Focal segmental glomerular sclerosis (FSGS) is a primary kidney disease that is commonly associated with proteinuria and progressive loss of glomerular function, leading to development of chronic kidney disease (CKD). FSGS is characterized by podocyte injury and depletion and collapse of glomerular capillary segments. Progression of FSGS is associated with TGF-β activation in podocytes; however, it is not clear how TGF-β signaling promotes disease. Here, we determined that podocyte-specific activation of TGF-β signaling in transgenic mice and BALB/c mice with Adriamycin-induced glomerulosclerosis is associated with endothelin-1 (EDN1) release by podocytes, which mediates mitochondrial oxidative stress and dysfunction in adjacent endothelial cells via paracrine EDN1 receptor type A (EDNRA) activation. Endothelial dysfunction promoted podocyte apoptosis, and inhibition of EDNRA or scavenging of mitochondrial-targeted ROS prevented podocyte loss, albuminuria, glomerulosclerosis, and renal failure. We confirmed reciprocal crosstalk between podocytes and endothelial cells in a coculture system. Biopsies from patients with FSGS exhibited increased mitochondrial DNA damage, consistent with EDNRA-mediated glomerular endothelial mitochondrial oxidative stress. Our studies indicate that segmental glomerulosclerosis develops as a result of podocyte-endothelial crosstalk mediated by EDN1/EDNRA-dependent mitochondrial dysfunction and suggest that targeting the reciprocal interaction between podocytes and endothelia may provide opportunities for therapeutic intervention in FSGS.

Here we report a computational method to improve efficiency of a de novo designed Kemp Eliminase enzyme KE15, by identifying mutations that enhance electric fields and chemical positioning of the substrate that contribute to free energy stabilization of the transition state.Starting from the design that has a kcat/KM of 27 M -1 s -1 , the most improved variant introduced 4 computationally targeted mutations to yield a kcat/KM of 403 M -1 s -1 , with almost all of the enzyme improvement realized through a 43-fold improvement in kcat, indicative of a direct impact on the chemical step. This work raises the prospect of computationally designing enzymes that achieve better efficiency with more minimal experimental intervention using electric field optimization as guidance. † authors contributed equally

High-grade serous ovarian cancer (HGSOC) is hallmarked by early onset of peritoneal dissemination, which distinguishes it from low-grade serous ovarian cancer (LGSOC). Here, we describe the aggressive nature of HGSOC ascitic tumor cells (ATCs) characterized by integrin α5high (ITGA5high) ATCs, which are prone to forming heterotypic spheroids with fibroblasts. We term these aggregates as metastatic units (MUs) in HGSOC for their advantageous metastatic capacity and active involvement in early peritoneal dissemination. Intriguingly, fibroblasts inside MUs support ATC survival and guide their peritoneal invasion before becoming essential components of the tumor stroma in newly formed metastases. Cancer-associated fibroblasts (CAFs) recruit ITGA5high ATCs to form MUs, which further sustain ATC ITGA5 expression by EGF secretion. Notably, LGSOC is largely devoid of CAFs and the resultant MUs, which might explain its metastatic delay. These findings identify a specialized MU architecture that amplifies the tumor–stroma interaction and promotes transcoelomic metastasis in HGSOC, providing the basis for stromal fibroblast-oriented interventions in hampering OC peritoneal propagation.

The electrical conductivity and Seebeck coefficient of the PPy/GNs composites have been greatly enhanced as the GNs content increases, while the thermal conductivity still keeps a relatively low value.

