medications, and asthma medications. TCM can treat COPD by suppressing inflammation, reducing oxidative stress, inhibiting apoptosis, and improving airway remodeling. CONCLUSIONS: This review enriches the theory of COPD treatments based on TCM, established the clinical significance and development prospects of TCM-based COPD treatments, and provided the necessary theoretical support for the further development of TCM resources for the treatment of COPD.

Inhibition of inflammasome activation via sphingolipid pathway in acute lung injury by Huanglian Jiedu decoction: An integrative pharmacology approach.

BACKGROUND: Acute lung injury (ALI) is a serious health issue which causes significant morbidity and mortality. Inflammation is an important factor in the pathogenesis of ALI. Even though ALI has been successfully managed using a traditiomal Chinese medicine (TCM), Huanglian Jiedu Decoction (HLD), its mechanism of action remains unknown. PURPOSE: This study explored the therapeutic potential of HLD in lipopolysaccharide (LPS)-induced ALI rats by utilizing integrative pharmacology. METHODS: Here, the therapeutic efficacy of HLD was evaluated using lung wet/dry weight ratio (W/D), myeloperoxide (MPO) activity, and levels of tumor necrosis factor (TNF-α), interleukin (IL)-1ß and IL-6. Network pharmacology predictd the active components of HLD in ALI. Lung tissues were subjected to perform Hematoxylin-eosin (H&E) staining, metabolomics, and transcriptomics. The acid ceramidase (ASAH1) inhibitor, carmofur, was employedto suppress the sphingolipid signaling pathway. RESULTS: HLD reduced pulmonary edema and vascular permeability, and suppressed the levels of TNF-α, IL-6, and IL-1ß in lung tissue, Bronchoalveolar lavage fluid (BALF), and serum. Network pharmacology combined with transcriptomics and metabolomics showed that sphingolipid signaling was the main regulatory pathway for HLD to ameliorate ALI, as confirmed by immunohistochemical analysis. Then, we reverse verified that the sphingolipid signaling pathway was the main pathway involed in ALI. Finally, berberine, baicalein, obacunone, and geniposide were docked with acid ceramidase to further explore the mechanisms of interaction between the compound and protein. CONCLUSION: HLD does have a better therapeutic effect on ALI, and its molecular mechanism is better elucidated from the whole, which is to balance lipid metabolism, energy metabolism and amino acid metabolism, and inhibit NLRP3 inflammasome activation by regulating the sphingolipid pathway. Therefore, HLD and its active components can be used to develop new therapies for ALI and provide a new model for exploring complex TCM systems for treating ALI.

Integrative pharmacology reveals the mechanisms of Erzhi Pill, a traditional Chinese formulation, against diabetic cardiomyopathy.

ETHNOPHARMACOLOGICAL RELEVANCE: Erzhi Pill (EZP) is a traditional Chinese prescription that has marked effects in treating type 2 diabetes mellitus and diabetic nephropathy. However, its underlying pharmacological mechanisms in the treatment of diabetic cardiomyopathy (DCM), remain to be elucidated. AIM OF THE STUDY: This study aimed to apply an integrative pharmacological strategy to systematically evaluate the pharmacological effects and molecular mechanisms of EZP, and provide a solid theoretical basis for the clinical application of EZP in the treatment of DCM. MATERIALS AND METHODS: In this study, the potential targets and key pathways of EZP were predicted and validated using network pharmacology and molecular docking, respectively. Changes in cardiac metabolites and major metabolic pathways in rat heart samples were examined using 1H-nuclear magnetic resonance (NMR) metabolomics. Finally, biochemical analysis was conducted to detect the protein expression levels of key pathways. RESULTS: We found that EZP decreased fasting blood glucose (FBG), triglycerides (TG), total cholesterol (TC), and low-density lipoprotein (LDL) levels, increased high-density lipoprotein (HDL) levels in the serum, and alleviated the morphological abnormalities of the heart tissue in diabetic rats. Furthermore, EZP effectively restored superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), caspase-3, caspase-8, and caspase-9 activity levels, as well as the levels of reactive oxygen species (ROS), malondialdehyde (MDA), B-cell lymphoma (Bcl)-2, and Bcl-2-associated X protein (Bax) in the heart tissue. Network pharmacology prediction results indicated that the mechanism of EZP in treating DCM was closely related to apoptosis, oxidative stress, and the HIF-1, PI3K-Akt, and FoxO signaling pathways. In addition, 1H-NMR metabolomics confirmed that EZP primarily regulated both energy metabolism and amino acid metabolism, including the tricarboxylic acid (TCA) cycle, ketone bodies metabolism, glutamine and glutamate metabolism, glycine metabolism, and purine metabolism. Finally, immunohistochemistry results indicated that EZP reduced the expression levels of p-AMPK, p-PI3K, p-Akt, and p-FoxO3a proteins, in the heart tissue of DCM rats. CONCLUSION: The results confirmed that the overall therapeutic effect of EZP in the DCM rat model is exerted via inhibition of oxidative stress and apoptosis, alongside the regulation of energy metabolism and amino acid metabolism, as well as the AMPK and PI3K/Akt/FoxO3a signaling pathways. This study provides an experimental basis for the use of EZP in DCM treatment.

