Modulating the HSP90 control over NFκB/NLRP3/Caspase-1 axis is a new therapeutic target in the management of liver fibrosis: Insights into the role of TAS-116 (Pimitespib).

Aberrant activation of the NLRP3 inflammasome is recognized to induce a chronic inflammatory response in the liver, ultimately leading to hepatic fibrosis. HSP90 is suggested to regulate NLRP3 activation and its downstream signaling. This study is the first to explore the potential therapeutic role of pimitespib in mitigating liver fibrosis in rats. The results of the study revealed that pimitespib effectively suppressed hepatic inflammation and fibrogenesis by modulating HSP90's control over the NFκB/NLRP3/caspase-1 axis. In vitro experiments demonstrated that pimitespib reduced LDH levels and increased hepatocyte survival, whereas in vivo, it prolonged the survival of rats with hepatic fibrosis. Additionally, pimitespib exhibited improvements in the function and microscopic characteristics of rat livers. Pimitespib effectively inhibited NFκB, which serves as the priming signal for NLRP3 activation. Pimitespib's inhibitory effect on NLRP3, identified as an HSP90 client protein, plays a central role in the observed anti-fibrotic effect. The simultaneous inhibition of both priming and activation signals of NLRP3 by pimitespib led to a reduction in caspase-1 activity and subsequent suppression of the N-terminal fragment of gasdermin D, ultimately constraining hepatocyte pyroptotic cell death. These diverse effects were associated with a decrease in the transcription of inflammatory mediators IL-1ß, IL-18, and TNF-α, as well as the fibrogenic mediators TGF-ß, TIMP-1, PDGF-BB, and Col1a1. Moreover, pimitespib induced the expression of HSP70, which could further contribute to the repression of fibrosis development. In summary, our findings provide an evolutionary perspective on managing liver fibrosis, positioning pimitespib as a promising candidate for anti-inflammatory and antifibrotic therapy.

Potential of honey against the onset of autoimmune diabetes and its associated nephropathy, pancreatitis, and retinopathy in type 1 diabetic animal model.

Honey has been used as a traditional remedy for various health benefits. This study investigated the potential of honey against the onset of autoimmune diabetes and its associated secondary complications in type 1 diabetic (T1D) experimental animals. Autoimmune diabetes was induced in Sprague Dawley rats, and at the same time, the rats were treated with honey or metformin. Sandwich ELISAs were used to estimate blood glucose, hemoglobin A1C (HbA1c), total cholesterol, and triglycerides. Histopathological examinations determined the T1D-induced lesions on kidneys, pancreas, cornea, and retina. Treatment of rats with honey during the course of T1D induction showed a significant reduction in fasting-blood-glucose and HbA1c (p < 0.01), and total lipid profile was also improved (p < 0.05). Not only these, but honey also reduced the T1D-induced lesions in the kidney, pancreas, and cornea/retina (p < 0.05). Metformin showed similar effects and was used as a positive control. In conclusion, honey showed therapeutic potential against the onset of autoimmune diabetes, as it reduces blood glucose/HbA1c and improves the lipid profile by reducing the plasma levels of total cholesterol, low-density lipoproteins (LDL), very low-density lipoprotein (VLDL), and triglycerides. Moreover, it also showed protective potential against the development of diabetic nephropathy, pancreatitis, and retinopathy.

Uropathogens and their antimicrobial resistance patterns: Relationship with urinary tract infections.

OBJECTIVES: This study was performed to determine the prevalence of uropathogens causing urinary tract infections (UTIs) and to determine their pattern of antimicrobial resistance. METHODS: This study was conducted on 273 urine samples collected from outpatient departments (OPDs) of Qassim University affiliated hospitals. Fully automated VITEK 2 compact system was used in the identification and antimicrobial susceptibility testing of causative microorganisms. RESULTS: Of 273 urine samples, only 89 (32.6%) were found to show significant growth for UTI, and overall, drug resistance was found in 92% (n = 82/89) of samples, with most (80%) being resistant to at least two drugs. Antibiotic resistance was commonly observed in ampicillin (88.3%), piperacillin (72.7%), clindamycin (66.7%), amoxicillin/clavulanic acid (66.2%), and trimethoprim/sulfamethoxazole (50%). The commonly isolated microorganisms were Escherichia coli 24 (27%), Klebsiella pneumoniae 11 (12.4%), Proteus mirabilis 4 (4.5%), Pseudomonas aeruginosa 4 (4.5%), Enterobacter cloacae 5 (5.6%), Enterococcus faecalis 5 (5.6%), and Staphylococcus saprophyticus 3 (3.4%). CONCLUSIONS: This research work has shown that patients with UTI in Qassim are at high risk of antibiotic resistance. The work also showed that multidrug-resistant bacteria can lead to momentous therapeutic problems in OPD patients.

