Diosgenin protects against cationic bovine serum albumin-induced membranous glomerulonephritis by attenuating oxidative stress and renal inflammation via the NF-κB pathway.

CONTEXT: Membranous glomerulonephritis (MGN) is a leading cause of nephrotic syndrome in adults. Diosgenin (DG) has been reported to exert antioxidative and anti-inflammatory effects. OBJECTIVE: To investigate the renoprotective activity of DG in a cationic bovine serum albumin-induced rat model of MGN. MATERIALS AND METHODS: Fourty male Sprague-Dawley rats were randomized into four groups. The MGN model was established and treated with a DG dose (10 mg/kg) and a positive control (TPCA1, 10 mg/kg), while normal control and MGN groups received distilled water by gavage for four consecutive weeks. At the end of the experiment, 24 h urinary protein, biochemical indices, oxidation and antioxidant levels, inflammatory parameters, histopathological examination, immunohistochemistry and immunoblotting were evaluated. RESULTS: DG significantly ameliorated kidney dysfunction by decreasing urinary protein (0.56-fold), serum creatinine (SCr) (0.78-fold), BUN (0.71-fold), TC (0.66-fold) and TG (0.73-fold) levels, and increasing ALB (1.44-fold). DG also reduced MDA (0.82-fold) and NO (0.83-fold) levels while increasing the activity of SOD (1.56-fold), CAT (1.25-fold), glutathione peroxidase (GPx) (1.55-fold) and GSH (1.81-fold). Furthermore, DG reduced Keap1 (0.76-fold) expression, Nrf2 nuclear translocation (0.79-fold), and induced NQO1 (1.25-fold) and HO-1 (1.46-fold) expression. Additionally, DG decreased IL-2 (0.55-fold), TNF-α (0.80-fold) and IL-6 (0.75-fold) levels, and reduced protein expression of NF-κB p65 (0.80-fold), IKKß (0.93-fold), p-IKKß (0.89-fold), ICAM-1 (0.88-fold), VCAM-1 (0.91-fold), MCP-1 (0.88-fold) and E-selectin (0.87-fold), and also inhibited the nuclear translocation of NF-κB p65 (0.64-fold). DISCUSSION AND CONCLUSIONS: The results suggest a potential therapeutic benefit of DG against MGN due to the inhibition of the NF-κB pathway, supporting the need for further clinical trials.

Ginseng fermentation solution affects the gut microbiota in zebrafish with alcoholic liver disease via PI3K/Akt pathway.

BACKGROUND: Ginsenosides have received increased amounts of attention due to their ability to modulate the intestinal flora, which may subsequently alleviate alcoholic liver disease (ALD). The effects of ginseng fermentation solution (GFS) on the gut microbiota and metabolism in ALD patients have not been explored. PURPOSE: This research aimed to explore the regulatory effect of GFS on ALD both in vitro and in vivo. METHOD: This study assessed the anti-ALD efficacy of GFS using an LO2 cell model and a zebrafish model. Untargeted metabolomics was used for differentially abundant metabolite analysis, and high-throughput 16S rRNA sequencing was used to examine the effect of GFS on ALD. RESULTS: The LO2 cell line experiments demonstrated that GFS effectively mitigated alcohol-induced oxidative stress and reduced apoptosis by upregulating PI3K and Bcl-2 expression and decreasing the levels of malondialdehyde, total cholesterol, and triglycerides. In zebrafish, GFS improved morphological and physiological parameters and diminished oxidative stress-induced ALD. Meanwhile, the results from Western blotting indicated that GFS enhanced the expression of PI3K, Akt, and Bcl-2 proteins while reducing Bax protein expression, thereby ameliorating the ALD model in zebrafish. Metabolomics data revealed significant changes in a total of 46 potential biomarkers. Among them, metabolites such as prostaglandin F2 alpha belong to arachidonic acid metabolism. In addition, GFS also partly reversed the imbalance of gut microbiota composition caused by alcohol. At the genus level, alcohol consumption elevated the presence of Flectobacillus, Curvibacter, among others, and diminished Elizabethkingia within the intestinal microbes of zebrafish. Conversely, GFS reversed these effects, notably enhancing the abundance of Proteobacteria and Archaea. Correlation analyses further indicated a significant negative correlation between prostaglandin F2 alpha, 11,14,15-THETA, Taurocholic acid and Curvibacter. CONCLUSION: This study highlights a novel mechanism by which GFS modulates anti-ALD activity through the PI3K/Akt signalling pathway by influencing the intestinal flora-metabolite axis. These results indicate the potential of GFS as a functional food for ALD treatment via modulation of the gut flora.

Kaempferol inhibits colorectal cancer metastasis through circ_0000345 mediated JMJD2C/ß-catenin signalling pathway.

