SRS 16-86 promotes diabetic nephropathy recovery by regulating ferroptosis.

Diabetic nephropathy (DN) is a common complication of diabetes mellitus (DM), and cell death plays an important role. Ferroptosis is a recently discovered type of iron-dependent cell death and one that is different from other kinds of cell death including apoptosis and necrosis. However, ferroptosis has not been described in the context of DN. This study explored the role of ferroptosis in DN pathophysiology and aimed to confirm the efficacy of the ferroptosis inhibitor SRS 16-86 on DN. Streptozotocin injection was used to establish the DM and DN animal models. To investigate the presence or occurrence of ferroptosis in DN, we assessed the concentrations of iron, reactive oxygen species and specific markers associated with ferroptosis in a rat model of DN. Additionally, we performed haematoxylin-eosin staining, blood biochemistry, urine biochemistry and kidney function analysis to evaluate the efficacy of the ferroptosis inhibitor SRS 16-86 in ameliorating DN. We found that SRS 16-86 could improve the recovery of renal function after DN by upregulating glutathione peroxidase 4, glutathione and system xc -light chain and by downregulating the lipid peroxidation markers and 4-hydroxynonenal. SRS 16-86 treatment could improve renal organization after DN. The inflammatory cytokines interleukin 1ß and tumour necrosis factor α and intercellular adhesion molecule 1 were significantly decreased following SRS 16-86 treatment after DN. The results indicate that there is a strong connection between ferroptosis and the pathological mechanism of DN. The efficacy of the ferroptosis inhibitor SRS 16-86 in DN repair supports its use as a new therapeutic treatment for DN.

A New Case of Hb Headington (HBB: c.217A>C) Due to a New DNA Transversion, Found in a Patient with Type 2 Diabetes Mellitus.

We here report a novel case of Hb Headington [ß72(E16)Ser→Arg, HBB: c.217A>C, p.Ser73Arg], in a 68-year-old woman with type 2 diabetes mellitus (T2DM). Glycosylated hemoglobin (Hb) was measured by capillary electrophoresis (CE). The spectrum showed abnormal peaks between the A0 and A2 peaks. DNA sequencing demonstrated a mutation on the HBB gene, which predicted a substitution of serine to arginine at position 73 in the ß-globin chain. Moreover, this amino acid substitution occurs at the same position as Hb Headington [ß72(E16)Ser→Arg, HBB: c.219T>A, p.Ser73Arg], which showed increased oxygen affinity.

Study on the clinical efficacy of bone-filled mesh vertebroplasty combined with posterior screw and rod internal fixation in the treatment of thoracolumbar metastases: a retrospective cohort study.

BACKGROUND: Thoracolumbar metastases is a difficult disease to deal with in spinal surgery. The aim of this study is to investigate the clinical efficacy of bone-filled mesh vertebroplasty combined with posterior spinal internal fixation in the treatment of thoracolumbar metastases. METHODS: The clinical data of 68 patients with thoracolumbar vertebral metastases from January 2018 to April 2020 were retrospectively analyzed. A total of 37 cases underwent bone filling mesh pocket vertebroplasty combined with posterior spinal internal fixation as the observation group, and 31 cases underwent routine vertebroplasty combined with posterior spinal internal fixation as the control group. The visual analogue scale (VAS) scores, Oswestry disability index (ODI) scores, Karnofsky performance status (KPS) scores, and the heights of the anterior margin and middle of the diseased vertebra were compared between the 2 groups before and 1 week, 3 months, 6 months, and 1 year after surgery. RESULTS: All cases successfully completed the operation, and there was no pulmonary embolism, paraplegia, or perioperative death in follow-up reported. Intraoperative bone cement leakage occurred in 4 cases with a total of 6 vertebrae in the observation group (leakage rate: 14.29%), and in 8 cases with a total of 11 vertebrae in control group (leakage rate: 31.43%). The differences in VAS scores, ODI scores, KPS scores, and the heights of the anterior margin and middle of the diseased vertebra between preoperative and postoperative periods at 1 week, 3 months, 6 months, and 1 year in both groups were statistically significant (P<0.05), while the differences between the 2 groups were not statistically significant (P<0.05). CONCLUSIONS: The application of bone-filled mesh vertebroplasty combined with posterior internal pedicle screws fixation for the treatment of thoracolumbar metastases can not only reduce the injury of the operation, but also achieve the purpose of relieving pain, controlling local tumor growth to a certain extent, restoring neural function, and rebuilding the stability of the spine, which has important clinical value.

