The question of whether variable risk factors and various nutrients are causally related to inflammatory bowel diseases (IBDs) has remained unanswered so far. Thus, this study investigated whether genetically predicted risk factors and nutrients play a function in the occurrence of inflammatory bowel diseases, including ulcerative colitis (UC), non-infective colitis (NIC), and Crohn’s disease (CD), using Mendelian randomization (MR) analysis. Utilizing the data of genome-wide association studies (GWASs) with 37 exposure factors, we ran Mendelian randomization analyses based on up to 458,109 participants. Univariable and multivariable MR analyses were conducted to determine causal risk factors for IBD diseases. Genetic predisposition to smoking and appendectomy as well as vegetable and fruit intake, breastfeeding, n-3 PUFAs, n-6 PUFAs, vitamin D, total cholesterol, whole-body fat mass, and physical activity were related to the risk of UC (p < 0.05). The effect of lifestyle behaviors on UC was attenuated after correcting for appendectomy. Genetically driven smoking, alcohol consumption, appendectomy, tonsillectomy, blood calcium, tea intake, autoimmune diseases, type 2 diabetes, cesarean delivery, vitamin D deficiency, and antibiotic exposure increased the risk of CD (p < 0.05), while vegetable and fruit intake, breastfeeding, physical activity, blood zinc, and n-3 PUFAs decreased the risk of CD (p < 0.05). Appendectomy, antibiotics, physical activity, blood zinc, n-3 PUFAs, and vegetable fruit intake remained significant predictors in multivariable MR (p < 0.05). Besides smoking, breastfeeding, alcoholic drinks, vegetable and fruit intake, vitamin D, appendectomy, and n-3 PUFAs were associated with NIC (p < 0.05). Smoking, alcoholic drinks, vegetable and fruit intake, vitamin D, appendectomy, and n-3 PUFAs remained significant predictors in multivariable MR (p < 0.05). Our results provide new and comprehensive evidence demonstrating that there are approving causal effects of various risk factors on IBDs. These findings also supply some suggestions for the treatment and prevention of these diseases.

The present study is designed to determine the effect of LCZ696 on DCM in rats and investigate the underlying mechanism involved. Diabetes was induced by feeding rats with a high-fat diet for six weeks following a single injection of STZ (30 mg/kg). Diabetic rats were divided into three groups (n = 10). LCZ696 and valsartan treatment was started two weeks after diabetic induction and continued for eight weeks. At the end of the treatment, serum and cardiac tissues were analyzed by RT-PCR, Western blot, and ELISA kits. LCZ696 and valsartan ameliorated DCM progression by inhibiting AGEs formation at activity levels; pro-apoptotic markers (BAX/Bcl2 ratio and caspase-3) in mRNA and protein expressions, the NF-κB at mRNA; and protein levels associated with the restoration of elevated proinflammatory cytokines such as the TNF-α, IL-6, and IL-1β at the activity level. Furthermore, LCZ696 and valsartan contribute to restoring the induction of ER stress parameters (GRP78, PERK, eIF2a, ATF4, and CHOP) at mRNA and protein levels. LCZ696 and valsartan attenuated DCM by inhibiting the myocardial inflammation, ER stress, and apoptosis through AGEs/NF-κB and PERK/CHOP signaling cascades. Collectively, the present results reveal that LCZ696 had a more protective solid effect against DCM than valsartan.

Chronic kidney disease (CKD) is the progressive loss of renal function and the leading cause of end-stage renal disease (ESRD). Despite optimal therapy, many patients progress to ESRD and require dialysis or transplantation. The pathogenesis of CKD involves inflammation, kidney fibrosis, and blunted renal cellular antioxidant capacity. In this review, we have focused on in vitro and in vivo experimental and clinical studies undertaken to investigate the mechanistic pathways by which these compounds exert their effects against the progression of CKD, particularly diabetic nephropathy and kidney fibrosis. The accumulated and collected data from preclinical and clinical studies revealed that these plants/bioactive compounds could activate autophagy, increase mitochondrial bioenergetics and prevent mitochondrial dysfunction, act as modulators of signaling pathways involved in inflammation, oxidative stress, and renal fibrosis. The main pathways targeted by these compounds include the canonical nuclear factor kappa B (NF-κB), canonical transforming growth factor-beta (TGF-β), autophagy, and Kelch-like ECH-associated protein 1 (Keap1)/nuclear factor erythroid factor 2-related factor 2 (Nrf2)/antioxidant response element (ARE). This review presented an updated overview of the potential benefits of these antioxidants and new strategies to treat or reduce CKD progression, although the limitations related to the traditional formulation, lack of standardization, side effects, and safety.