There is an urgent need to make cisplatin (cDDP) more effective and less toxic in the treatment of ovarian cancer for its systemic side effects and high resistance rate. In this study, we investigated the effect of quercetin (Qu) pretreatment on the potentiation of cDDP in ovarian cancer. We found that Qu pretreatment significantly enhanced cDDP cytotoxicity in an ovarian cancer cell line and primary cancer cells. In addition, we demonstrated that Qu elicited obvious endoplasmic reticulum stress (ERS) and activated all three branches of ERS in ovarian cancer. Specific inhibitors of each ERS pathway, as well as the general ERS stabilizer tauroursodeoxycholic acid, notably diminished such enhancing effects. Furthermore, Qu notably suppressed STAT3 phosphorylation, leading to downregulation of the BCL-2 gene downstream of STAT3. Moreover, blocking ERS restored the protein levels of phosphorylated STAT3 as well as BCL-2 expression, thus abolishing the chemosensitization potency of Qu; these results revealed that Qu affected the STAT3 pathway to enhance cDDP cytotoxicity, and this effect involved ERS signaling. In a xenograft mouse model of ovarian cancer, Qu enhanced the antitumor effect of cDDP. Tumors from mice treated with cDDP in combination with Qu pretreatment had repressed STAT3 phosphorylation, lower BCL-2 and higher apoptosis levels compared with those from the other groups. Meanwhile, Qu markedly reduced the elevation of blood creatinine during cDDP intervention. These data indicate that Qu pretreatment potentiates the antitumor effects of cDDP in ovarian cancer while protecting the kidneys against damage. Therefore the strategy of Qu pretreatment may be beneficial in enhancing the therapeutic efficacy of cDDP against ovarian cancer.

The authors regret that in their original paper, the Masson's image of the control group in Fig. 7 J was incorrect as a result of an error during figure preparation. The corrected figure appears below.

TGFb signaling plays a central role in the development of acute and chronic kidney diseases. Previous in vivo studies involved systemic alteration of TGFb signaling, however, limiting conclusions about the direct role of TGFb in tubular cell injury. Here, we generated a double transgenic mouse that inducibly expresses a ligand-independent constitutively active TGFb receptor type 1 (TbR1) kinase specifically in tubular epithelial cells, with expression restricted by the Pax8 promoter. In this model, activation of TGFb signaling in the tubular epithelium alone was sufficient to cause AKI characterized by marked tubular cell apoptosis and necrosis, oxidative stress, dedifferentiation and regenerative cell proliferation, reduced renal function, and interstitial accumulation of inflammatory cells. This tubular injury was associated with mitochondrial-derived generation of reactive oxygen species (ROS), but cell damage and apoptosis were partially independent of mitochondrial-derived ROS.

Ovarian cancer is a devastating disease due to its high incidence of relapse and chemoresistance. The tumor microenvironment, especially the tumor stroma compartment, was proven to contribute tremendously to the unsatisfactory chemotherapeutic efficacy in ovarian cancer. Cytotoxic agents not only effect tumor cells, but also modulate the phenotype and characteristics of the vast stromal cell population, which can in turn alter the tumor cell response to chemointervention. In this study, we focused on the tumor stroma response to cytotoxic agents and the subsequent effect on the ovarian cancer tumor cells. First, we found a significant stromal overexpression of IL6 in patient samples that received cisplatin-based treatment, which was further validated in purified fibroblasts challenged with cisplatin. Stromal fibroblast-derived IL6 was proven to mediate ovarian cancer tumor cell chemoresistance. For the first time, we found that the tumor stroma of patients with routine metformin administration exhibited lower IL6 expression. Thus, we presumed that metformin was a potent alleviator of stromal inflammation in ovarian cancer. We found that metformin partly reversed cisplatin-stimulated IL6 secretion in the stromal fibroblasts and attenuated fibroblast-facilitated tumor growth in 3D organotypic cocultures and murine xenograft models. Mechanistically, we found that metformin inhibited IL6 secretion via suppressing NFκB signaling, an upstream controller of stromal inflammation. Collectively, our findings introduced a novel mechanism of metformin in suppressing ovarian cancer progression through diminishing chemotherapy-induced stromal activation. Therefore, we provide an alternative therapeutic option in targeting stromal inflammation and a potential scheme of combination therapy to improve the chemosensitivity in ovarian cancer. .