Clinical and Experimental Pharmacology and Physiology最新文献

Ulcerative colitis (UC) is a condition characterized by inflammation and ulcer formation in the colon and rectum due to genetic and environmental factors. It is a common condition, with a global prevalence rate exceeding 0.3%. Current treatments have limited efficacy and can cause unwanted side effects, leading to a high recurrence rate and reduced quality of life for patients. This study suggests that Bacillus clausii has a beneficial role in reducing intestinal inflammation and relieving colitis symptoms in mice. The study aimed to examine B. clausii's potential to reduce the progression and pathogenesis of dextran sulphate sodium (DSS)–induced UC. Bacillus clausii was administered to mice as a pre-treatment, post-treatment and adjunct treatment with sulfasalazine for 14 days. The study found that B. clausii effectively reduced the severity of colitis in mice when used preventatively. Administering B. clausii after the onset of colitis also effectively alleviated symptoms. Combining B. clausii with standard sulfasalazine as adjunct therapy was more effective in reducing intestinal inflammation than using a single therapy alone. B. clausii has shown the potential to prevent colon damage and decrease the likelihood and severity of the disease. Immunohistochemistry results revealed a decrease in the expression of pro-inflammatory cytokines such as IL-1β, TNF-α and NFkB in colon tissue. Additionally, mice that received B. clausii showed a significant increase in anti-oxidant levels and improved haematological markers. In conclusion, it must be emphasized that B. clausii possesses the potential to alleviate the symptoms of UC.

Evodiamine is a biologically active alkaloid extracted from the fruit of the traditional Chinese medicine Evodia rutaecarpa (Juss.) Benth. (Fructus Evodiae, Wuzhuyu). However, due to its lipophilic chemical structure, low water solubility results in poor bio-availability, which limits its broader application. 3-Amino-10-hydroxyl-evodiamine (E2) was a water-soluble derivative of evodiamine with good anti-tumour bioactivity previously developed by our team; however, its anti-osteoporosis activity remains unclear. This study demonstrates that E2 inhibits the maturation of osteoclasts and bone resorption promoted by receptor activator of nuclear factor-κB ligand (RANKL). Mechanistically, E2 reduced RANKL-induced activation of nuclear factor kappa B (NF-κB) as well as mitogen-activated protein kinase (MAPK) pathways, causing the suppression of the expression of genes associated with osteoclasts in vitro. These genes included nuclear factor of activated T cells c1 (NFATc1), tartrate-resistant acid phosphatase (TRAP), cathepsin k (CTSK) and dendritic cell–specific transmembrane protein (DC-STAMP). Treatment with E2 in vitro resulted in the attenuation of p-ERK, p-JNK, p-p38 and NFATc1 levels. Furthermore, ovariectomized (OVX) mice treated with E2 showed a decrease in osteoclast formation as well as preservation of bone mass. This study concludes with evidence that E2 decreases osteoclast maturation and bone resorption through the regulation of multiple signalling pathways, thereby exhibiting an osteoprotective role in OVX mice. Consequently, E2 exhibits significant potential as a prospective drug candidate for treating osteoporosis.

Senescence impairs liver physiology, mitochondrial function and circadian regulation, resulting in systemic metabolic dysregulation. Given the limited research on the effects of combined exercise on an ageing liver, this study aimed to evaluate its impact on liver metabolism, circadian rhythms and mitochondrial function in senescence-accelerated mouse-prone 8 (SAMP8) and senescence-accelerated mouse-resistant 1 (SAMR1) mice. Histological, reverse transcription quantitative polymerase chain reaction (RT-qPCR) and immunoblotting analyses were conducted, supplemented by transcriptomic data sets and AML12 hepatocyte studies. Sedentary SAMP8 mice exhibited decreased muscle strength, reduced mitochondrial complex I levels and increased lipid droplet accumulation. In contrast, combined exercise mitigated muscle strength loss, upregulated proteins involved in mitochondrial complexes (CIII, CIV, CV) and increased Bmal1 messenger RNA (mRNA) expression in the liver. These molecular adaptations are associated with healthier liver phenotypes and may influence metabolic function and cellular longevity. Notably, elevated lipid content in aged mice was reduced post-exercise, indicating liver benefits even after a relatively short intervention. The combined exercise regimen did not improve aerobic capacity, likely due to the low volume and brief duration of running. Moreover, no significant effects were observed in SAMR1 mice, possibly because the training intensity was insufficient for younger, healthier animals. These findings underscore the potential of combined strength and endurance exercise to attenuate age-related liver dysfunction, particularly in ageing populations.