Life-history responses of insects to water-deficit stress: a case study with the aphid Sitobion avenae.

BACKGROUND: Drought may become one of the greatest challenges for cereal production under future warming scenarios, and its impact on insect pest outbreaks is still controversial. To address this issue, life-history responses of the English grain aphid, Sitobion avenae (Fabricius), from three areas of different drought levels were compared under three water treatments. RESULTS: Significant differences were identified in developmental time, fecundity and adult weight among S. avenae clones from moist, semiarid and arid areas under all the three water treatments. Semiarid and arid area clones tended to have higher heritability for test life-history traits than moist area clones. We identified significant selection of water-deficit on the developmental time of 1st instar nymphs and adult weight for both semiarid and arid area clones. The impact of intermediate and severe water-stress on S. avenae's fitness was neutral and negative (e.g., decreased fecundity and weight), respectively. Compared with arid-area clones, moist- and semiarid-area clones showed higher extents of adaptation to the water-deficit level of their respective source environment. Adult weight was identified as a good indicator for S. avenae's adaptation potential under different water-stress conditions. After their exposure to intermediate water-deficit stress for only five generations, adult weight and fecundity tended to decrease for moist- and semiarid-area clones, but increase for arid-area clones. CONCLUSIONS: It is evident from our study that S. avenae clones from moist, semiarid and arid areas have diverged under different water-deficit stress, and such divergence could have a genetic basis. The impact of drought on S. avenae's fitness showed a water-level dependent pattern. Clones of S. avenae were more likely to become adapted to intermediate water-deficit stress than severe water-deficit stress. After continuous water-deficit stress of only five generations, the adaptation potential of S. avenae tended to decrease for moist and semiarid area clones, but increase for arid area clones. The rapid shift of aphids' life-history traits and adaptation potential under drought could have significant implications for their evolutionary dynamics and outbreak risks in future climate change scenarios.

Impact of water-deficit stress on tritrophic interactions in a wheat-aphid-parasitoid system.

Increasing temperature and CO2 concentrations can alter tritrophic interactions in ecosystems, but the impact of increasingly severe drought on such interactions is not well understood. We examined the response of a wheat-aphid-parasitoid system to variation in water-deficit stress levels. Our results showed that arid area clones of the aphid, Sitobion avenae (Fabricius), tended to have longer developmental times compared to semiarid and moist area clones, and the development of S. avenae clones tended to be slower with increasing levels of water-deficit. Body sizes of S. avenae clones from all areas decreased with increasing water-deficit levels, indicating their declining adaptation potential under drought. Compared to arid area clones, moist area clones of S. avenae had a higher frequency of backing under severe water stress only, but a higher frequency of kicking under well-watered conditions only, suggesting a water-deficit level dependent pattern of resistance against the parasitoid, Aphidius gifuensis (Ashmead). The number of S. avenae individuals attacked by the parasitoid in 10 min showed a tendency to decrease with increasing water-deficit levels. Clones of S. avenae tended to have lower parasitism rates under treatments with higher water-deficit levels. The development of the parasitoid tended to be slower under higher levels of water-deficit stress. Thus, the bottom-up effects of water-deficit stressed plants were negative on S. avenae. However, the top-down effects via parasitoids were compromised by water-deficit, which could favor the growth of aphid populations. Overall, the first trophic level under water-deficit stress was shown to have an indirect and negative impact on the third trophic level parasitoid, suggesting that parasitoids could be increasingly vulnerable in future warming scenarios.