R-type ginsenoside Rg3 attenuates cisplatin-induce intestinal injury via restoring autophagy flux blockade.

Cisplatin-induced nephrotoxicity is closely associated with an increase in lipid peroxidation. In several previous reports it was claimed that acetylsalicylic acid (ASA) shows its therapeutic potential as a free radical scavenger. The aim of the study was to investigate effects of ASA on cisplatin induced nephrotoxicity in an experimental rat model. Control animals (n:7) were administered 1 mL saline solution intraperitoneal (i.p.). Cisplatin group (n:7) was treated with a single dose of cisplatin i.p. (6 mg/kg), ASA group (n:7) was treated with i.p. (2.5 mg/kg) per day during the study, cisplatin plus ASA group (n:7) was administered single dose cisplatin i.p. (6 mg/kg) plus ASA (2.5 mg/kg) during 5 days. At the end of the study, Catalase (CAT), Glutathione Peroxidase (GSH-Px), Superoxide Dismutase (SOD), Nitric Oxide Synthase (NOS) enzymes activities and Malondialdehyde (MDA), Antioxidant Potential (AOP) levels were measured in both erythrocytes and renal tissues. Urea and creatinine levels and renal tissue necrosis in cisplatin plus ASA group were significantly lower than cisplatin group (p = 0.000, p = 0.014, p = 0.015). SODr activities and MDAr levels of cisplatin plus ASA group were also significantly lower than cisplatin group (p = 0.000, p = 0.029). These results show that cisplatin and ASA combination decreases the levels of urea and creatinine, reduces necrosis and improves antioxidant enzyme activities, MDA and AOP in rat kidney.

Cisplatin (CIS) is an antineoplastic agent used for treating solid organ tumors. Toxic side effects of CIS treatment include nephrotoxicity, neurotoxicity, ototoxicity, myelosuppression and hepatotoxicity. Dexpanthenol (DEX) exhibits antioxidant and anti-inflammatory effects and protective effects against free oxygen radicals. We investigated the protective effects of DEX on CIS induced nephrotoxicity. Animals were divided into four groups of 10. The control group was given saline. The DEX group was treated with DEX for 10 days. The CIS group was treated with a single dose of CIS. The DEX + CIS group was given a single dose of CIS followed by DEX for 10 days. We found increased levels of malondialdehyde (MDA), blood urea nitrogen (BUN) and creatinine, while superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) and myeloperoxidase (MPO) levels were decreased in the CIS group. MDA, BUN and creatinine levels were decreased, while SOD, CAT, GPx and MPO levels were increased in the DEX + CIS group. Renal tubule damage, inflammation and histopathology scores were significantly higher in the CIS group than the control. The DEX + CIS group exhibited less renal tubule damage and inflammation, and lower histopathological assessment scores than the CIS group. Significant cortical tubule damage and interstitial inflammation were observed in the CIS group. Tubule damage was slightly less, and mild tubule dilation and less cast formation were observed in the DEX + CIS group; also, inflammation was less severe than for the CIS group. DEX may have therapeutic potential for treating CIS induced nephrotoxicity due to its antioxidant and anti-inflammatory properties.

BackgroundChelerythrine (CHE) exhibits notable anti-inflammatory and antitumor properties, while its impact on esophageal squamous cell carcinoma (ESCC), especially the underlying mechanisms remain unclear. In this study, we aim to investigate the roles and mechanism of CHE in the ESCC treatment.MethodsHuman ESCC cell lines and organoids were used for in vitro cell experiments, BALB/c nude mice were used for in vivo animal experiments. To investigate the underlying mechanism of CHE treatment, drug library screen, RNA sequencing analysis, TMT-based quantitative proteomic analysis, western blotting analysis, immunofluorescence, immunohistochemistry, quantitative real-time polymerase chain reaction, mitochondrial membrane potential assay, apoptosis assay, detection of mitochondrial reactive oxygen species (mtROS), autophagic flux monitoring, transmission electron microscopy, and seahorse XF-96 metabolic flux analysis were used to assess the effect of CHE and relevant mechanism.ResultsCHE dose-dependently inhibited the proliferation, migration, and invasion of ESCC cells. CHE also induced cell apoptosis and triggered PTEN-induced kinase 1 (PINK1)-Parkin-mediated mitophagy-mediated cell death by elevating the production of reactive oxygen species in mitochondria and diminishing mitochondrial membrane potential (MMP). However, the production of autophagosomes and autolysosomes induced by CHE altered when used in combination with the autophagy inhibitors 3-methyladenine (3-MA) or bafilomycin A1 (BafA1), indicating that it induced complete autophagic flux in the cells. Mechanistically, CHE affected multiple signaling pathways associated with ubiquitin-mediated proteolysis, mitophagy, and mitochondrial energy metabolism, indicating its close involvement in mitophagy occurrence. In addition, CHE treatment significantly reduced tumor size and weight in nude mice bearing KYSE150 tumors and retarded the growth of organoids derived from patients, it also reduced the ratio of M2 macrophage in tumor microenvironment and cell metabolism.ConclusionsCHE activates PINK1-Parkin-mediated mitophagy and disrupts mitochondrial homeostasis, and it also affects the tumor environment and cell metabolism, ultimately leading to cell death, supporting the potential of CHE for ESCC therapy.Supplementary InformationThe online version contains supplementary material available at 10.1186/s12967-025-07025-w.