Diabetic nephropathy (DN) is a severe renal disorder that arises as a complication of diabetes. Liraglutide, an analogue of a glucagon-like peptide 1 (GLP-1) receptor agonist, has been shown to decrease diabetes-caused renal damage. Nevertheless, the complete understanding of the roles and mechanism remains unclear. In our study, diabetic rat models were created through a single intraperitoneal injection of streptozotocin (STZ). The level of fasting blood glucose, 24-h urine protein, serum creatinine (Scr) and blood urea nitrogen (BUN) were assessed. Periodic acid-Schiff (PAS) staining was applied to examine the pathological changes in renal tissues. Reactive oxygen species (ROS) formation was measured via dichloro-dihydro-fluorescein diacetate (DCFH-DA) probes. Western blot was conducted to examine the levels of oxidative stress-related and extracellular matrix (ECM)-associated proteins. The nuclear translocation of NRF2 was investigated through immunofluorescence and Western blot assays. We demonstrated that liraglutide attenuated DN-induced oxidative stress and ECM deposition in vitro and in vivo. Liraglutide exerted a reno-protective effect by promoting nuclear translocation of NRF2 in mesangial cells. ML385, an NRF2 inhibitor, counteracted the beneficial impact of liraglutide.

Myocardial fibrosis is a critical concern in clinical medicine. This study explores the potential of odoratin as a treatment for myocardial fibrosis and investigates its underlying mechanisms. In vitro experiments involved stimulating primary mouse cardiomyocytes with TGF-β1, followed by odoratin treatment, to assess levels of reactive oxygen species (ROS) and nitric oxide (NO). In vivo, a mouse model of myocardial fibrosis was established using abdominal aortic constriction (AAC) and treated with odoratin. ROS and NO levels in myocardial tissue were then evaluated. Immunofluorescence and Western blotting analysis showed that odoratin reduced excess ROS, enhanced NO production and decreased fibrosis-related protein expression in vitro. In vivo, odoratin significantly improved cardiac function, reduced ROS, increased NO levels and mitigated fibrosis in AAC-induced mice. Both in vitro and in vivo, odoratin inhibited the expression of NADPH oxidase 4 and EZH2, while promoting the expression of phosphorylated endothelial nitric oxide synthase (p-eNOS) and PPARγ. The anti-fibrotic effects of odoratin were reversed by PPARγ antagonism, and EZH2 overexpression diminished PPARγ activation by odoratin. These findings suggest that odoratin may combat myocardial fibrosis by balancing ROS and NO through PPARγ activation, with EZH2 inhibition likely playing a key regulatory role.

Among the numerous treatment options for rheumatoid arthritis (RA), the promotion of synoviocyte apoptosis and inhibition of inflammation are considered the most effective. However, the potential pro-apoptotic effects of gross saponins of Tribulus terrestris (GSTT), which are natural saponins derived from the herb Tribulus terrestris L., on rheumatoid arthritis fibroblast-like synoviocytes (RA-FLSs) and their essential molecular mechanisms remain unclear. The aim of the present study was to investigate the influence of different concentrations of GSTT on RA-FLSs using various assays, including cell counting kit-8 (CCK-8), reverse transcription polymerase chain reaction (RT-PCR), enzyme-linked immunosorbent assay (ELISA), flow cytometry, terminal deoxynucleotidyl transferase dUTP nick end labelling (TUNEL) and western blot analysis. These assessments were conducted to evaluate the cell viability, changes in the levels of inflammatory cytokines, apoptosis rates and alterations in protein expression related to this process. In vivo, arthritis clinical score, haematoxylin and eosin (HE) staining and ELISA were used to assess paw inflammation, histopathology and serum inflammatory cytokine changes. Our findings demonstrated that GSTT substantially promotes the apoptosis of RA-FLSs and reduces pro-inflammatory cytokine levels. GSTT also reduced the Bcl-2/Bax ratio and inhibited JNK and p38 phosphorylation. Furthermore, GSTT exhibits positive effects on RA by improving clinical scores, reducing synovial inflammatory infiltration and lowering serum pro-inflammatory cytokine levels. Therefore, by promoting the apoptosis of RA-FLSs and suppressing inflammation through the inhibition of the MAPK signalling pathway, GSTT is a promising therapeutic intervention for RA.

