Clinical and Experimental Pharmacology and Physiology最新文献

The rough morphotype of Mycobacterium abscessus exhibits significantly higher virulence compared to the smooth morphotype, yet the underlying molecular mechanisms remain incompletely understood. Pyroptosis in macrophages plays a pivotal role in lung tissue damage; however, its specific involvement in Mycobacterium abscessus infection remains to be fully clarified. In this study, we identified that the rough morphotype of Mycobacterium abscessus upregulates the ROS/p65/NLRP3/GSDMD signalling pathway, thereby mediating pyroptosis in THP-1-derived macrophages. This heightened ability to induce macrophage pyroptosis is attributed to the bacterium's capacity to sustain intracellular viability and proliferation. These findings offer valuable insights into the virulence mechanisms of Mycobacterium abscessus and provide a foundation for future therapeutic interventions.

Sepsis-induced organ failure is a major health problem, characterised by massive inflammatory and oxidative stress responses. Endothelin-1 (ET-1) is one of the peptides expressed during septicemia with proapoptotic, proinflammatory, and oxidant effects. ET-1 plays a role in heart and kidney injuries in sepsis. Accordingly, the current study was conducted to investigate, on a mechanistic basis, whether inhibition of ET-1 signalling either by blocking its receptors or inhibiting its formation attenuates sepsis-induced acute cardiorenal injuries. To analyse the role of ET-1 in sepsis, we used a cecal ligation and puncture (CLP) model of sepsis. The animals were divided into five groups: CLP non-treated group, CLP-treated groups with bosentan, ambrisentan, and phosphoramidon (30, 5, and 0.5 mg/kg, respectively), and sham-operated group. In addition to the same set of groups, survival analysis was assigned Survival rate, histopathological assessment, and cardiorenal functions were analysed. Oxidant and antioxidant activities, ET-1, IL-6, and lactate were measured. The expression of TNF-α, p38, Klotho, and caspase-3 was evaluated by immunohistochemistry. CLP caused acute cardiorenal damage, high mortality, upregulated levels of ET-1, IL-6, and lactate, as well as an imbalance in oxidant/antioxidant activities, elevated expression of TNF-α, p38, caspase-3 and reduced expression of klotho. Bosentan, ambrisentan, or phosphoramidon improved survival, reduced the levels of inflammatory and oxidative stress parameters, improved cardiorenal functions and structure, elevated the tissue contents of GSH and SOD, raised the expression of klotho protein, and reduced the cardiorenal expression of p38, TNF-α and caspase-3. Endothelin receptor antagonists (ERAs); bosentan and ambrisentan, or endothelin converting enzyme inhibitor (ECE-i) phosphoramidon, are promising agents against sepsis-induced organ damage. This was evident in their cardiorenal protective effects, up-regulation of klotho, suppression of inflammation, oxidation, apoptosis, and enhancement of the antioxidant status.

Lung ischemia–reperfusion injury (LIRI) is a critical pathological process associated with various clinical conditions, characterised by excessive inflammatory responses and cell death, which can lead to severe respiratory dysfunction and even mortality. However, no effective therapeutic strategy is currently available. This study investigates the protective effects and underlying mechanisms of the Hsp90 inhibitor 17-dimethylaminoethylamino (17-DMAG) in LIRI. An in vivo mouse model of LIRI was established by transiently occluding the left pulmonary hilum with a microvascular clamp, followed by reperfusion. In vitro, necroptosis was induced in BEAS-2B cells using TSZ (TNF-α, Smac mimetic and z-VAD-FMK). Our results demonstrate that 17-DMAG significantly attenuates lung injury, inflammation and epithelial cell necroptosis in mice. Additionally, 17-DMAG mitigates TSZ-induced cell death and inflammatory responses in BEAS-2B cells. Mechanistically, 17-DMAG inhibits the phosphorylation of RIPK1, RIPK3 and MLKL—key necroptotic regulators and client proteins of Hsp90—thereby suppressing necroptosis and reducing the associated inflammatory response. In conclusion, 17-DMAG alleviates LIRI by inhibiting necroptosis and its consequent acute inflammatory cascade. These findings suggest that 17-DMAG may serve as a promising therapeutic candidate for LIRI treatment.

Hypertriglyceridaemia (HTG) is a common and well-established aetiology of acute pancreatitis (AP). Although the underlying pathophysiology of hypertriglyceridaemic pancreatitis (HTGP) is complex, some animal models of HTAP have been successfully reproduced by repeated caerulein injections based on HTAP. However, most of the current HTGP models are critically dependent on the “two-attack” of cholecystokinin analogue, which may not be consistent with the fact of HTGP aetiologies due to ignored the initial effects of HTG in the development of HTGP. Here, we showed that HTGP could be induced by HTG independently, the HTGP mice with the typical characteristics and typical complications of pancreatitis. We found that the HTGP mice with mild pancreatic oedema, but the necrosis and immune cell infiltration were extensive. In addition, the immune cell infiltration and immune dysregulation that widely observed in HTGP patients were well reproduced in this model, including innate and adaptive immune cells. Our results suggest that the murine HTGP model independently induced by HTG could recapitulate the pathological and immunological profiles of HTGP in the clinic. More importantly, the model generated by this method could sustain a prolonged, non-life-threatening course of the disease and is suitable for research into the underlying mechanisms and for application to the preclinical evaluation of HTGP drugs.

