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Osteoporosis, an age-related metabolic bone disease, is mainly caused by an imbalance between osteoblast-mediated bone formation and osteoclast-mediated bone resorption. At present, there are many osteoporosis drugs that can promote bone formation or inhibit bone resorption. However, there were few therapeutic drugs that can simultaneously promote bone formation and inhibit bone resorption. Oridonin (ORI), a tetracyclic diterpenoid compound isolated from Rabdosia rubescens, has been proved to have anti-inflammatory, anti-tumor effects. However, little is known about the osteoprotective effect of oridonin. Thioacetamide (TAA) is a common organic compound with significant hepatotoxicity. Recent studies have found that there was a certain association between TAA and bone injury. In this work, we investigated the effect and mechanism of ORI on TAA-induced osteoclastogenesis and inhibition of osteoblast differentiation. The results showed that TAA could promote the osteoclastogenesis of RAW264.7 by promoting the MAPK/NF-κB pathway, and also promoted p65 nuclear translocation and activated intracellular ROS generation, and ORI can inhibit these effects to inhibit TAA-induced osteoclastogenesis. Moreover, ORI can also promote the osteogenic differentiation pathway and inhibit adipogenic differentiation of BMSCs to promote bone formation. In conclusion, our results revealed that ORI, as a potential therapeutic drug for osteoporosis, could protect against TAA-induced bone loss and TAA-inhibited bone formation.

Hepatic encephalopathy (HE), a neuropsychiatric complication secondary to liver cirrhosis and hepatic failure, represents the leading cause of mortality in end-stage liver disease. While hyperammonemia remains the central pathogenic factor in HE progression, emerging evidence implicates oxidative stress, neuroinflammation, and neuronal apoptosis as critical synergistic contributors to HE pathogenesis. Hydrogen-rich water, known for its antioxidant, anti-inflammatory, and anti-apoptotic properties, has not been systematically investigated for therapeutic efficacy in HE management. In the current investigation, we successfully established a HE rat model by administering thioacetamide via intraperitoneal injection. By observing the general state and behavioral changes of the rats, detecting liver function and blood ammonia, and observing the pathological changes of liver and brain tissue, it was discussed whether hydrogen-rich water had a preventive and therapeutic effect on hepatic encephalopathy. Oxidative stress, inflammation and neuronal apoptosis were detected in plasma, prefrontal cortex and hippocampus to explore the possible mechanism of its protective effect. The results showed that hydrogen-rich water can improve the behavioral changes of the HE rats, reduce blood ammonia, reduce liver function damage, alleviate the pathological changes of liver and brain tissue, significantly inhibit the systemic and local oxidative stress and inflammation of the brain tissue of the HE rats, and reduce neuronal apoptosis. In summary, hydrogen-rich water might stabilize liver-brain disturbance in thioacetamide-induced HE rats by anti-inflammation, anti-oxidative stress and reducing neuronal apoptosis.

Liver fibrosis is associated with increased rates of morbidity and mortality. At present, there are no specific treatments that can directly reverse hepatic fibrosis. The endocannabinoid system has been found to play a significant role in regulating the development and progression of liver diseases, in addition to having protective effects. In this study, we investigate the protective potential of β-Caryophyllene (BCP) against Thioacetamide (TAA)-induced liver fibrosis. Wistar rats were injected with TAA (200 mg/kg) three times per week for 8 weeks to induce liver fibrosis. They also received oral BCP before the TAA injections. AM630 (1 mg/kg) was administered to confirm the CB2 receptor-dependent effect of BCP. The BCP treatment (50 mg/kg) protected against cell injury and potentiated antioxidant defense by replenishing hepatic GSH, improving catalase activity, and inhibiting the formation of MDA. The co-administration of BCP mitigated the TAA-induced inflammatory response by decreasing the release of proinflammatory cytokines. Histological examination showed preserved cellular integrity, decreased collagen deposits with other extracellular matrix proteins, and low levels of myofibroblast activation. In addition, the BCP-treated rats demonstrated upregulated sirtuin 1 (SIRT1) expression, which had a direct inhibitory effect on hypoxia inducible factor (HIF-1α). AM630 pre-treatment inhibited all the aforementioned protective mechanisms of BCP. Based on our findings, BCP exerts protective effects in liver fibrosis, which can be attributed to its agonist action on CB2 receptors. This study provides preclinical evidence of the potential preventative benefits of BCP in liver fibrosis.

