Ischemic colitis induced by a platelet-raising capsule: A case report.

BACKGROUND: Ischemic colitis (IC) is also known as colon ischemia and is caused by colon vascular occlusion or nonocclusion, which results in a reduced blood supply to the colon and is not significant enough to maintain the metabolic function of cells, leading to intestinal wall ischemia. Its main symptoms include abdominal pain, diarrhea, and bloody stool. In severe cases, intestinal gangrene, peritonitis, intestinal stenosis and even intestinal obstruction may occur. IC induced by long-term use of certain special drugs is relatively rare in clinical practice. This article describes the clinical diagnosis and treatment of a typical case and provides a new treatment idea for the treatment of IC. CASE SUMMARY: The patient was admitted to the hospital with "abdominal pain for half a month and bloody stool with mucous and pus for 3 d" and was diagnosed with "IC". Symptomatic and supportive treatment, such as antibiotics (levofloxacin), acid inhibition and stomach protection, fluid replenishment, and intravenous nutrition, was given. The patient's colonic ulcers were considered to be related to the oral administration of platelet (PLT)-raising capsules; the patient was asked to stop PLT-raising drugs for selective review via colonoscopy, and antibiotics and mesalazine enteric-coated tablets were stopped. Under the guidance of hematology consultation, 60 mg of methylprednisolone was given in combination with PLT infusion to increase the PLT. After treatment, the patient's condition stabilized, the patient's stool turned yellow, the patient's symptoms improved, and the patient was allowed to leave the hospital. CONCLUSION: PLT-raising capsules can lead to IC, so clinicians should have a full understanding of the application of these drugs in the treatment of various causes of thrombocytopenia, weigh the advantages and disadvantages, and observe patients closely.

Hyperglycolysis in endothelial cells drives endothelial injury and microvascular alterations in peritoneal dialysis.

BACKGROUND: Endothelial cell (EC) dysfunction leading to microvascular alterations is a hallmark of technique failure in peritoneal dialysis (PD). However, the mechanisms underlying EC dysfunction in PD are poorly defined. METHODS: We combined RNA sequencing with metabolite set analysis to characterize the metabolic profile of peritoneal ECs from a mouse model of PD. This was combined with EC-selective blockade of glycolysis by genetic or pharmacological inhibition of 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3) in vivo and in vitro. We also investigated the association between peritoneal EC glycolysis and microvascular alterations in human peritoneal samples from patients with end-stage kidney disease (ESKD). RESULTS: In a mouse model of PD, peritoneal ECs had a hyperglycolytic metabolism that shunts intermediates into nucleotide synthesis. Hyperglycolytic mouse peritoneal ECs displayed a unique active phenotype with increased proliferation, permeability and inflammation. The active phenotype of mouse peritoneal ECs can be recapitulated in human umbilical venous ECs and primary human peritoneal ECs by vascular endothelial growth factor that was released from high glucose-treated mesothelial cells. Importantly, reduction of peritoneal EC glycolysis, via endothelial deficiency of the glycolytic activator PFKFB3, inhibited PD fluid-induced increases in peritoneal capillary density, vascular permeability and monocyte extravasation, thereby protecting the peritoneum from the development of structural and functional damages. Mechanistically, endothelial PFKFB3 deficiency induced the protective effects in part by inhibiting cell proliferation, VE-cadherin endocytosis and monocyte-adhesion molecule expression. Pharmacological PFKFB3 blockade induced a similar therapeutic benefit in this PD model. Human peritoneal tissue from patients with ESKD also demonstrated evidence of increased EC PFKFB3 expression associated with microvascular alterations and peritoneal dysfunction. CONCLUSIONS: These findings reveal a critical role of glycolysis in ECs in mediating the deterioration of peritoneal function and suggest that strategies targeting glycolysis in peritoneal ECs may be of therapeutic benefit for patients undergoing PD.

Dapagliflozin reverses the imbalance of T helper 17 and T regulatory cells by inhibiting SGK1 in a mouse model of diabetic kidney disease.