Norisoboldine (NIB) displays beneficial effects on cardiovascular diseases, although its protective role and underlying mechanisms in myocardial ischemia (MI) injury remain elusive. The aim of this study is to explore the potential cardioprotective mechanism of NIB on MI injury caused by isoproterenol (ISO). We administered NIB to SD rats at 20 and 40 mg/kg daily for 7 days in this study; this was followed by an ISO injection to induce MI injury. Parameters such as electrocardiogram readings, heart rate, serum concentrations of creatine kinase (CK) and creatine kinase-MB (CK-MB), levels of inflammatory markers, some histopathological assessments and oxidative stress markers were evaluated. We conducted Western blot analyses to evaluate protein expression related to apoptosis and the TLR4–MyD88-mediated NF-κB activation pathway. The L-type Ca²⁺ current (ICa-L) and contraction of isolated ventricular cells from rats were identified using patch-clamp methods and the IonOptix detection system. The treatment with NIB resulted in improvements in heart rate and ST-segment changes, a reduction in CK and CK-MB levels, the restoration of superoxide dismutase, catalase and glutathione levels and a decrease in malondialdehyde accumulation. Furthermore, NIB reduced the expression of inflammatory markers, lowered Ca²⁺ levels and reactive oxygen species production and improved myocardial tissue morphology. It also countered ISO-induced alterations in apoptosis and the TLR4–MyD88-dependent NF-κB activation pathway. Additionally, NIB considerably attenuated ICa-L and reduced the contractile function of cardiomyocytes. These results suggest that NIB effectively mitigates ISO-induced MI injury through anti-inflammatory, antioxidative, and anti-apoptotic mechanisms, potentially involving the TLR4–MyD88-dependent NF-κB activation pathway and calcium balance.

Lung cancer is most terrible cause of cancer-related death throughout the world. This study focused on the synthesis and characterisation of novel flavokawain A ruthenium-p-cymene complex and to investigate the chemotherapeutic activity against lung carcinoma via in silico, in vitro and in vivo approaches. The complex was characterised via several spectroscopic techniques. In vitro study including cell viability, transwell migration, Western blot and flow cytometric analysis have been executed on both A549 and NCI-H460 cells. The toxicological assessment was performed and subsequently anticancer activity of complex was evaluated in benzo[α]pyrene persuaded lung carcinoma in mice. The molecular docking study demonstrated the compound has greater binding ability with β-catenin, Akt, HER2 and PARP. Followed by the complex treatment, the downregulation of β-catenin, PI3K, Akt, HER2 and PARP were investigated by Western blot analysis and cell cycle arrest was determined through flow cytometry. The outcomes of in vivo experimentation represented fruitful restoration of typical lung architecture after complex treatment. Immunohistochemical analysis demonstrated the downstream of β-catenin/m-TOR/Akt and upstream of caspase-3 and p53 expression, thereby initiating apoptosis. The complex exhibited a potent chemotherapeutic activity via the alteration of tumour microenvironment by modulating PI3K/Akt/β-catenin/HER2/PARP transduction in correlates with apoptotic events in lung carcinoma.

Rhamnetin is a naturally occurring flavonoid compound found in many wild plant species and indigenous fruits. Despite its numerous biological potentials, such as anti-inflammatory, antioxidant and antimicrobial effects, there is a lack of literature elucidating its gastroprotective action and anticipating molecular mechanism. Natural products can be a good alternative to overcome the side effects and relapses associated with anti-ulcer drugs. This study aims to elucidate rhamnetin's acute toxicity and gastroprotective effects using the indomethacin ulceration model. Animals were arbitrarily divided into five groups: a negative control group (A) and a positive control group (B), both treated with 1% carboxymethyl cellulose; a reference group (C) receiving 20 mg/kg omeprazole; and low-dose (D) and high-dose (E) rhamnetin groups receiving 30 and 60 mg/kg, respectively. After 1 h, rats in Groups B–E were subjected to indomethacin-induced ulceration. Toxicity evaluations indicated the safety of rhamnetin at doses of up to 400 mg/kg in rats, without any noticeable physiological alterations. Rhamnetin (30 and 60 mg/kg) administered orally 1 h before indomethacin-induced gastric ulcer ameliorated the stomach lesions and lowered the ulcer index area by 73.81% and 77.87%, respectively. Rhamnetin supplementation ameliorated histopathological alterations and restored gastric barriers, including gastric pH and mucin secretion. Moreover, rhamnetin-treated rats exhibited increased anti-apoptotic heat shock protein 70 and decreased Bax protein in stomach tissues. These findings were in line with lowered accumulated MDA, increased superoxide dismutase, catalase and prostaglandin E2 levels, reduced serum inflammatory mediators (TNF-α and interleukin-6) and elevated interleukin-10 cytokines. The outcomes indicate rhamnetin's cicatrising and gastroprotective effects against indomethacin-mediated ulceration, possibly due to its modulatory actions on oxidative stress, inflammation and apoptotic pathways.