Spleen tyrosine kinase­induced JNK­dependent NLRP3 activation is involved in diabetic cardiomyopathy.

Diabetic cardiomyopathy (DCM) is a leading contributor to the increased morbidity and mortality rates associated with diabetes. Persistent inflammation has previously been reported to be involved in the pathogenesis of DCM. However, the exact underlying molecular mechanisms remain to be fully elucidated. In the present study, the role of spleen tyrosine kinase (Syk) and c­Jun N­terminal kinase (JNK) in NLR family pyrin domain­containing 3 (NLRP3 inflammasome) activation in DCM were investigated in vivo and in vitro. Streptozotocin (65 mg/kg) was injected intraperitoneally into Sprague­Dawley rats to induce a rat model of diabetes. Neonatal rat cardiomyocytes and H9c2 cells were cultured to detect the expression of JNK, NLRP3 and its associated downstream molecules, following treatment with Syk/JNK inhibitor or Syk/JNK­small interfering (si)RNA in high glucose (HG) conditions. It was revealed that the protein and mRNA expression levels of phospho (p)­Syk, p­JNK, NLRP3 and its associated downstream molecules, including interleukin (IL)­1ß, were upregulated in vivo and in vitro. The JNK inhibitor significantly decreased the expression of NLRP3 and its downstream molecules in neonatal rat cardiomyocytes and H9c2 cells treated with HG. Furthermore, Syk­siRNA and the Syk inhibitor markedly inhibited the HG­induced activation of JNK, followed by the downregulation of NLRP3 and its downstream molecules at the mRNA and protein levels in cells. Therefore, it was demonstrated that the HG­induced activation of NLRP3 was mediated by the activation of Syk/JNK, which subsequently increased the protein expression levels of mature IL­1ß, suggesting that the Syk/JNK/NLRP3 signaling pathway serves a critical role in the pathogenesis of DCM.

Spleen tyrosine kinase promotes NLR family pyrin domain containing 3 inflammasome­mediated IL­1ß secretion via c­Jun N­terminal kinase activation and cell apoptosis during diabetic nephropathy.

Diabetic nephropathy (DN) is a serious complication of diabetes and can cause an increased mortality risk. It was previously reported that NLR family pyrin domain containing 3 (NLRP3) inflammasome is involved in the pathogenesis of diabetes. However, the underlying mechanism is not clearly understood. In the present study, the effects of spleen tyrosine kinase (Syk) and c­Jun N­terminal kinase (JNK) on the NLRP3 inflammasome were examined in vivo and in vitro. Sprague­Dawley rats were injected intraperitoneally with streptozotocin (65 mg/kg) to induce diabetes. HK2 cells and rat glomerular mesangial cells (RGMCs) were examined to detect the expression of JNK and NLRP3 inflammasome­associated proteins following treatment with a Syk inhibitor or Syk­small interfering (si)RNA in a high glucose condition. In the present study, it was revealed that the protein and mRNA expression levels of NLRP3 inflammasome­associated molecules and the downstream mature interleukin (IL)­1ß were upregulated in vivo and in vitro. The Syk inhibitor and Syk­siRNA suppressed high glucose­induced JNK activation, and subsequently downregulated the activation of the NLRP3 inflammasome and mature IL­1ß in HK2 cells and RGMCs. Furthermore, high glucose­induced apoptosis of HK2 cells was reduced by the Syk inhibitor BAY61­3606. Therefore, the present results determined that high glucose­induced activation of the NLRP3 inflammasome is mediated by Syk/JNK activation, which subsequently increased the protein expression level of IL­1ß and mature IL­1ß. The present study identified that the Syk/JNK/NLRP3 signaling pathway may serve a vital role in the pathogenesis of DN.