As a small molecule flavonoid, astragalin (AST) has anti-inflammatory, anti-cancer, and anti-oxidation effects. However, the impact and molecular mechanism of AST in Alzheimer’s disease (AD) are still not clear. This study aims to investigate the neuroprotective effect and mechanism of AST on APP/PS1 mice and Aβ25-35-injured HT22 cells. In this study, we found that AST ameliorated cognitive dysfunction, reduced hippocampal neuronal damage and loss, and Aβ pathology in APP/PS1 mice. Subsequently, AST activated autophagy and up-regulated the levels of autophagic flux-related protein in APP/PS1 mice and Aβ25-35-induced injury in HT22 cells. Interestingly, AST down-regulated the phosphorylation level of PI3K/Akt-mTOR pathway-related proteins, which was reversed by autophagy inhibitors 3-Methyladenine (3-MA) or Bafilomycin A1 (Baf A1). At the same time, consistent with the impacts of Akt inhibitor MK2206 and mTOR inhibitor rapamycin, inhibited levels of autophagy in Aβ25-35-injured HT22 cells were activated by the administration of AST. Taken together, these results suggested that AST played key neuroprotective roles on AD via stimulating PI3K/Akt-mTOR pathway-mediated autophagy and autophagic flux. This study revealed a new mechanism of autophagy regulation behind the neuroprotection impact of AST for AD treatment.

Kampo medicines Rikkunshito and Hangeshashinto prevent cisplatin-induced intestinal mucosal injury in rats

Cisplatin (CP) treatment has been long associated with the development of acute kidney injury (AKI) through mechanisms involving inflammation and oxidative stress. α-Bisabolol (BIS), a sesquiterpene alcohol isolated from the essential oil of various plants, including chamomile, has garnered popularity lately due to its antioxidant, anti-inflammatory, and anticancer properties. Therefore, we investigated the nephroprotective effects of BIS in the murine model of CP-induced AKI and the underlying mechanism of action. BALB/c mice were given BIS orally at 25 mg/kg for 7 days. On day 7, they were given a single dose of CP at 20 mg/kg intraperitoneally. BIS treatment continued for 3 more days. The animals were sacrificed at the end of the experiment (day 11). Kidneys, plasma, and urine were collected, and subsequently, various physiological, biochemical, and histological parameters were assessed. BIS has significantly normalized the alterations of water intake, urine volume, relative kidney weight, and the concentrations of urea and creatinine, as well as the creatinine clearance induced by CP treatment. BIS significantly mitigated the effects of CP-induced kidney injury by reducing kidney injury molecule-1, neutrophil gelatinase-associated lipocalin, adiponectin, and cystatin C. Likewise, the renal concentrations of proinflammatory cytokines, tumor necrosis factor α, interleukin (IL)-6 and IL-1β that were elevated in CP group were significantly reduced in mice treated with BIS and CP. A similar significant reduction was also observed in the CP-induced augmented levels of markers of oxidative stress, as well as the metabolite pteridine. Moreover, BIS significantly reduced the CP–induced renal DNA damage, and markedly lessened the acute tubular necrosis observed in kidney histology. Additionally, BIS significantly reduced the CP-induced increase in the phosphorylated nuclear factor κB (NFκB) in the kidney. These data strongly suggest that BIS exerts a protective action against CP-induced nephrotoxicity by mitigating inflammation and oxidative stress through the inhibition of NFκB activation. No overt adverse effects were noted with BIS treatment. Additional investigations should be done to consider BIS as an efficacious nephroprotective agent against CP.

