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.

IL-17 deficiency aggravates the streptozotocin-induced diabetic nephropathy through the reduction of autophagosome formation in mice.

BACKGROUND: Diabetic nephropathy (DN) is one of the most important medical complications of diabetes mellitus. Autophagy is an important mediator of pathological response and plays a critical role in inflammation during the progression of diabetic nephropathy. Interleukin (IL)-17A favorably modulates inflammatory disorders including DN. In this study, we examined whether IL-17A deficiency affected the autophagy process in the kidneys of mice with streptozotocin (STZ)-induced DN. METHODS: The autophagic response of IL-17A to STZ-induced nephrotoxicity was evaluated by analyzing STZ-induced functional and histological renal injury in IL-17A knockout (KO) mice. RESULTS: IL-17A KO STZ-treated mice developed more severe nephropathy than STZ-treated wild-type (WT) mice, with increased glomerular damage and renal interstitial fibrosis at 12 weeks. IL-17A deficiency also increased the up-regulation of proinflammatory cytokines and fibrotic gene expression after STZ treatment. Meanwhile, autophagy-associated proteins were induced in STZ-treated WT mice. However, IL-17A KO STZ-treated mice displayed a significant decrease in protein expression. Especially, the levels of LC3 and ATG7, which play crucial roles in autophagosome formation, were notably decreased in the IL-17A KO STZ-treated mice compared with their WT counterparts. CONCLUSIONS: IL-17 deficiency aggravates of STZ-induced DN via attenuation of autophagic response. Our study demonstrated that IL-17A mediates STZ-induced renal damage and represents a potential therapeutic target in DN.

Protective effects of combination of Stauntonia hexaphylla and Cornus officinalis on testosterone-induced benign prostatic hyperplasia through inhibition of 5α- reductase type 2 and induced cell apoptosis.

Benign prostatic hyperplasia (BPH) is a progressive pathological condition associated with proliferation of prostatic tissues, prostate enlargement, and lower-urinary tract symptoms. However, the mechanism underlying the pathogenesis of BPH is unclear. The aim of this study was to investigate the protective effects of a combination of Stauntonia hexaphylla and Cornus officinalis (SC extract) on a testosterone propionate (TP)-induced BPH model. The effect of SC extract was examined in a TP-induced human prostate adenocarcinoma cell line. Male Sprague-Dawley rats were randomly divided into 5 groups (n = 6) for in vivo experiments. To induce BPH, all rats, except those in the control group, were administered daily with subcutaneous injections of TP (5 mg/kg) and orally treated with appropriate phosphate buffered saline/drugs (finasteride/saw palmetto/SC extract) for 4 consecutive weeks. SC extract significantly downregulated the androgen receptor (AR), prostate specific antigen (PSA), and 5α-reductase type 2 in TP-induced BPH in vitro. In in vivo experiments, SC extract significantly reduced prostate weight, size, serum testosterone, and dihydrotestosterone (DHT) levels. Histologically, SC extract markedly recovered TP-induced abnormalities and reduced prostatic hyperplasia, thereby improving the histo-architecture of TP-induced BPH rats. SC extract also significantly downregulated AR and PSA expression, as assayed using immunoblotting. Immunostaining revealed that SC extract markedly reduced the 5α-reductase type 2 and significantly downregulated the expression of proliferating cell nuclear antigen. In addition, immunoblotting of B-cell lymphoma 2 (Bcl-2) family proteins indicated that SC extract significantly downregulated anti-apoptotic Bcl-2 and markedly upregulated pro-apoptotic B cell lymphoma-associated X (Bax) expression. Furthermore, SC treatment significantly decreased the Bcl-2/Bax ratio, indicating induced prostate cell apoptosis in TP-induced BPH rats. Thus, our findings demonstrated that SC extract protects against BPH by inhibiting 5α-reductase type 2 and inducing prostate cell apoptosis. Therefore, SC extract might be useful in the clinical treatment of BPH.

Korean red ginseng attenuates hyperglycemia-induced renal inflammation and fibrosis via accelerated autophagy and protects against diabetic kidney disease.