Liver fibrosis, marked by excessive extracellular matrix deposition and chronic inflammation, is a significant health concern that can progress to cirrhosis and liver failure. Current treatments are limited, highlighting the need for novel therapies. Nicorandil (NIC), a potassium channel opener with nitric oxide-donating properties, has shown cytoprotective and anti-inflammatory effects. This study evaluates the efficacy of NIC in attenuating thioacetamide (TAA)-induced liver fibrosis in rats, focusing on the AMPK/SIRT-1/HIF-1α signaling pathway. Twenty-four adult male albino rats were randomly assigned to four groups: a control group, a TAA-treated group, and two groups treated with NIC at doses of 7.5 mg/kg/day and 15 mg/kg/day, respectively, for six weeks. TAA was administered intraperitoneally for six weeks to induce fibrosis, while NIC was given concurrently at both doses. TAA administration caused marked liver injury and fibrosis, as shown by increased ALT, AST, collagen-1α, and hydroxyproline levels. NIC treatment, particularly at 15 mg, significantly reduced these markers, indicating improved liver function and less fibrosis. NIC also alleviated oxidative stress by increasing SOD and GSH while lowering MDA, NO₂⁻, and iNOS. At the molecular level, NIC upregulated AMPK, SIRT-1, P53, and PGC-1α, and downregulated HIF-1α and STAT3. It further suppressed pro-inflammatory cytokines (IL-6, IL-1β, TNF-α, NF-κB, TGF-β1) while elevating IL-10. Histopathology confirmed improved liver structure with reduced collagen deposition, and immunohistochemistry showed decreased COX-II expression. In conclusion, both NIC doses showed therapeutic potential, with the 15 mg dose demonstrating superior efficacy. These findings highlight NIC’s promise as an effective treatment for liver fibrosis by mediating the AMPK/SIRT-1/HIF-1α pathway and modulating key molecular and cellular processes.

Acute liver failure (ALF) is a fulminant complication of multiple etiologies, characterized by rapid hepatic destruction, multi-organ failure and mortality. ALF treatment is mainly limited to supportive care and liver transplantation. Here we utilize the acetaminophen (APAP) and thioacetamide (TAA) ALF models in characterizing 56,527 single-cell transcriptomes to define the mouse ALF cellular atlas. We demonstrate that unique, previously uncharacterized stellate cell, endothelial cell, Kupffer cell, monocyte and neutrophil subsets, and their intricate intercellular crosstalk, drive ALF. We unravel a common MYC-dependent transcriptional program orchestrating stellate, endothelial and Kupffer cell activation during ALF, which is regulated by the gut microbiome through Toll-like receptor (TLR) signaling. Pharmacological inhibition of MYC, upstream TLR signaling checkpoints or microbiome depletion suppress this cell-specific, MYC-dependent program, thereby attenuating ALF. In humans, we demonstrate upregulated hepatic MYC expression in ALF transplant recipients compared to healthy donors. Collectively we demonstrate that detailed cellular/genetic decoding may enable pathway-specific ALF therapeutic intervention. A single-cell map of transcriptomic changes during acute liver failure unveils new insights into pathogenesis and potential therapeutic targets.

Background TGF-β1 and SMAD3 are particularly pathogenic in the progression of renal fibrosis. Aim This study aimed to evaluate the kidney protective potentials of silymarin (SM) and exosomes of mesenchymal stem cells against the nephrotoxin thioacetamide (TAA) in rats. Methods 32 female rats were randomly assigned into four groups: the control group, the TAA group, the TAA + SM group, and the TAA + Exosomes group. The kidney homogenates from all groups were examined for expression levels of TGF-β receptors I and II using real-time PCR, expression levels of collagen type I and CTGF proteins using ELISA, and the expression levels of nuclear SMAD2/3/4, cytoplasmic SMAD2/3, and cytoplasmic SMAD4 proteins using the western blot technique. Results Compared to the control group, the injection of TAA resulted in a significant increase in serum levels of urea and creatinine, gene expression levels of TβRI and TβRII, protein expression levels of both collagen I and CTGF proteins, cytoplasmic SMAD2/3 complex, and nuclear SMAD2/3/4 (p-value < 0.0001), with significantly decreased levels of the co-SMAD partner, SMAD4 (p-value < 0.0001). Those effects were reversed considerably in both treatment groups, with the superiority of the exosomal treatment regarding the SMAD proteins and the expression levels of the TβRI gene, collagen I, and CTGF proteins returning to near-control values (p-value > 0.05). Conclusion Using in vitro and in vivo experimental approaches, the research discovered a reno-protective role of silymarin and exosomes of BM-MSCs after thioacetamide-induced renal fibrosis in rats, with the advantage of exosomes.