Helios but not CD226, TIGIT and Foxp3 is a Potential Marker for CD4+ Treg Cells in Patients with Rheumatoid Arthritis.

BACKGROUND/AIMS: Rheumatoid arthritis (RA) is a progressive, chronic, even disabling systemic autoimmune disease. Imbalance between pathogenic immune cells and immunosuppressive cells is associated with the pathogenesis and development of RA and other autoimmune diseases. As Foxp3 is also expressed on activated CD4+ cells in the presence of inflammation, the identification of Treg cells in patients with RA remains a challenge. METHODS: Comprehensive analyses were carried out by Flow cytometry. Expression of Helios, CD226, T cell immunoreceptor with Ig and ITIM domains clinical samples and healthy controls. RESULTS: We have systemically examined three potential markers, Helios, CD226 and TIGIT, that are possibly related to Treg identification, and found that Helios expression on CD4+Foxp3+cells was decreased and negatively correlated with the disease activity of RA patients, while CD226 and TIGIT both showed elevated expression levels in CD4+Foxp3+cells in RA patients and they were not associated with disease activity of RA patients. CONCLUSION: Taken together, our findings indicate that CD4+CD25hiCD127low/-Foxp3+Helios+ may represent the real Treg cell population in patients with RA.

Dihydropyrazothiazole derivatives as potential MMP-2/MMP-8 inhibitors for cancer therapy.

MMP-2/MMP-8 is established as one of the most important metalloenzymes for targeting cancer. A series of dihydropyrazothiazole derivatives (E1-E18) bearing a salicylaldehyde group linked to Pyrazole ring were designed, synthesized, and evaluated for their pharmacological activity as MMP-2/MMP-8 inhibitors. Among them, compound E17 exhibited most potent inhibitory activity (IC50 = 2.80 µM for MMP-2 and IC50 = 5.6 µM for MMP-8), compared to the positive drug CMT-1 (IC50 = 1.29 µM). Compounds (E1-E18) were scrutinized by CoMFA and CoMSIA techniques of Three-dimensional quant. structure-activity relationship (3D-QSAR), as well as a docking simulation. Moreover, treatment with compound E4 could induce MCF-7 cell apoptosis. Overall, the biological profile of E1-E18 may provide a research basis for the development of new agents against cancer.

Pharmacodynamic and pharmacokinetic characteristics of YMR-65, a tubulin inhibitor, in tumor-bearing mice.

YMR-65​, 5-(5-bromo-1-methyl-1H-indol-3-yl)-3-(3-methoxyphenyl)-4, 5-dihydro-1H-pyrazole-1-carboxamide, is a potential tubulin inhibitor exhibiting good anticancer activity. In our study, we illustrated the biological activities in HepG2 cells and the pharmacodynamic and pharmacokinetic profiles were evaluated in murine H22 hepatoma-bearing mice. Molecular docking assay and colchicine competition assay indicated that YMR-65 could bind tightly to the colchicine binding site of tubulin. Further investigation demonstrated that YMR-65 arrested cells in the G2/M phase of cell cycle and induced apoptosis in HepG2 cells. Compared with control group, the tumor growth inhibition determined by final relative volume of tumor/the initial tumor volume were 32.57%, 24.00% and 34.95%, respectively, for YMR-65 (10 mg/kg), YMR-65 (20 mg/kg) and CA4P (10 m/kg) groups. Besides there were no obvious body change or tissue damage (enhanced by histopathology study). YMR-65 administration at 10 and 20 mg/kg in H22 tumor-bearing mice resulted in 1.87- and 1.80-fold longer half time (t1/2) and 0.36- and 0.78-fold lower area under concentration-time curve (AUC0-∞) in plasma in contrast with normal mice at 10 mg/kg. Furthermore, YMR-65 showed a wide distribution to various tissues or tumor and the highest distribution index (the ratio of AUCtissue or tumor/AUCplasma) was found in tumor, which implied that it might accumulate in tumor after administration. In brief, our results indicated that YMR-65 was a promising candidate with high antitumor efficacy and low tissue damage.

uPAR promotes tumor-like biologic behaviors of fibroblast-like synoviocytes through PI3K/Akt signaling pathway in patients with rheumatoid arthritis.