ETHNOPHARMACOLOGICAL RELEVANCE: Panax ginseng C.A. Mey. (Korean ginseng) has been widely used in traditional medicine to treat diabetes mellitus for thousands of years. It also plays a key role in health maintenance owing to its anti-oxidant and anti-fatigue properties, and is quite popular as a dietary supplement. AIM OF THE STUDY: This study was designed to offer a complementary and alternative medicine to manage the diabetic kidney disease (DKD), which causes long-term damage to the renal structure. We also investigated the regulation of the autophagy mechanism, which is the underlying the pathogenesis of DKD. MATERIALS AND METHODS: The effect of Korean red ginseng (KRG) on DKD was evaluated using human kidney proximal tubular cells and streptozotocin (STZ)-treated Sprague-Dawley rat models. In vitro experiments were conducted to evaluate the proteins related to fibrosis and autophagy. This was followed by in vivo experiments involving rats treated with single intraperitoneal administration of STZ (60 mg/kg) and then with KRG solution orally for 4 weeks. Proteins related to renal injury, fibrosis, and autophagy were determined by immunoblotting. Hematoxylin and eosin (H&E), Periodic acid-Schiff (PAS), Sirius red, and immunostaining were processed for histological studies. RESULTS: KRG diminished the levels of metabolic measurements and blood parameters. Western blotting showed a decreased expression of proteins, such as TGF-ß1, KIM1, and AGE, which are responsible for renal inflammation, injury, and fibrosis. Histological studies also supported these results and revealed that the KRG-treated groups recovered from renal injury and fibrosis. Furthermore, the autophagy marker, LC3, was upregulated, whereas p62 was downregulated. The levels of proteins related to the autophagy mechanism, such as ATG7, increased, while mammalian target of rapamycin (mTOR) decreased with the KRG treatment and exhibited accelerated autophagy compared to the STZ alone group. CONCLUSIONS: KRG can suppress renal inflammation, injury, and fibrosis by blocking TGF-ß1 activation and can induce cellular autophagy. Therefore, this study strongly suggests that KRG exhibits a renoprotective effect against the STZ-induced DKD.

The therapeutic effects of Stauntonia hexaphylla in benign prostate hyperplasia are mediated by the regulation of androgen receptors and 5α-reductase type 2.

ETHNOPHARMACOLOGICAL RELEVANCE: Stauntonia hexaphylla (Lardizabalaceae, S. hexaphylla) is traditionally used as a folk remedy for alleviating fever and for its anti- inflammatory and analgesic properties. In Korea and China, S. hexaphylla has been used as a traditional medicine that acts as diuretic and analgesic. S. hexaphylla has also been reported to inhibit osteoporosis and aldose reductase activity. AIM OF THE STUDY: The study aimed to evaluate the therapeutic effects of an extract of S. hexaphylla on testosterone induced benign prostate hyperplasia (BPH) models and to observe its mechanism of action. MATERIALS AND METHODS: To induce a BPH model in vitro and in vivo, a testosterone-treated LNCaP cell line and Sprague Dawley (SD) rats were used, respectively. Androgen receptors (ARs) and prostate-specific antigens (PSA), which are typical BPH-related proteins, were evaluated using western blotting. Prostate weights and dihydrotestosterone (DHT) levels were measured in vivo, and histopathology of the prostate examined using hematoxylin and eosin staining. Proliferating cell nuclear antigen (PCNA) and 5α-reductase type 2 were also evaluated via immunohistochemistry (IHC). In addition, TUNEL (terminal deoxynucleotidyl transferase dUTP nick end labeling) staining and LC3 staining of IHC were performed to evaluate apoptosis and autophagy. RESULTS: S. hexaphylla reduced prostates weights and the thickness of prostate epithelial cells. In vivo and in vitro, PSA and ARs were downregulated following S. hexaphylla treatment. The S. hexaphylla extracts also reduced DHT and 5α-reductase type 2 expression. In addition, the expression of PCNA was reduced, and in the TUNEL staining and IHC of LC3, the number of positive cells was increased in the groups treated with S. hexaphylla. CONCLUSIONS: It was observed that extracts of S. hexaphylla inhibited both 5α -reductase type 2 and ARs. The results indicate that the use of S. hexaphylla extract in BPH is probably beneficial through 5α-reductase inhibition and α-adrenergic receptor blockade. In addition, apoptosis and autophagy were induced, and PCNA was downregulated after S. hexaphylla treatment. Therefore, it can be concluded that S. hexaphylla has a therapeutic effect on BPH.