The objective of this study was to elucidate the impact of D-(-)-Quinic acid (D-(-)-QA), a natural phenolic acid, on the molecular mechanisms of inflammation and oxidative stress in brain and liver damage in thioacetamide (TAA)-induced hepatic encephalopathy (HE) in rats. To establish an experimental HE model, rats were injected with three doses (200 mg/kg, intraperitoneally) of TAA every other day, followed by the administration of D-(-)- QA (200 or 400 mg/kg, orally) for fourteen days. Serum ammonia, alanine transaminase (ALT), and aspartate transaminase (AST) levels were detected. Tumor necrosis factor (TNF-α), interleukin-1beta IL-1β, and malondialdehyde (MDA), superoxide dismutase (SOD), and glutathione (GSH) levels were analyzed to assess inflammation and oxidative damage in brain and liver tissues. Histopathological examinations, immunofluorescence (PI3K and AKT expressions), and immunohistochemical (HSP70 expression) examinations were also performed. TAA administration causedhyperammonemia and increased ALT and AST levels, along with histopathological changes indicating damage to hepatocytes and neurons. Additionally, it disrupted the inflammatory response and promoted oxidative damage by activating the PI3K/AKT-related HSP70 response in the brain and liver. Treatment with D-(-)-QA significantly prevented the increase in ammonia levels and improved the liver function. In addition, the increase in TNF-α, and IL-1β, proinflammatory cytokines in liver and brain tissues as well as the increase in MDA and decrease in SOD and GSH were significantly suppressed by D-(-)-QA. By suppressing HSP70 and PI3K/AKT signaling in brain and liver tissues, D-(-)-QA administration attenuated inflammation and oxidative damage. D-(-)-QA may be an alternative to current clinical interventions by inhibiting inflammation and oxidative damage signaling toward the pathogenesis of HE.

With the rapid emergence of antibiotic resistance, efforts are being made to obtain new selective antimicrobial agents. Hybridization between quinazolinone and benzenesulfonamide can provide new antimicrobial candidates. Also, the use of nanoparticles can help boost drug efficacy and lower side effects. Novel quinazolinone-benzenesulfonamide derivatives were synthesized and screened for their antimicrobial activity against Gram-positive bacteria, Gram-negative bacteria, MRSA and yeast. The most potent compound was conjugated with copper oxide nanoparticles 16-CuONPs by gamma irradiation (4.5 KGy). Characterization was performed using UV-Visible, TEM examination, XRD patterns and DLS. Moreover, compound was used to synthesize two nanoformulations: 16-CNPs by loading in chitosan nanoparticles and the nanocomposites 16-CuONPs-CNPs. Characterization of these nanoformulations was performed using TEM and zeta potential. Besides, the inhibitory profile against DNA gyrase was assayed. Cytotoxic evaluation of , 16-CNPs and 16-CuONPs-CNPs on normal VERO cell line was carried out to determine its relative safety. Molecular docking of was performed inside the active site of DNA gyrase. Compound was the most active in this series against all the tested strains and showed inhibition zones and MICs in the ranges of 25-36 mm and 0.31-5.0 µg/mL, respectively. The antimicrobial screening of the synthesized nanoformulations revealed that 16-CuONPs-CNPs displayed the most potent activity. The MBCs of and the nanoformulations were measured and proved their bactericidal mode of action. The inhibitory profile against DNA gyrase showed IC ranging from 10.57 to 27.32 µM. Cytotoxic evaluation of , 16-CNPs and 16-CuONPs-CNPs against normal VERO cell lines proved its relative safety (IC = 927, 543 and 637 µg/mL, respectively). Molecular docking of inside the active site of DNA gyrase showed that it binds in the same manner as that of the co-crystallized ligand, ciprofloxacin. Compound could be considered as a new antimicrobial lead candidate with enhanced activity upon nanoformulation.

Galectin-3 protein is critical to the development of liver fibrosis because galectin-3 null mice have attenuated fibrosis after liver injury. Therefore, we examined the ability of novel complex carbohydrate galectin inhibitors to treat toxin-induced fibrosis and cirrhosis. Fibrosis was induced in rats by intraperitoneal injections with thioacetamide (TAA) and groups were treated with vehicle, GR-MD-02 (galactoarabino-rhamnogalaturonan) or GM-CT-01 (galactomannan). In initial experiments, 4 weeks of treatment with GR-MD-02 following completion of 8 weeks of TAA significantly reduced collagen content by almost 50% based on Sirius red staining. Rats were then exposed to more intense and longer TAA treatment, which included either GR-MD-02 or GM-CT-01 during weeks 8 through 11. TAA rats treated with vehicle developed extensive fibrosis and pathological stage 6 Ishak fibrosis, or cirrhosis. Treatment with either GR-MD-02 (90 mg/kg ip) or GM-CT-01 (180 mg/kg ip) given once weekly during weeks 8-11 led to marked reduction in fibrosis with reduction in portal and septal galectin-3 positive macrophages and reduction in portal pressure. Vehicle-treated animals had cirrhosis whereas in the treated animals the fibrosis stage was significantly reduced, with evidence of resolved or resolving cirrhosis and reduced portal inflammation and ballooning. In this model of toxin-induced liver fibrosis, treatment with two galectin protein inhibitors with different chemical compositions significantly reduced fibrosis, reversed cirrhosis, reduced galectin-3 expressing portal and septal macrophages, and reduced portal pressure. These findings suggest a potential role of these drugs in human liver fibrosis and cirrhosis.