BACKGROUND: Recurrence and metastasis are the main causes of disease deterioration in colorectal cancer (CRC) patients, yet efficient therapeutic strategies are lacking. Natural compounds for efficient antitumour therapeutics are becoming increasingly prominent. Kaempferol, one of the main components of flavonoids in plants, displays a variety of pharmacological activities. Our preliminary experiments suggested that kaempferol could inhibit CRC metastasis and is significantly associated with the ß-catenin signalling pathway. Moreover, we also defined the regulatory roles of JMJD2C in ß-catenin signalling in our previous work. PURPOSE: This study aims to reveal the mechanism by which kaempferol inhibits CRC progression and regulates the JMJD2C/ß-catenin signalling pathway. METHODS: The migratory capabilities of CRC cells after kaempferol intervention were measured by scratch wound healing and transwell assays. Circ_0000345 knockdown CRC stable cell lines were generated by lentivirus infection. The possible mechanism of kaempferol on circ_0000345 was verified by molecular-protein docking and verification program cellular thermal shift assay (CETSA). A dual luciferase reporter gene assay was carried out for the targeting relationship among circ_0000345, miR-205-5p and JMJD2C. Fluorescence in situ hybridization (FISH) was performed to determine the expression of circ_0000345 in tumour tissues. A pulmonary metastatic model of CRC in vitro was built to assess the antimetastatic effect and mechanism of kaempferol in vivo. RESULTS: In vitro, kaempferol inhibits the ability to migrate of CRC cells by reducing the activation of the JMJD2C/ß-catenin signalling pathway. MiR-205-5p is a key bridge for kaempferol to inhibit the expression of JMJD2C. The function of miR-205-5p is impeded by circ_0000345, which shows higher expression levels in human metastatic CRC tissues than nonmetastatic CRC tissues, and its formation is regulated by the RNA-binding proteins HNRNPK and HNRNPL. Mechanistically, kaempferol physically interacts with HNRNPK and HNRNPL to suppress JMJD2C by downregulating the expression of circ_0000345. In vivo, kaempferol suppresses CRC lung metastasis. Kaempferol inhibits the activation of JMJD2C/ß-catenin signalling through reducing the expression of circ_0000345 in the CRC lung metastasis model. CONCLUSION: Circ_0000345 enhances activation of the JMJD2C/ß-catenin signalling pathway through miR-205-5p to promote CRC metastasis. Kaempferol inhibits CRC metastasis through the circ_0000345-mediated JMJD2C/ß-catenin signalling pathway, and this effect is influenced as a direct consequence of the binding of kaempferol with HNRNPK and HNRNPL. This provides promising therapeutic and/or adjuvant agents for advanced CRC and sheds light on the multifaceted role of phytomedicine in cancer.

Film-forming polymer solutions containing cholesterol myristate and berberine mediate pressure ulcer repair via the Wnt/ß-catenin pathway.

Pressure ulcer (PU) is a worldwide problem that is difficult to address because of the related inflammatory response, local hypoxia, and repeated ischaemia/reperfusion, causing great suffering and financial burden to patients. Traditional Chinese medicine turtle plate powder can treat skin trauma, but its composition is complex and inconvenient to use. Here, we combined cholesterol myristate (S8) with berberine (BBR), with anti-inflammatory and antibacterial effects, as a drug and used hydroxypropyl methylcellulose and polyvinylpyrrolidone K30 as carriers to construct a novel film-forming polymeric solution (S8 + BBR FFPS), comprehensively study its reparative effect on PU and explore the potential mechanism in rat PU models. The results showed that S8 + BBR FFPS inhibits excessive inflammatory response, promotes re-epithelialization, and promotes hair follicle growth during the healing process of PU, which may be related to the activation of the Wnt/ß-catenin signalling pathway by S8 + BBR FFPS to mediate hair follicle stem cell proliferation and maintain skin homeostasis. Therefore, S8 + BBR FFPS may be a potential candidate for the treatment of chronic skin injury, and its association with the Wnt/ß-catenin signalling pathway may provide new ideas to guide the design of biomaterial-based wound dressings for chronic wound repair.

Gualou-Xiebai herb pair ameliorate atherosclerosis in HFD-induced ApoE-/- mice and inhibit the ox-LDL-induced injury of HUVECs by regulating the Nrf2-mediated ferroptosis.