LCZ696 (valsartan/sacubitril) has the potential to slow the progression of diabetic kidney disease (DKD) according to previous reports. However, the renoprotective mechanism underlying LCZ696 remains unknown. This study aimed to investigate the therapeutic potential and underlying mechanism of LCZ696 in DKD in a type 2 diabetic (T2D) rat model. This model was established in this experiment by feeding a high-fat diet (HFD) for six weeks with a single dose of streptozotocin (STZ, 30 mg/kg body weight). Valsartan or LCZ696 was orally administered to T2D animals for eight weeks. HFD/STZ rats showed hyperglycemia, impaired insulin secretion, significant increases in urea, creatinine, cytokines, nuclear factor kappa B (NF-κB), oxidative stress, caspase-3 activity, glomerular and tubular damage, glomerulsclerosis, Bax and caspese-3 expressions along with a significant decline in IL-10, antioxidant markers, and Bcl-2 expression. The administration of LCZ696 to diabetic rats reduced the serum concentrations of glucose, urea, and creatinine. In addition, ELISA results demonstrated that diabetic rats treated with LCZ696 exhibited a reduction in inflammatory (IL-1β, TNF-α, IL-6) and an increase in anti-inflammatory (IL-10) cytokine levels. In addition, a notable decrease in NF-κB and caspase-3 activity was observed. At the level of renal tissue homogenate, diabetic animals treated with LCZ696 demonstrated clear restorations in GSH content and other antioxidant enzyme levels, in addition to a significant decrease in TBARS levels. In addition, LCZ696 inhibited the expression of the Bax and cleaved caspase-3 proteins and enhanced the expression of the Bcl-2 protein. Improvements in histopathological changes in kidney tissues confirmed and significantly supported these biochemical findings. In summary, LCZ696 alleviated DKD with possible mechanisms including inhibition of inflammation and apoptosis.

Helicobacter pylori (H. pylori) is a persistent bacterial inhabitant in the stomachs of approximately half the global populace. This bacterium is directly linked to chronic gastritis, leading to a heightened risk of duodenal and gastric ulcer diseases, and is the predominant risk factor for gastric cancer - the second most common cause of cancer-related deaths globally. The increasing prevalence of antibiotic resistance necessitates the exploration of innovative treatment alternatives to mitigate the H. pylori menace. Initiating our study, we curated a list of thirty phytochemicals based on previous literature and subjected them to molecular docking studies. Subsequently, eight phytocompounds—Glabridin, Isoliquiritin, Sanguinarine, Liquiritin, Glycyrrhetic acid, Beta-carotin, Diosgenin, and Sarsasapogenin—were meticulously chosen based on superior binding scores. These were further subjected to an extensive computational analysis encompassing ADMET profiling, drug-likeness evaluation, principal component analysis (PCA), and molecular dynamic simulations (MDs) in comparison with the conventional drug, Mitomycin. The natural compounds investigated demonstrated superior docking affinities to H. pylori targets compared to the standard Mitomycin. Notably, the phytocompounds Diosgenin and Sarsasapogenin stood out due to their exceptional binding affinities and pharmacokinetic properties, including favorable ADMET profiles. Our comprehensive and technologically-advanced approach showcases the potential of identified phytocompounds as pioneering therapeutic agents against H. pylori-induced gastric malignancies. In light of our promising in silico results, we recommend these natural compounds as potential candidates for advancing H. pylori-targeted drug development. Given their potential, we strongly advocate for subsequent in vitro and in vivo studies to validate their therapeutic efficacy against this formidable gastrointestinal bacterium.