Tissue Mechanics and Hedgehog Signaling Crosstalk as a Key Epithelial-Stromal Interplay in Cancer Development.

Epithelial-stromal interplay through chemomechanical cues from cells and matrix propels cancer progression. Elevated tissue stiffness in potentially malignant tissues suggests a link between matrix stiffness and enhanced tumor growth. In this study, employing chronic oral/esophageal injury and cancer models, it is demonstrated that epithelial-stromal interplay through matrix stiffness and Hedgehog (Hh) signaling is key in compounding cancer development. Epithelial cells actively interact with fibroblasts, exchanging mechanoresponsive signals during the precancerous stage. Specifically, epithelial cells release Sonic Hh, activating fibroblasts to produce matrix proteins and remodeling enzymes, resulting in tissue stiffening. Subsequently, basal epithelial cells adjacent to the stiffened tissue become proliferative and undergo epithelial-to-mesenchymal transition, acquiring migratory and invasive properties, thereby promoting invasive tumor growth. Notably, transcriptomic programs of oncogenic GLI2, mechano-activated by actin cytoskeletal tension, govern this process, elucidating the crucial role of non-canonical GLI2 activation in orchestrating the proliferation and mesenchymal transition of epithelial cells. Furthermore, pharmacological intervention targeting tissue stiffening proves highly effective in slowing cancer progression. These findings underscore the impact of epithelial-stromal interplay through chemo-mechanical (Hh-stiffness) signaling in cancer development, and suggest that targeting tissue stiffness holds promise as a strategy to disrupt chemo-mechanical feedback, enabling effective cancer treatment.

The effects of probiotics supplements on metabolic indices and clinical signs in patients with diabetic retinopathy, a randomized double blind clinical trial.

Purpose: This study was carried out to evaluate the effects of probiotics administration on clinical status and metabolic profiles in diabetic retinopathy (DR) patients. Methods: This randomized, double-blind, placebo-controlled trial was conducted among 72 DR patients. Subjects received probiotics including Lactobacillus acidophilus, Bifidobacterium bifidum, Bifidobacterium langum, Bifidobacterium lactis daily (2 × 109 CFU/each strain) (n = 36) or placebo (starch) (n = 36) and were instructed to take one capsule daily for 12 weeks. Finally, 55 participants [probiotic group (n = 30) and placebo group (n = 25)] completed the study. Fasting blood samples were obtained at baseline and after the 12-week intervention to determine metabolic profiles. To determine the effects of probiotic supplementation on clinical symptoms and biochemical variables, we used one-way repeated measures analysis of variance. Results: After the 12-week intervention, compared with the placebo, probiotic supplementation significantly decreased means serum insulin concentrations (Probiotic group: -4.9 ± 6.5vs. Placebo group: 3.0 ± 7.7 µIU/mL, Ptime×group<0.001), homeostatic model assessment for insulin resistance (Probiotic group: -2.5 ± 3.8 vs. Placebo group: 1.1 ± 2.7, Ptime×group<0.001) and hemoglobin A1c (HbA1C) (Probiotic group: -0.4 ± 0.7 vs. Placebo group: -0.02 ± 0.2%, Ptime×group=0.01), and significantly increased the quantitative insulin sensitivity check index (QUICKI) (Probiotic group: 0.02 ± 0.03 vs. Placebo group: -0.03 ± 0.04, Ptime×group<0.001). There was no significant effect of probiotic administration on other metabolic profiles and clinical symptoms. Conclusions: Overall, probiotic supplementation after 12 weeks in DR patients had beneficial effects on few metabolic profiles. This study was registered under the Iranian website for clinical trials as http://www.irct.ir: IRCT20130211012438N29.

Metabolic responses, PPAR-γ and TNF-α gene expression in type2 diabetic rats subsequent vanadyl sulfate treatment.

Vanadyl sulfate (VS), is a component of some food supplements and experimental drugs. This study was carried out to present a novel method for induction of Type 2 diabetes in rats, then for the first time in literature, for evaluating the effect of VS on metabolic parameters and gene expression, simultaneously. 40 male wistar rats were distributed between the four groups, equally. High fat diet and fructose were used for diabetes induction. Diabetic rats treated by two different dose of VS for 12 weeks. Metabolic profiles were evaluated by commercial available kits and gene expression were assayed by real time-PCR. Compared to controls, in non-treated diabetic rats, weight, glucose, triglyceride, total cholesterol, insulin and insulin resistance were increased significantly (p-value <0.05) that indicated induction of type 2 diabetes. Further, the results showed that VS significantly reduced weight, insulin secretion, Tumor Necrosis Factor-alpha (TNF-α) genes expression, lipid profiles except HDL that we couldn't find any significant change and increased Peroxisome Proliferator-Activated Receptor- gamma (PPAR-γ) gene expression in VS-treated diabetic animals in comparison with the non-treated diabetics. Our study demonstrated that vanadyl supplementation in diabetic rats had advantageous effects on metabolic profiles and related gene expression.

Targeting Nuclear Mechanics Mitigates the Fibroblast Invasiveness in Pathological Dermal Scars Induced by Matrix Stiffening.

Pathological dermal scars such as keloids present significant clinical challenges lacking effective treatment options. Given the distinctive feature of highly stiffened scar tissues, deciphering how matrix mechanics regulate pathological progression can inform new therapeutic strategies. Here, it is shown that pathological dermal scar keloid fibroblasts display unique metamorphoses to stiffened matrix. Compared to normal fibroblasts, keloid fibroblasts show high sensitivity to stiffness rather than biochemical stimulation, activating cytoskeletal-to-nuclear mechanosensing molecules. Notably, keloid fibroblasts on stiff matrices exhibit nuclear softening, concomitant with reduced lamin A/C expression, and disrupted anchoring of lamina-associated chromatin. This nuclear softening, combined with weak adhesion and high contractility, facilitates the invasive migration of keloid fibroblasts through confining matrices. Inhibiting lamin A/C-driven nuclear softening, via lamin A/C overexpression or actin disruption, mitigates such invasiveness of keloid fibroblasts. These findings highlight the significance of the nuclear mechanics of keloid fibroblasts in scar pathogenesis and propose lamin A/C as a potential therapeutic target for managing pathological scars.