ETHNOPHARMACOLOGICAL RELEVANCE: Atherosclerosis (AS) is a chronic vascular ailment characterized by inflammatory and lipid deposition in the arterial wall caused by endothelial injury. Ferroptosis is a novel type of cell death, and endothelial ferroptosis is a significant contributor to the progression of AS. Gualou-Xiebai (GLXB) is a renowned Chinese herb pair that serves a crucial function in treating AS. However, whether the underlying mechanism of GLXB plays a role in anti-atherosclerotic effects by inhibiting ferroptosis in endothelial cells has not been determined. AIM OF THE STUDY: To explore the influence of GLXB on endothelial ferroptosis and determine its underlying mechanism of action in AS. MATERIALS AND METHODS: In ApoE-/- mice, ultrasound was performed in mice fed a high-fat diet (HFD) for 12 weeks to assess the success of AS establishment. Then, ApoE-/- mice were treated with GLXB and Simvastatin (positive control) for 4 weeks. The effects of GLXB on AS pathology were assessed through aorta imaging and hematoxylin-eosin (HE) staining. To confirm the presence of ferroptosis, mitochondrial damage was observed using transmission electron microscope (TEM), along with analysis of free iron and lipid peroxidation levels. In vitro: ox-LDL-induced human vascular endothelial cells (HUVECs) injury and treated with GLXB, the ferroptosis inducer Erastin and an Nrf2 inhibitor ML385. Cell viability was evaluated using the CCK-8 assay in all groups. Flow cytometry was employed to detect lipid peroxidation and intracellular ferrous iron levels. Immunofluorescence staining microscopy verified Nrf2 nuclear translocation. Protein expression were measured by Western blot analysis. RESULTS: GLXB improved atherosclerotic aortic lesions and vascular plaques. GLXB inhibited endothelial injury in the aorta by decreasing the levels of inflammatory factors and adhesion factors, and by decreasing the shedding of endothelial cells. GLXB suppressed ferroptosis in ApoE-/- mice by attenuating mitochondrial damage in ECs, increasing the levels of glutathione (GSH) and superoxide dismutase (SOD) in aortic tissues and down-regulating the levels of levels of lipid peroxide (LPO) and malondialdehyde (MDA). Interestingly, Erastin was used to demonstrate in vitro that GLXB inhibition of ferroptosis attenuated ox-LDL-induced injuring effects on HUVECs that were reversed by Erastin. Mechanistically, GLXB activates the Nrf2 signaling pathway to inhibit ferroptosis by increasing downstream anti-ferroptosis target proteins and promoting the interaction between Nrf2 and SLC7A11. More convincingly, ML385 (Nrf2 inhibitor) reversed the anti-ferroptosis effect of GLXB. CONCLUSION: GLXB inhibits ferroptosis-mediated endothelial cell injury via activating the Nrf2 signaling pathway and further alleviates AS pathological damage.

Artesunate improves glucose and lipid metabolism in db/db mice by regulating the metabolic profile and the MAPK/PI3K/Akt signalling pathway.

BACKGROUND: Diabetes is a metabolic disorder characterized by chronic hyperglycaemia. Chronic metabolic abnormalities and long-term hyperglycaemia may result in a wide range of acute and chronic consequences. Previous studies have demonstrated that artesunate(ART) has antidiabetic, anti-inflammatory, antiatherosclerotic, and other beneficial effects, but the specific regulatory mechanism is not completely clear. AIM: This study investigated the effects of ART on metabolic disorders in type 2 diabetes mellitus (T2DM) model db/db mice and explored the underlying mechanisms involved. METHODS: C57BL/KsJ-db/db mice were used to identify the targets and molecular mechanism of ART. Metabolomic methods were used to evaluate the efficacy of ART in improving T2DM-related metabolic disorders. Network pharmacology and transcriptomic sequencing were used to analyse the targets and pathways of ART in T2DM. Finally, molecular biology experiments were performed to verify the key targets and pathways selected by network pharmacology and transcriptomic analyses. RESULTS: After a 7-week ART intervention (160 mg/kg), the glucose and lipid metabolism levels of the db/db mice improved. Additionally, the oxidative stress indices, namely, the MDA and SOD levels, significantly improved (p<0.01). Linoleic acid and glycerophospholipid metabolism, amino acid metabolism, bile acid synthesis, and purine metabolism disorders in db/db mice were partially corrected after ART treatment. Network pharmacology analysis identified important targets of ART for the treatment of metabolic disorders in T2DM . These targets are involved in key signalling pathways, including the highest scores observed for the PI3K/Akt signalling pathway. Transcriptomic analysis revealed that ART could activate the MAPK signalling pathway and two key gene targets, HGK and GADD45. Immunoblotting revealed that ART increases p-PI3K, p-AKT, Glut2, and IRS1 protein expression and suppresses the phosphorylation of p38, ERK1/2, and JNK, returning HGK and GADD45 to their preartesunate levels. CONCLUSION: Treatment of db/db mice with 160 mg/kg ART for 7 weeks significantly reduced fasting blood glucose and lipid levels. It also improved metabolic imbalances in amino acids, lipids, purines, and bile acids, thereby improving metabolic disorders. These effects are achieved by activating the PI3K/AKT pathway and inhibiting the MAPK pathway, thus demonstrating the efficacy of the drug.

Triptolide promotes nerve repair after cerebral ischemia reperfusion injury by regulating the NogoA/NgR/ROCK pathway.

Activation of the NogoA/NgR/ROCK pathway limits nerve repair after brain ischemia-reperfusion (I/R) injury. Triptolide displays anti-inflammatory, anti-oxidant, and immunosuppressive effects and is derived from the traditional Chinese medicine Tripterygium wilfordii Hook F. This agent can also penetrate the blood-brain barrier, where it has a neuroprotective effect and ameliorates cerebral I/R injury via an as yet unknown mechanism(s). Here, an animal model of middle cerebral artery occlusion and reperfusion (MCAO/R) was employed to assess triptolide's therapeutic impact on brain I/R injury and the possible mechanism of action. The results indicate that triptolide treatment can decrease cerebral infarction and nerve injury after cerebral I/R injury. Importantly, in vivo and in vitro experiments revealed that treatment with triptolide decreased NogoA, NgR, p75NTR and ROCK2 expression, and upregulated the expression of GAP43 and PSD-95, thus suggesting improved synaptic function. These results indicate that triptolide can promote nerve repair following brain I/R injury by inhibiting NogoA/NgR/ROCK signalling.