Cisplatin (CP) is used as an effective chemotherapeutic drug in the treatment of various solid tumors. However, side effects such as hepatotoxicity limit the use of the drug. We investigated the protective effects of caffeic acid phenethyl ester (CAPE), one of the active ingredients of propolis, against hepatotoxicity caused by CP treatment in the liver. 38 Wistar albino rats were divided into 4 groups. Control group was given physiological saline solution for 12 day. CP group was given a single dose of CP (7 mg/kg) on the day 7. CP+CAPE group, was given CAPE (10 μmol/kg/day) for 12 days and a single dose of CP (7 mg/kg) on day 7. CAPE group was given CAPE (10 μmol/kg/day for 12 days. Livers of rats sacrificed on the 14th day were stained with hematoxylin-eosin after histological tissue follow-up. The preparations were evaluated histopathologically and scored. Rat weights were measured and recorded at the beginning and end of the experiment. CP caused significant histopathological changes in the liver. CP also prevented the increase in rat weight. CAPE played an effective role as a protective agent against the histopathological changes caused by CP and showed signs of tissue healing. Our results show that CAPE can be protective against hepatotoxicity associated with CP.

Autophagy and hepatic stellate cell activation – Partners in crime?

Background: Epimedii Folium, as a natural botanical medicine, has been reported to have protective effects on intestinal diseases by modulating multiple signaling pathways. This study aimed to explore the potential targets and molecular mechanisms of Epimedii Folium extract (EFE) against cisplatin-induced intestinal injury through network pharmacology, molecular docking, and animal experiments. Methods: Network pharmacology was used to predict potential candidate targets and related signaling pathways. Molecular docking was used to simulate the interactions between significant potential candidate targets and active components. For experimental validation, mice were intraperitoneally injected with cisplatin 20 mg/kg to establish an intestinal injury model. EFE (100, 200 mg/kg) was administered to mice by gavage for 10 days. The protective effect of EFE on intestinal injury was analyzed through biochemical index detection, histopathological staining, and western blotting. Results: Network pharmacology analysis revealed that PI3K-Akt and apoptosis signaling pathways were thought to play critical roles in EFE treatment of the intestinal injury. Molecular docking results showed that the active constituents of Epimedii Folium, including Icariin, Epimedin A, Epimedin B, and Epimedin C, stably docked with the core AKT1, p53, TNF-α, and NF-κB. In verified experiments, EFE could protect the antioxidant defense system by increasing the levels of glutathione peroxidase (GSH-Px) and catalase (CAT) while reducing the content of malondialdehyde (MDA). EFE could also inhibit the expression of NF-κB and the secretion of inflammatory factors, including TNF-α, IL-1β, and IL-6, thereby relieving the inflammatory damage. Further mechanism studies confirmed that EFE had an excellent protective effect on cisplatin-induced intestinal injury by regulating PI3K-Akt, caspase, and NF-κB signaling pathways. Conclusion: In summary, EFE could mitigate cisplatin-induced intestinal damage by modulating oxidative stress, inflammation, and apoptosis.

Based on the Maillard reaction principle of red ginseng, this study innovatively synthesized a new amino acid derivative by combining arginine with lactose through simulated synthesis and was separated and purified through repeated silica gel and polyacrylamide gel (Bio-gel P-II) column chromatography. The work was aimed at elucidating the synthesis of a novel amino acid derivative and investigating the intestinal protective activity of the novel amino acid derivative and possible molecular mechanism by establishing the intestinal injury model induced by cisplatin in mice. The purity and molecular weight of the amino acid derivatives were determined to be by electrospray ionization mass spectrometry (ESI-MS). Subsequently, by establishing cisplatin (20 mg/kg)-induced intestinal injury in vivo for 10 days and IEC-6 cell model. The biochemical indexes and histopathological analysis were used to evaluate the oxidative stress and inflammatory and pathological changes of intestinal tissue in mice. The protein expression levels of p-Nuclear transcription factor-κB (p-NF-κB), cleaved caspase 3/caspase 3, cleaved caspase 9/caspase-9, Bcl-2, Bax, cytochrome C, phosphatidylinositol 3-kinase (PI3K), Protein Kinase B (Akt), p-PI3K, p-Akt were quantified through immunofluorescence staining and western blot analysis. The new amino acid derivatives of chemical structure were identified to be 1- (arginine-Nαgroup)-1-deoxy-4-O-(β-D-galactopyranosyl)-D-fructose, named Argininylfructosyl- galactose (AFGA, C18H34N4O12). The results showed that pretreatment with a single AFGA dose remarkably alleviated cisplatin-evoked intestinal oxidative stress injury, and the levels of reactive oxygen species (ROS) were lessening in IEC-6 cells (p<0.05, p<0.01) and could effectively reduce the secretion of TNF-α and IL-1β in serum and the expression level of NF-κB protein in intestinal tissues (p<0.01). Meantime, AFGA also significantly suppressed the caspase 3, caspase 9, cytochrome C and Bax protein expression in intestinal tissue in mice (p<0.01), and regulated the PI3K/Akt pathway (p<0.05, p<0.01). Importantly, the molecular docking results of AFGA also suggested a better binding ability with the above-mentioned related target proteins. The results clearly revealed AFGA as a potential multifunctional therapeutic agent with a clear protective effect against cisplatin-induced intestinal injury may be related to the PI3K/Akt signaling pathway.

