Molecular and Cellular Biochemistry最新文献

Doxorubicin (DOX), a cornerstone chemotherapeutic, induces dose-limiting nephrotoxicity through NOX-4-mediated oxidative stress, inflammatory signalling, and apoptosis, thereby compromising its long-term clinical utility. This study investigated whether 5,4'-dihydroxy-6,8-dimethoxy-7-O-rhamnosylflavone (DDR), a bioactive flavonoid, protects against chronic DOX-induced renal injury. To evaluate DDR's renoprotective efficacy and elucidate its mechanistic involvement of NOX-4, NRF2, and apoptotic pathways. Male Swiss albino mice (n = 6/group) received: control vehicle, DOX (2.5 mg/kg i.p., weekly × 6 weeks), DOX + DDR (25 or 50 mg/kg i.p., twice weekly), or DDR alone. Renal function (creatinine, urea, NGAL, KIM-1), oxidative stress markers (MDA, SOD, CAT, GSH), cytokines (pNFκB, TNF-α, IL-6, IL-1β), and protein expression (NOX-4, NRF2, BCL2, BCL-XL, Caspase-3) were quantified. Histopathology employed H&E and Masson's trichrome with semi-quantitative injury scoring. DOX induced severe nephrotoxicity (serum creatinine ↑347%, tubular injury score 14.8 ± 1.4, p < 0.001), characterized by NOX-4 overexpression, NRF2 suppression, and apoptosis (Caspase-3 ↑412%). DDR elicited dose-dependent protection; high-dose DDR restored renal function (creatinine ↓78%), normalized histopathology (score 2.8 ± 0.9, p < 0.001), suppressed NOX and reactivated NRF2, and prevented apoptosis. DDR provides potent, mechanistically defined renoprotection against DOX nephrotoxicity through multi-target modulation of oxidative, inflammatory, and apoptotic pathways. These preclinical findings support DDR's development as a clinically translatable chemotherapeutic adjuvant (Human equivalent dose: 2-4 mg/kg).

Mouse intestinal organoids are ideal models for investigating intestinal development and diseases. The full potential of these models hinges on the ability to precisely engineer their genome, yet traditional methods for CRISPR-based editing in 3D cultures often surfer from low efficiency, high cytotoxicity, and inconsistent post-editing differentiation, which limits their applications. Here, we developed an electroporation approach mediated by ribonucleoprotein (RNP)-CRISPR that achieves over 90% gene editing efficiency in mouse intestinal organoids. Using this optimized method, we generated APC-knockout organoids that exhibit Wnt pathway hyperactivation, demonstrated by R-spondin1-independent growth, increased nuclear β-catenin, and enhanced proliferation. Our method addresses a critical technical gap in murine organoid research, offering a scalable platform for intestinal disease modeling.

Metabolic dysfunction-associated steatotic liver disease (MASLD), formerly known as non-alcoholic fatty liver disease (NAFLD), is a prevalent chronic liver disorder with complex pathogenesis and limited therapeutic options. Here, we identify the solute carrier SLC13A3 as a critical regulator of MASLD progression. In a mouse model fed a high-fat, high-cholesterol, and high-fructose (HFHCHF) diet, hepatic SLC13A3 expression was significantly upregulated and positively correlated with disease severity. Liver-specific overexpression of Slc13a3 exacerbated hepatic steatosis, lipid accumulation, and metabolic dysfunction, whereas Slc13a3 knockdown attenuated these pathological phenotypes. Targeted metabolomic analysis revealed that SLC13A3 modulates hepatic NAD⁺ levels, thereby influencing the expression of key lipid metabolism genes, including SREBF1, CD36, PPARγ, and SCD1. These findings highlight a previously unrecognized role of SLC13A3 in MASLD pathogenesis and suggest its potential as a therapeutic target.

Diabetic nephropathy (DN) is a severe complication of type 2 diabetes mellitus (T2DM) that is frequently accompanied by cardiovascular disease (CVD) and chronic kidney disease (CKD). The current therapeutic options for DN and CVD are limited and often produce significant adverse effects. In this study, we evaluated the renal and cardioprotective effects of natural Gomisin A, alone and in combination with metformin, in a diabetic model. While treatment with Gomisin A at 20 mg/kg slightly improved glycemic control and renal function, co-administration with metformin yielded better results. The combined treatment significantly lowered blood glucose levels and improved β-cell integrity. It also prevented renal hypertrophy and reduced inflammation, as evidenced by decreased serum creatinine, urea, phosphorus, lactate dehydrogenase (LDH), and malondialdehyde (MDA) levels. Additionally, the combination modulated the AGE/RAGE pathway, thereby downregulating NF-κB expression, reducing proinflammatory cytokines, and lowering TGF-β expression in renal tissues. Cardiac protective effects were also observed, including inhibition of myocardial thickening and hypertrophy. These findings suggest that Gomisin A and metformin work synergistically to mitigate the progression of DN and CVD, supporting the potential of Gomisin A as a nutraceutical adjunct to conventional anti-diabetic treatments.