Extraction, rapid preparation and neuroprotective effect of texasin, a main active constituent from Caragana jubata (Pall.) Poir.

Searching for new anti-ischemic stroke (anti-IS) drugs has always been a hot topic in the pharmaceutical industry. Natural products are an important source of discovering anti-IS drugs. The aim of the present study is to extract, rapidly prepare and explore the neuroprotective effect of texasin, a main active constituent from Caragana jubata (Pall.) Poir., which is a kind of Tibetan medicine with a clear anti-IS effect. The results showed that 95% ethanol was the optimal extraction solvent. A three-step rapid preparation method for texasin was successfully established, with a purity of 99.2%. Texasin at the concentration of 25-100 µM had no effect on the viability of normal cultured PC12 cells; 12.5 and 25 µM texasin could enhance the viability of PC12 cells damaged by oxygen and glucose deprivation/reoxygenation (OGD/R), and their effects are comparable to the positive drug edaravone at the concentration of 50 µM. Compared with the normal group, the expression of Bcl-2 protein in OGD/R-injured PC12 cells was downregulated (p < 0.01), and that of PERK, eIF2α, ATF4, CHOP, Bax and Cleaved caspase-3 proteins were upregulated (p < 0.01, p < 0.001). Compared with the OGD/R group, 25 µM texasin could upregulate the expression of Bcl-2 protein (p < 0.01), and downregulate that of PERK, eIF2α, ATF4, CHOP, Bax and Cleaved caspase-3 proteins (p < 0.01, p < 0.001). The 7-OH and 1-O of texasin formed H-bonds with residues Cys891 of the hinge ß-strand of PERK, which is crucial for kinase inhibitors. The above results suggest that the method established in the present study achieved rapid preparation of high-purity texasin. Texasin might inhibit neuronal apoptosis via the regulation of endoplasmic reticulum stress PERK/eIF2α/ATF4/CHOP signalling pathway to exert a protective effect on OGD/R-injured PC12 cells. Aiding by molecular docking, texasin was assumed to be a potential PERK inhibitor.

Substance basis and pharmacological mechanism of heat-clearing herbs in the treatment of ischaemic encephalopathy: a systematic review and network pharmacology.

BACKGROUND AND OBJECTIVE: Ischaemic encephalopathy is a common cerebrovascular disease caused by insufficient blood supply to the cerebral vessels. The ischaemic encephalopathy is closely associated with the development of many chronic diseases such as obesity, hypertension and diabetes. Neurotrophic therapy has become the main therapeutic strategy for ischaemic encephalopathy. However, neurotrophic drugs only slightly recover the neurological function of patients, and their long-term efficacy is uncertain. Previous reports revealed that the active ingredients of natural medicines play important roles in the treatment of cerebral ischemia. In this study, we reviewed clearing herbs with anti-ischaemic encephalopathy functions using the data from quantitative statistical and network pharmacological exploration methods. We also discussed the different bioactive components and pharmacological effects of these herbs. METHODS: First, we collected Chinese herbal prescriptions against ischaemic encephalopathy in four databases. Then, we statistically analysed the frequency of application of heat-clearing herbs to obtain the commonly used heat-clearing herbs against ischaemic encephalopathy, and classified them according to their efficacy according to the statistical results, to summarize the mechanism of anti-ischaemic effects of different bioactive components; Second, the network database was used to obtain the above components of heat-clearing Chinese medicines and their corresponding targets of action, disease targets of ischaemic stroke; Venny 2.1.0 was used to obtain component-disease target intersections; Cytoscape was used to construct the 'Drug-Active Ingredient-Target Network Graph '; DAVID was used for GO and KEGG enrichment analysis. RESULTS: Literature and database screening involved 149 prescriptions, with a total of 269 flavours of Chinese medicines and 20 flavours of single-flavour heat-clearing Chinese medicines; The top nine in terms of frequency of use were Radix Paeoniae Rubra、Rehmanniae Radix Praeparata、Figwort Root、Cortex Moutan、Scutellariae Radix、Coptidis Rhizoma、Gardeniae Fructus、Cassiae Semen、Lonicerae Japonicae Flos. The common components obtained from network pharmacology were beta-sitosterol, quercetin, and stigmasterol, which mainly act on key targets such as RELA, AKT1, JUN, PRKACA, PTGS2, RAF1 and CHUK; and their active ingredients are mainly involved in signalling pathways such as Calcium, PI3K-Ak, MAPK, cAMP, IL-17, HIF-1, TNF, T-cell receptor, NF-kappa B and JAK-STAT. CONCLUSIONS: Heat-clearing herbs are useful and promising for the protection against and prevention of ischemic encephalopathy. The results of the network pharmacological studies are similar to the mechanisms of anti-ischemic encephalopathy of the active ingredients of the purgative herbs we have listed; Thin either directly protects cerebrovascular tissues by improving vascular permeability and reducing the area of infarcted tissues, or produces protective effects through molecular signaling pathways. It can be seen that the components of heat-clearing Chinese medicines can exert cerebroprotective effects through multiple pathways, which provides us with a reference for further development and study of heat-clearing Chinese medicines in the treatment of ischemic cerebrovascular diseases.