An imbalance between T helper 17 (Th17) and T regulatory (Treg) cell subsets contributes to the pathogenesis of diabetic kidney disease (DKD). However, the underlying regulatory mechanisms that cause this imbalance are unknown. Serum/glucocorticoid-regulated kinase 1 (SGK1) has been suggested to affect Th17 polarization in a salt-dependent manner, and sodium/glucose cotransporter 2 inhibitors (SGLT2i) have been demonstrated to regulate sodium-mediated transportation in the renal tubules. This study aimed to evaluate the potential benefits of dapagliflozin (Dap) on DKD, as well as its influence on shifting renal T-cell polarization and related cytokine secretion. We treated male db/db mice with Dap or voglibose (Vog) and measured blood and kidney levels of Th17 and Treg cells using flow cytometry. We found that Th17 cells were significantly increased, while Treg cells were significantly decreased in diabetic mice. Moreover, Dap suppressed the polarization of Th17/Treg cells by inhibiting SGK1 in diabetic kidneys, and this was accompanied by attenuation of albuminuria and tubulointerstitial fibrosis independent of glycemic control. Taken together, these results demonstrate that the imbalance of Th17/Treg cells plays an important role in the progression of DKD. Moreover, Dap protects against DKD by inhibiting SGK1 and reversing the T-cell imbalance.

Inhibiting Rab27a in renal tubular epithelial cells attenuates the inflammation of diabetic kidney disease through the miR-26a-5p/CHAC1/NF-kB pathway.

The effect of exosomes on receptor cells participating in intercellular communication has been extensively studied, but the effect of exosomes on donor cells remains unclear. It has been reported that exosomes secreted by renal proximal tubular epithelial cells (PTECs) under different stimuli accelerate acute and chronic kidney diseases. This study aimed to explore whether inhibiting exosomal secretion in PTECs by knocking out Rab27a, a key exosome regulatory gene, inhibits the excessive inflammatory response in PTECs and delays diabetic kidney disease (DKD). First, we proved that the bovine serum albumin (BSA)-induced inflammatory response in HK-2 cells was inhibited by knocking out Rab27a and that Rab27a, IL-6, TNF-α and COL-1 expression was markedly increased in an HFD/STZ-induced diabetic mouse model. Furthermore, miR-26a-5p expression in exosomes secreted by BSA-treated HK-2 cells was significantly increased but correspondingly decreased in the cells; after knocking out Rab27a, miR-26a-5p levels in the cells rebounded. Next, we confirmed that a miR-26a-5p mimic suppressed the inflammatory response, while a miR-26a-5p inhibitor accelerated the inflammatory response. Then, we found that miR-26a-5p targets the 3'-untranslated region (UTR) of CHAC1. Furthermore, the inflammatory response and NF-κB signalling pathway activation induction by the miR-26a-5p inhibitor were abolished by CHAC1 knockout. Therefore, we conclude that inhibiting exosome secretion by BSA-induced PTECs promotes miR-26a-5p expression in cells, thereby inhibiting the CHAC1/NF-κB pathways to prevent the inflammatory response in PTECs and delaying the development of DKD. This study provides new insight into the pathogenic mechanism of exosomes and a new therapeutic target for DKD.

Long noncoding RNA NEAT1 is involved in the protective effect of Klotho on renal tubular epithelial cells in diabetic kidney disease through the ERK1/2 signaling pathway.

Klotho, an antiaging protein, has been shown to play a protective role in renal tubular epithelial-mesenchymal transition (EMT) during the development of diabetic kidney disease (DKD). Long noncoding RNAs (lncRNAs) participate in the progression of EMT in many diseases. However, the effect of Klotho on lncRNAs during the development of DKD is still unknown. In this study, we found that Klotho overexpression in high-fat diet (HFD)- and streptozotocin (STZ)-induced DKD mice significantly inhibited the expression of lncRNA nuclear-enriched abundant transcript 1 (Neat1). We demonstrated that NEAT1 was significantly upregulated in both bovine serum albumin (BSA)-stimulated HK2 cells and mice with HFD- and STZ-induced diabetes. In addition, we observed that Klotho displays colocalization with NEAT1. Furthermore, overexpression of Klotho can inhibit the high expression of NEAT1 in BSA-stimulated HK2 cells, while silencing Klotho can further upregulate the expression of NEAT1. Silencing NEAT1 in HK2 cells resulted in inhibition of the EMT-related markers alpha smooth muscle actin (α-SMA) and vimentin (VIM) and the renal fibrosis-related markers transforming growth factor-ß1 (TGF-ß1) and connective tissue growth factor (CTGF). The effect of NEAT1 on DKD was partly mediated by regulation of the ERK1/2 signaling pathway. Finally, we found that silencing NEAT1 can reverse the activation of EMT and fibrosis caused by Klotho silencing in a manner dependent on the ERK1/2 signaling pathway. These findings reveal a new regulatory pathway by which Klotho regulates ERK1/2 signaling via NEAT1 to protect against EMT and renal fibrosis, suggesting that NEAT1 is a potential therapeutic target for DKD.