Sepsis-induced acute lung injury (ALI) is characterized by inflammatory damage to pulmonary endothelial and epithelial cells. The aim of this study is to probe the significance and mechanism of tripartite motif-containing protein 21 (TRIM21) in sepsis-induced ALI. The sepsis-induced ALI mouse model was established by cecum ligation and puncture. The mice were infected with lentivirus and treated with proteasome inhibitor MG132. The lung respiratory damage, levels of interleukin-6 (IL-6), tumour necrosis factor α (TNF-α), IL-10 and pathological changes were observed. The expression levels of TRIM21, interferon regulatory factors 1 (IRF1) and triggering receptor expressed on myeloid cells 2 (TREM2) were measured and their interactions were analysed. The ubiquitination level of IRF1 was detected. TRIM21 and TREM2 were downregulated and IRF1 was upregulated in sepsis-induced ALI mice. TRIM21 overexpression eased inflammation and lung injury. TRIM21 promoted IRF1 degradation via ubiquitination modification. IRF1 bonded to the TREM2 promoter to inhibit its transcription. Overexpression of IRF1 or silencing TREM2 reversed the improvement of TRIM21 overexpression on lung injury in mice. In conclusion, TRIM21 reduced IRF1 expression by ubiquitination to improve TREM2 expression and ameliorate sepsis-induced ALI.

Adipocyte enhancer-binding protein 1 (AEBP1) is closely implicated in osteoblastic differentiation and bone fracture; this research aimed to investigate the effect of AEBP1 on restoring osteoblastic differentiation under dexamethasone (Dex) treatment, and its interaction with the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) pathway. Pre-osteoblastic MC3T3-E1 cells were cultured in osteogenic medium and treated by Dex to mimic steroid-induced osteonecrosis cellular model. They were then further transfected with control or AEBP1-overexpressed lentiviral vectors. Finally, cells were treated with the PI3K inhibitor LY294002, with or without AEBP1-overexpressed lentiviral vectors. AEBP1 expression showed a downward trend in MC3T3-E1 cells under Dex treatment in a dose-dependent manner. AEBP1-overexpressed lentiviral vectors increased relative cell viability, alkaline phosphatase (ALP) staining, Alizarin red staining and osteoblastic differentiation markers including osteocalcin (OCN), osteopontin (OPN), collagen type I alpha 1 (COL1A1), runt-related transcription factor 2 (RUNX2) and bone morphogenetic protein 2 (BMP2), but decreased cell apoptosis rate in MC3T3-E1 cells under Dex treatment; besides, AEBP1-overexpressed lentiviral vectors positively regulated p-PI3K and p-AKT expressions. Furthermore, LY294002 treatment decreased relative cell viability, Alizarin red staining, osteoblastic differentiation markers including OCN, OPN, RUNX2 and BMP, increased cell apoptosis rate and did not affect ALP staining in MC3T3-E1 cells under Dex treatment; meanwhile, LY294002 treatment weakened the effect of AEBP1 overexpression vectors on the above cell functions. AEBP1 restores osteoblastic differentiation under Dex treatment by activating the PI3K/AKT pathway.

Neuropathic pain arises from impairments or malfunctions within the nervous system, resulting in atypical transmission and interpretation of pain signals. In the present study, we examined the neuroprotective effects of agomelatine (AGM) and agomelatine-loaded nanostructured lipid carriers (AGM-NLCs) in neuropathic animal models induced by chronic constriction injury (CCI) of the sciatic nerve. Male Sprague Dawley rats were divided into seven experimental groups to compare the effects of AGM and AGM-NLCs, which were administered at 20 mg/kg for 14 consecutive days after CCI. Our finding demonstrated that CCI triggered the onset of analgesia in these animals, corroborated by mechanical allodynia and thermal hyperalgesia. Furthermore, CCI induced an elevation in inflammatory mediators such as interleukin (IL)-1β and inducible nitric oxide synthase (iNOS), and downregulated heme oxygenase-1 (HO-1) and nuclear factor E2-related factor (Nrf2). Treatment with AGM and AGM-NLCs reversed inflammatory cascades and elevated antioxidant enzyme levels, leading to a reduction in paw withdrawal latency and threshold in rats. To further investigate the effect of AGM and AGM-NLCs, all-trans retinoic acid (ATRA) was administered, which antagonizes Nrf2. ATRA substantially downregulated Nrf2 expression and exacerbated thermal hyperalgesia, whereas Nrf2 and HO-1 expressions were significantly upregulated after AGM-NLCs administration. Overall, the results demonstrated that AGM-NLCs offer promising antinociceptive and anti-inflammatory properties in alleviating neuropathic pain symptoms, which can be attributed to improved drug delivery and therapeutic outcomes compared with AGM alone.