Essential oil from Fructus Alpiniae zerumbet ameliorates vascular endothelial cell senescence in diabetes by regulating PPAR-γ signalling: A 4D label-free quantitative proteomics and network pharmacology study.

ETHNOPHARMACOLOGICAL RELEVANCE: Vascular endothelial cell senescence is associated with cardiovascular complications in diabetes. Essential oil from Fructus Alpiniae zerumbet (Pers.) B.L.Burtt & R.M.Sm. (EOFAZ) has potentially beneficial and promising diabetes-related vascular endothelial cell senescence-mitigating effects; however, the underlying molecular mechanisms remain unclear. AIM OF THE STUDY: To investigate the molecular effects of EOFAZ on vascular endothelial cell senescence in diabetes. MATERIALS AND METHODS: A diabetes mouse model was developed using a high-fat and high-glucose diet (HFD) combined with intraperitoneal injection of low-dose streptozotocin (STZ, 30 mg/kg) and oral treatment with EOFAZ. 4D label-free quantitative proteomics, network pharmacology, and molecular docking techniques were employed to explore the molecular mechanisms via which EOFAZ alleviates diabetes-related vascular endothelial cell senescence. A human aortic endothelial cells (HAECs) senescence model was developed using high palmitic acid and high glucose (PA/HG) concentrations in vitro. Western blotting, immunofluorescence, SA-ß-galactosidase staining, cell cycle, reactive oxygen species (ROS), cell migration, and enzyme linked immunosorbent assays were performed to determine the protective role of EOFAZ against vascular endothelial cell senescence in diabetes. Moreover, the PPAR-γ agonist rosiglitazone, inhibitor GW9662, and siRNA were used to verify the underlying mechanism by which EOFAZ combats vascular endothelial cell senescence in diabetes. RESULTS: EOFAZ treatment ameliorated abnormal lipid metabolism, vascular histopathological damage, and vascular endothelial aging in diabetic mice. Proteomics and network pharmacology analysis revealed that the differentially expressed proteins (DEPs) and drug-disease targets were associated with the peroxisome proliferator-activated receptor gamma (PPAR-γ) signalling pathway, a key player in vascular endothelial cell senescence. Molecular docking indicated that the small-molecule compounds in EOFAZ had a high affinity for the PPAR-γ protein. Western blotting and immunofluorescence analyses confirmed the significance of DEPs and the involvement of the PPAR-γ signalling pathway. In vitro, EOFAZ and rosiglitazone treatment reversed the effects of PA/HG on the number of senescent endothelial cells, expression of senescence-related proteins, the proportion of cells in the G0/G1 phase, ROS levels, cell migration rate, and expression of pro-inflammatory factors. The protective effects of EOFAZ against vascular endothelial cell senescence in diabetes were aborted following treatment with GW9662 or PPAR-γ siRNA. CONCLUSIONS: EOFAZ ameliorates vascular endothelial cell senescence in diabetes by activating PPAR-γ signalling. The results of the present study highlight the potential beneficial and promising therapeutic effects of EOFAZ and provide a basis for its clinical application in diabetes-related vascular endothelial cell senescence.

Mechanisms of Traditional Chinese medicine/natural medicine in HR-positive Breast Cancer: A comprehensive Literature Review.

ETHNOPHARMACOLOGICAL RELEVANCE: With the emergence of endocrine resistance, the survival and good prognosis of HR-positive breast cancer (HR + BC) patients are threatened. As a common complementary and alternative therapy in cancer treatment, traditional Chinese medicine (TCM) has been widely used, and its internal mechanisms have been increasingly explored. AIM OF THE REVIEW: In this review, the development status and achievements in understanding of the mechanisms related to the anti-invasion and anti-metastasis effects of TCM against HR + BC and the reversal of endocrine drug resistance by TCM in recent years have been summarized to provide ideas for antitumour research on the active components of TCM/natural medicine. METHODS: We searched the electronic databases PubMed, Web of Science, and China National Knowledge Infrastructure database (CNKI) (from inception to July 2023) with the key words "HR-positive breast cancer" or "HR-positive breast carcinoma", "HR + BC" and "traditional Chinese medicine", "TCM", or "natural plant", "herb", etc., with the aim of elucidating the intrinsic mechanisms of traditional Chinese medicine and natural medicine in the treatment of HR + BC. RESULTS: TCM/natural medicine monomers and formulas can regulate the expression of related genes and proteins through the PI3K/AKT, JAK2/STAT3, MAPK, Wnt and other signalling pathways, inhibit the proliferation and metastasis of HR + BC tumours, play a synergistic role in combination with endocrine drugs, and reverse endocrine drug resistance. CONCLUSION: The wide variety of TCM/natural medicine components makes the research and development of new methods of TCM for BC treatments more selective and innovative. Although progress has been made on research on TCM/natural medicine, there are still many problems in clinical and basic experimental designs, and more in-depth scientific explorations and research are still needed.