Cisplatin is a highly effective chemotherapeutic agent. However, its use is limited by nephrotoxicity. Enalapril is an angiotensin I-converting enzyme inhibitor used for the treatment of hypertension, mainly through the reduction of angiotensin II formation, but also through the increase of kinins half-life. Kinin B1 receptor is associated with inflammation and migration of immune cells into the injured tissue. We have previously shown that the deletion or blockage of kinin B1 and B2 receptors can attenuate cisplatin nephrotoxicity. In this study, we tested enalapril treatment as a tool to prevent cisplatin nephrotoxicity. Male C57Bl/6 mice were divided into 3 groups: control group; cisplatin (20 mg/kg i.p) group; and enalapril (1.5 mg;kg i.p) + cisplatin group. The animals were treated with a single dose of cisplatin and euthanized after 96 h. Enalapril was able to attenuate cisplatin-induced increase in creatinine and urea, and to reduce tubular injury and upregulation of apoptosis-related genes, as well as inflammatory cytokines in circulation and kidney. The upregulation of B1 receptor was blocked in enalapril + cisplatin group. Carboxypeptidase M expression, which generates B1 receptor agonists, is blunted by cisplatin + enalapril treatment. The activity of aminopeptidase P, a secondary key enzyme able to degrade kinins, is restored by enalapril treatment. These findings were confirmed in mouse renal epithelial tubular cells, in which enalaprilat (5 μM) was capable of decreasing tubular injury and inflammatory markers. We treated mouse renal epithelial tubular cells with cisplatin (100 μM), cisplatin+enalaprilat and cisplatin+enalaprilat+apstatin (10 μM). The results showed that cisplatin alone decreases cell viability, cisplatin plus enalaprilat is able to restore cell viability, and cisplatin plus enalaprilat and apstatin decreases cell viability. In the present study, we demonstrated that enalapril prevents cisplatin nephrotoxicity mainly by preventing the upregulation of B1 receptor and carboxypeptidase M and the increased concentrations of kinin peptides through aminopeptidase activity restoration.

Background: Cisplatin is a major antitumor drug used for treatment of solid tumors. Nephrotoxicity is its main limiting side effect. Exenatide is described as an incretin mimetic polypeptide, it acts as a GLP-1 receptor agonist and its insulinotropic activity is mediated through binding to and stimulation of GLP-1 receptors on human pancreatic β-cells. Aim: the present work was designed to study the effect of exenatide on experimentally cisplatin induced nephropathy in non- diabetic rats. Materials and Methods: Thirty two male adult Sprague Dawley rats randomly divided into four groups, each consisted of 8 animals, and distributed as follows: Group I: (control) normal group and received saline vehicle. Group II: (cisplatin) group includes rats injected intraperitoneally by a single dose of cisplatin (6 mg/kg) to induce nephrotoxicity, received no treatment and were sacrificed 7 days after cisplatin administration. Group III: (exenatide) group: rats treated by exenatide (10 mg/kg/day s.c.) for 4 weeks. Group IV: (exenatide+cisplatin) group: rats treated by exenatide (10 mg/kg/day s.c.) for 4 weeks before induction of nephrotoxicity by cisplatin. The following parameters were measured: fasting blood glucose, serum urea, serum creatinine, reduced glutathion (GSH) level in the renal tissue, tumor necrosis factor-α (TNF-α) level in the renal tissue, renal blood flow changes and histopathological changes of the kidney. Results: Pretreatment with exenatide resulted in significant reduction in serum urea, serum creatinine level and renal TNF- α level compared to cisplatin group but still significantly higher than control group with significant increase in renal GSH level and renal blood flow compared to cisplatin group but still also significantly lower than control group. Cisplatin group showing tubular degeneration with infiltration of inflammatory cells while pretreatment with exenatide showing certain improvement in general histological structure with mild tubular degeneration and less inflammatory cell infiltration. Conclusion: it can be concluded that the use of exenatide improved the biochemical and histopathological changes that occur in the renal tissue by cisplatin. Â