Urokinase-type plasminogen activator receptor (uPAR), is a multifunctional receptor on cell surface, widely present in endothelial cells, fibroblasts, and a variety of malignant cells. Current studies have suggested that uPAR overexpressed on synovial tissues or in synovial fluid or plasma in patients with rheumatoid arthritis (RA). However, there are limited researches regarding the role of uPAR on fibroblast-like synoviocytes of rheumatoid arthritis (RA-FLSs) and its underlying mechanisms. Here, our studies show that the expression of uPAR protein was significantly higher in fibroblast-like synoviocytes (FLSs) from RA than those from osteoarthritis or traumatic injury patients. uPAR gene silencing significantly inhibited RA-FLSs cell proliferation, restrained cell transformation from the G0/G1 phase to S phase, aggravated cell apoptosis, interfered with RA-FLSs cell migration and invasion, and reduced activation of the PI3K/Akt signaling pathway, which may be associated with ß1-integrin. Cell supernatants from uPAR gene-silenced RA-FLSs markedly inhibited the migration and tubule formation ability of the HUVECs (a human endothelial cell line). Therefore, we demonstrate that uPAR changes the biological characteristics of RA-FLSs, and affects neoangiogenesis of synovial tissues in patients with RA. All of these may be associated with the ß1-integrin/PI3K/Akt signaling pathway. These results imply that targeting uPAR and its downstream signal pathway may provide therapeutic effects in RA.

Synthesis and Biological Evaluation of 1-Methyl-1H-indole-Pyrazoline Hybrids as Potential Tubulin Polymerization Inhibitors.

A series of 1-methyl-1H-indole-pyrazoline hybrids were designed, synthesized, and biologically evaluated as potential tubulin polymerization inhibitors. Among them, compound e19 [5-(5-bromo-1-methyl-1H-indol-3-yl)-3-(3,4,5-trimethoxyphenyl)-4,5-dihydro-1H-pyrazole-1-carboxamide] showed the most potent inhibitory effect on tubulin assembly (IC50 =2.12 µm) and in vitro growth inhibitory activity against a panel of four human cancer cell lines (IC50 values of 0.21-0.31 µm). Further studies confirmed that compound e19 can induce HeLa cell apoptosis, cause cell-cycle arrest in G2 /M phase, and disrupt the cellular microtubule network. These studies, along with molecular docking and 3D-QSAR modeling, provide an important basis for further optimization of compound e19 as a potential anticancer agent.

Design, synthesis and biological evaluation of pyrazolyl-nitroimidazole derivatives as potential EGFR/HER-2 kinase inhibitors.

A series of novel pyrazole-nitroimidazole derivatives had been arranged and evaluated for their EGFR/HER-2 tyrosine kinase inhibitory activity as well as their antiproliferative properties on four kinds of cancer cell lines (MCF-7, Hela, HepG2, B16-F10). The bioassay results showed most of the designed compounds exhibited potential antiproliferation activity, with the IC50 values ranging from 0.13µM to 128.06µM in four tumor cell lines. Among them, compound 5c exhibited remarkable inhibitory activity against EGFR/HER-2 tyrosine kinase with IC50 value of 0.26µM/0.51µM, respectively, comparable to the positive control erlotinib (IC50=0.41µM for HER-2 and IC50=0.20µM for EGFR) and lapatinib (IC50=0.54µM for HER-2 and IC50=0.28µM for EGFR). Molecular modeling simulation studies were performed in order to predict the biological activity of the proposed compounds and activity relationship (SAR) of these pyrazole-nitroimidazole derivatives.

Design, synthesis and biological evaluation of novel pyrazoline-containing derivatives as potential tubulin assembling inhibitors.

A series of novel pyrazoline-containing derivatives (15-47) has been designed, synthesized and evaluated for their biological activities. Among them, compound 18 displayed the most potent antiproliferative activity against A549, MCF-7 and HepG-2 cells line (IC50 = 0.07 µM, 0.05 µM, 0.03 µM, respectively) and the tubulin polymerization inhibitory activity (IC50 = 1.88 µM), being comparable to CA-4. Furthermore, we also tested that compound 18 was a potent inducer of apoptosis in HepG-2 cells and it had cellular effects typical for microtubule interacting agents, causing accumulation of cells in the G2/M phase of the cell cycle. These studies, along with molecular docking, provided a new molecular scaffold for the further development of antitumor agents that target tubulin.

Synthesis, biological evaluation and molecular modeling of 1,3,4-thiadiazol-2-amide derivatives as novel antitubulin agents.

A series of 1,3,4-thiadiazol-2-amide derivatives (6a-w) were designed and synthesized as potential inhibitors of tubulin polymerization and as anticancer agents. The in vitro anticancer activities of these compounds were evaluated against three cancer cell lines by the MTT method. Among all the designed compounds, compound 6f exhibited the most potent anticancer activity against A549, MCF-7 and HepG2 cancer cell lines with IC50 values of 0.03 µM, 0.06 µM and 0.05 µM, respectively. Compound 6f also exhibited significant tubulin polymerization inhibitory activity (IC50=1.73 µM), which was superior to the positive control. The obtained results, along with a 3D-QSAR study and molecular docking that were used for investigating the probable binding mode, could provide an important basis for further optimization of compound 6f as a novel anticancer agent.