Protective Role of Myricetin and Fisetin Against Nephrotoxicity Caused by Lead Acetate Exposure through Up-regulation of Nrf2/HO-1 Signalling Pathway.

The effect of various flavonoids against oxidative stress and inflammation caused by lead exposure has been investigated. However, the protective effects of myricetin (MYC) and fisetin (FST), which are known to have potent antioxidant properties, against nephrotoxicity caused by exposure to lead acetate (LA), the water-soluble form of lead, have not been investigated. Our study investigated the protective role of these flavonoids against LA intoxication-induced nephrotoxicity. In our study, 42 male rats were used. The rats were randomly selected and divided into 6 groups. These groups were: control, LA (100 g/kg), LA + MYC (100 mg/kg), LA + MYC (200 mg/kg), LA + FST (100 mg/kg) and LA + FST (200 mg/kg). All chemicals were administered daily by gavage for 28 days. According to the experimental protocol, the animals were sacrificed and their kidney tissues were isolated. Serum biochemical parameters, histological examinations, levels of several trace elements, oxidative stress and inflammatory parameters at both biochemical and molecular levels in kidney tissues were examined. After LA administration, tissue lead levels increased and zinc levels decreased. This situation was reversed by MYC and FST treatment. Oxidative stress and inflammatory response were increased in the kidney tissue of LA-treated rats and renal function was impaired. It was observed that both doses of MYC and high dose of FST could prevent nephrotoxicity. Oral administration of both doses of MYC and high dose FST ameliorated the changes in biochemical, oxidative and inflammatory parameters. Restoration of normal renal tissue architecture was also demonstrated by histological studies. MYC and FST were found to have promising biological activity against LA-induced nephrotoxicity, acting by attenuating inflammation and oxidative stress and improving antioxidant status.

Effects of combined electroacupuncture and medication therapy on the RhoA/ROCK-2 signaling pathway in the striatal region of rats afflicted by cerebral ischemia.

OBJECTIVE: To investigate the effects of electroacupuncture(EA), gastrodin(Gas), and their combination on the signaling pathways involving Ras homologous gene family member A (RhoA) and Rho-associated frizzled helix protein kinase (ROCK-2) within the striatal region of rats subjected to cerebral ischemia. Additionally, we aim to elucidate the therapeutic effects and potential underlying mechanisms associated with the concurrent application of electroacupuncture and medication in the treatment of cerebral ischemia. METHODS: Rats were randomly assigned to one of five groups, namely, the sham operation (Sham) group, model group, EA group, Gas group, and the EA combined with Gas group (referred to as the "EA+Gas group"). Each group consisted of ten rats. Following the induction of cerebral ischemia, the EA group and EA+Gas group received EA stimulation at the Baihui(GV20) and Zusanli(ST36) acupoints for 30 min per session, administered once daily for 14 consecutive days. The Gas group and EA+Gas group were intraperitoneally injected with Gas at a dosage of 10 mg/kg, also administered once daily for 14 consecutive days. Nissl staining was employed to observe morphological alterations in the striatal nerve cells of rats in each group. Immunohistochemistry and western blot techniques were employed to evaluate the expression levels of striatal RhoA and ROCK-2 proteins. RESULTS: In comparison to the Sham group, the model group exhibited a substantial reduction in the number of striatal nerve cells on the ischemic side, accompanied by notable changes in cell morphology, characterized by reduced cytoplasm, defective and atrophied cytosol, solidified nuclei, loosely arranged cells, and enlarged intercellular spaces. Additionally, there was a notable increase in the positive expression of RhoA and ROCK-2. In contrast, when compared to the model group, the EA, Gas, and EA+Gas groups demonstrated an elevated number of normal nerve cells within the ischemic striatal region, with a significant improvement in cell count and morphology. Furthermore, positive expression levels of RhoA and ROCK-2 were notably reduced in these groups. Compared with the EA group or the GAS group, the number of normal nerve cells in the striatum on the ischemic side of the EA+GAS group was further increased, and the positive expression level of RhoA and ROCK-2 were both further reduced. CONCLUSION: The protective mechanism underlying the therapeutic efficacy of EA combined with Gas against cerebral ischemic striatal injury in rats may be associated with the inhibition of the activation of the RhoA/ROCK-2 signaling pathway. Importantly, the therapeutic effects observed with the combination of electroacupuncture and medication were superior to those achieved with EA alone or the sole administration of Gas.

AMPK Signalling Pathway: A Potential Strategy for the Treatment of Heart Failure with Chinese Medicine.