This study was performed to investigate the effect of ethyl pyruvate on changes in renal functions and oxidative stress related renal injury caused by cisplatin (cis-dichlorodiammine platinum-II; CDDP).Male Wistar albino rats were divided into four groups (n = 8): (1) control group (1 ml Ringer's lactate solution i.p.); (2) ethyl pyruvate (EP) group (50 mg/kg Ringer's EP solution (REPS) i.p.); (3) cisplatin group (a single dose of cisplatin (5 mg/kg, i.p.); and (4) cisplatin + EP group (a single dose of cisplatin (5 mg/kg, i.p.) + REPS 50 mg/kg/day, i.p.) for five days. At the sixth day, kidneys of rats were mounted to a Langendorff apparatus. Renal perfusion pressures were recorded. Blood samples were taken for serum urea, creatinine, total oxidant status (TOS), total antioxidant status (TAS) and oxidative stres index (OSI) evaluations. Kidney tissues were obtained for malondialdehyde (MDA) analyses and histopathological examination.Perfusion pressures, serum urea, creatinine, TOS, OSI and tissue MDA levels were found significantly higher, whereas TAS was notably lower in cisplatin group. Histopathological examination showed apparent renal paranchymal injury in cisplatin group. In cisplatin + REPS group, perfusion pressures, serum urea, creatinine and tissue MDA levels were decreased. Moreover, EP co-administration provided less inflammatory cell infiltration, tubular dilatation, whereas TOS, TAS and OSI improved significantly versus cisplatin group.These findings show that EP has protective effects against cisplatin nephrotoxicity.

Matrine has potent antitumor activity against a broad variety of cancer cells and our previous study showed that both autophagy and apoptosis were activated during matrine-induced gastric cancer cell death. The aim of the present study was to determine the significance of autophagy in antineoplastic effects of matrine and the molecular mechanism by which matrine induces autophagy in gastric cancer cells. Western blot analysis showed that exposure of gastric cancer cells to matrine resulted in the extent of autophagy increasing in a dose- and time-dependent manner by detecting micro-tubule-associated protein 1 light chain 3 (LC3). This induction was due to activation of autophagic flux, as supported using the lysosome inhibitor, bafilomycin A1, which produced an accumulation of LC3-II. Propidium iodide staining demonstrated that matrine induced cell death in a dose-dependent manner and the autophagy inhibitor 3-methyladenine (3-MA) or bafilomycin A1 enhanced lethality of matrine against gastric cancer cells. Moreover, after pretreatment with 3-MA, some of the gastric cancer cells treated with matrine exhibited prototypical characteristics of apoptosis by transmission electron microscopy. The ability of 3-MA to increase matrine-induced apoptosis was further confirmed by Annexin V-FITC/PI staining. Also, the combination of matrine and 3-MA was more potent than matrine alone in inhibiting the proliferation of SGC-7901 cells assessed by sulphorhodamine B assay. Furthermore, administration of the pan-caspase inhibitor zVAD-fmk or autophagy inducer rapamycin decreased the matrine-induced cell death. In addition, matrine treatment did not inhibit the phosphorylation of Akt and its downstream effectors mammalian target of rapamycin (mTOR) as well as p70 ribosomal protein S6 kinase (p70S6K), although the levels of the total Akt and mTOR were decreased. These results suggest that autophagy was activated as a protective mechanism against matrine-induced apoptosis and inhibition of autophagy may be an attractive strategy for enhancing the antitumor potential of matrine in gastric cancer.

Paris saponin-induced autophagy promotes breast cancer cell apoptosis via the Akt/mTOR signaling pathway