Heart failure (HF) is a complex clinical syndrome that represents the advanced stage of cardiovascular disease, characterized by systolic and diastolic dysfunction of the heart. Despite continuous updates in HF treatment drugs, the morbidity and mortality rates remain high, necessitating ongoing exploration for new therapeutic targets. Adenosine monophosphate-activated protein kinase (AMPK) is the serine/threonine protein kinase which responds to adenosine monophosphate (AMP) levels.Activation of AMPK shifts cellular metabolic patterns from synthesis to catabolism, enhancing energy metabolism in pathological conditions such as inflammation, ischemia, obesity, and aging. Numerous studies have identified AMPK as a vital target for HF treatment, with herbal monomers/extracts and compounds affecting key signaling factors including rapamycin targeting protein (mTOR), silencing regulator protein 1 (SIRT1), nuclear transcription factor E2-related factor 2 (Nrf2), and nuclear transcription factor-κB (NF-κB) through regulation of the AMPK signaling pathway.This modulation can achieve the effects of improving metabolism, autophagy, reducing oxidative stress and inflammatory response in the treatment of heart failure, with the advantages of multi-targeting, comprehensive action and low toxicity.The modulation of the AMPK pathway by Traditional Chinese Medicine (TCM) has emerged as a crucial research direction for the prevention and treatment of HF, but a systematic summary and generalization in this field is lacking. This article provides an overview of the composition, regulation, and mechanism of the AMPK signaling pathway's influence on HF, as well as a summary of current research on the regulation of the AMPK pathway by TCM for HF prevention and treatment. The aim is to serve as a reference for the diagnosis and treatment of HF using TCM and the development of new drugs.

Drynaria Naringin alleviated mechanical stress deficiency-caused bone loss deterioration via Rspo1/Lgr4-mediated Wnt/ß-catenin signalling pathway.

Osteoporosis is a metabolic condition distinguished by the degradation of bone microstructure and mechanical characteristics. Traditional Chinese medicine (TCM) has been employed in China for the treatment of various illnesses. Naringin, an ingredient found in Drynariae TCM, is known to have a significant impact on bone metabolism. For this research, we studied the precise potential effect of Drynaria Naringin on protecting against bone loss caused by stress deficiency. In this study, a tail-suspension (TS) test was performed to establish a mouse model with hind leg bone loss. Some mice received subcutaneous injections of Drynaria Naringin for 30 d. Trabecular bone microarchitecture was evaluated using micro-computed tomography analysis and bone histological analysis. Bone formation and resorption markers were quantified in blood samples from mice or in the supernatant of MC3T3-E1 cells by ELISA analysis, Western blotting, and PCR. Immunofluorescence was utilized to visualize the location of ß-catenin. Additionally, siRNA was employed to knockdown-specific genes in the cells. Our findings highlight the efficacy of Drynaria Naringin in protecting against the deterioration of bone loss and promoting bone formation and Rspo1 expression in a mouse model following the TS test. Specifically, in vitro experiments also indicated that Drynaria Naringin may promote osteogenesis through the Wnt/ß-catenin signalling pathway. Moreover, our results suggest that Drynaria Naringin upregulates the expression of Rspo1/Lgr4, leading to the promotion of osteogenesis via the Wnt/ß-catenin signalling pathway. Therefore, Drynaria Naringin holds potential as a therapeutic medication for osteoporosis. Drynaria Naringin alleviates bone loss deterioration caused by mechanical stress deficiency through the Rspo1/Lgr4-mediated Wnt/ß-catenin signalling pathway.

Extraction technology, components analysis and anti-inflammatory activity in vitro of total flavonoids extract from Artemisia anomala S. Moore.

Artemisia anomala S. Moore exerts many pharmacological activities, including the removing of the blood stasis, relieving of the fever and analgesia, reducing the swelling and dampness. In this study, the extraction technology, chemical compositions and anti-inflammatory effect in vitro and mechanism of total flavonoids extract from Artemisia anomala S. Moore were studied. The optimal yield rate of total flavonoids extract was optimized by single factor experiments and response surface method, and the chemical constituents were analyzed by UPLC-QTOF-MS method; and the anti-inflammatory activity of the extract was evaluated with lipopolysaccharide induced RAW 264.7 cells. The highest extraction rate was 2.02% under these conditions of the concentration of ethanol 50%, the ultrasonic extraction time 30 min, and the ratio of solvent volume to material weight 20:1 (ml/g). In addition, the main components of total flavonoid extract were preliminarily identified and deduced based on mass spectrometry information and relevant literatures, and its stronger anti-inflammatory activity was demonstrated by reducing the phagocytosis, the content of nitric oxide and the level of related cytokines (tumor necrosis factor-α, interleukin-10, interleukin-6). Furthermore, it was further revealed that the anti-inflammatory effect of the extract was closely connected with the activation of TLR4-MyD88-NF-κB signalling pathway. This study indicated that the total flavonoids extract from Artemisia anomala S. Moore may be a better candidate anti-inflammatory natural medicine.

An Overview of the Enhanced Effects of Curcumin and Chemotherapeutic Agents in Combined Cancer Treatments.

Due to the progressive ageing of the human population, the number of cancer cases is increasing. For this reason, there is an urgent need for new treatments that can prolong the lives of cancer patients or ensure them a good quality of life. Although significant progress has been made in the treatment of cancer in recent years and the survival rate of patients is increasing, limitations in the use of conventional therapies include the frequent occurrence of side effects and the development of resistance to chemotherapeutic agents. These limitations are prompting researchers to investigate whether combining natural agents with conventional drugs could have a positive therapeutic effect in cancer treatment. Several natural bioactive compounds, especially polyphenols, have been shown to be effective against cancer progression and do not exert toxic effects on healthy tissues. Many studies have investigated the possibility of combining polyphenols with conventional drugs as a novel anticancer strategy. Indeed, this combination often has synergistic benefits that increase drug efficacy and reduce adverse side effects. In this review, we provide an overview of the studies describing the synergistic effects of curcumin, a polyphenol that has been shown to have extensive cytotoxic functions against cancer cells, including combined treatment. In particular, we have described the results of recent preclinical and clinical studies exploring the pleiotropic effects of curcumin in combination with standard drugs and the potential to consider it as a promising new tool for cancer therapy.

Mechanism insights of curcumin and its analogues in cancer: An update.

Cancer is the world's second leading cause of mortality and one of the major public health problems. Cancer incidence and mortality rates remain high despite the great advancements in existing therapeutic, diagnostic, and preventive approaches. Therefore, a quest for less toxic and more efficient anti-cancer strategies is still at the forefront of the current research. Traditionally important, curcumin commonly known as a wonder molecule has received considerable attention as an anti-cancer, anti-inflammatory, and antioxidant candidate. However, limited water solubility and low bioavailability restrict its extensive utility in different pathological states. The investigators are making consistent efforts to develop newer strategies to overcome its limitations by designing different analogues with better pharmacokinetic and pharmacodynamic properties. The present review highlights the recent updates on curcumin and its analogues with special emphasis on various mechanistic pathways involved in anti-cancer activity. In addition, the structure-activity relationship of curcumin analogues has also been precisely discussed. This article will also provide key information for the design and development of newer curcumin analogues with desired pharmacokinetic and pharmacodynamic profiles and will provide in depth understanding of molecular pathways involved in the anti-cancer activities.

Melatonin as a regulator of apoptosis in leukaemia: molecular mechanism and therapeutic perspectives.

Leukaemia is a dangerous malignancy that causes thousands of deaths every year throughout the world. The rate of morbidity and mortality is significant despite many advancements in therapy strategies for affected individuals. Most antitumour medications used now in clinical oncology use apoptotic signalling pathways to induce cancer cell death. Accumulated data have shown a direct correlation between inducing apoptosis in cancer cells with higher tumour regression and survival. Until now, the efficacy of melatonin as a powerful antitumour agent has been firmly established. A change in melatonin concentrations has been reported in multiple tumours such as endometrial, hematopoietic, and breast cancers. Findings show that melatonin's anticancer properties, such as its prooxidation function and ability to promote apoptosis, indicate the possibility of utilizing this natural substance as a promising agent in innovative cancer therapy approaches. Melatonin stimulates cell apoptosis via the regulation of many apoptosis facilitators, including mitochondria, cytochrome c, Bcl-2, production of reactive oxygen species, and apoptosis receptors. This paper aimed to further assess the anticancer effects of melatonin through the apoptotic pathway, considering the role that cellular apoptosis plays in the pathogenesis of cancer. The effect of melatonin may mean that it is appropriate for use as an adjuvant, along with other therapeutic approaches such as radiotherapy and chemotherapy.

Dietary grape seed proanthocyanidin extract supplementation improves antioxidant capacity and lipid metabolism in finishing pigs.

Grape seed proanthocyanidin extract (GSPE) plays a significant role in body health, including improving antioxidant capacity and maintaining lipid metabolism stability. However, whether dietary GSPE supplementation can improve lipid metabolism in finishing pigs remains unclear. Here 18 castrated male Duroc × Landrace × Yorkshire finishing pigs were randomly divided into three groups with six replicates and one pig per replicate. Pigs were fed a basal diet (control), a basal diet supplemented with 100 mg/kg GSPE, or a basal diet supplemented with 200 mg/kg GSPE for 30 days. Antioxidant analysis showed that dietary 200 mg/kg GSPE supplementation increased glutathione, total antioxidant capacity and glutathione peroxidase levels, and reduced malondialdehyde levels in serum, muscle and liver. Dietary 200 mg/kg GSPE supplementation also upregulated the mRNA and protein levels of nuclear-related factor 2 (Nrf2). Lipid metabolism analysis showed that dietary GSPE supplementation increased serum high-density lipoprotein cholesterol levels and reduced serum triglyceride and total cholesterol levels. Besides, GPSE upregulated the mRNA expression of lipolysis- and fatty acid oxidation-related genes downregulated the mRNA expression of lipogenesis-related genes, and activated the AMPK signal in finishing pigs. Together, we provided evidence that dietary GSPE supplementation improved the antioxidant capacity and lipid metabolism in finishing pigs.