Short-term efficacy of microwave ablation in the treatment of liver cancer and its effect on immune function.

BACKGROUND: Hepatectomy is the first choice for treating liver cancer. However, inflammatory factors, released in response to pain stimulation, may suppress perioperative immune function and affect the prognosis of patients undergoing hepatectomies. AIM: To determine the short-term efficacy of microwave ablation in the treatment of liver cancer and its effect on immune function. METHODS: Clinical data from patients with liver cancer admitted to Suzhou Ninth People's Hospital from January 2020 to December 2023 were retrospectively analyzed. Thirty-five patients underwent laparoscopic hepatectomy for liver cancer (liver cancer resection group) and 35 patients underwent medical image-guided microwave ablation (liver cancer ablation group). The short-term efficacy, complications, liver function, and immune function indices before and after treatment were compared between the two groups. RESULTS: One month after treatment, 19 patients experienced complete remission (CR), 8 patients experienced partial remission (PR), 6 patients experienced stable disease (SD), and 2 patients experienced disease progression (PD) in the liver cancer resection group. In the liver cancer ablation group, 21 patients experienced CR, 9 patients experienced PR, 3 patients experienced SD, and 2 patients experienced PD. No significant differences in efficacy and complications were detected between the liver cancer ablation and liver cancer resection groups (P > 0.05). After treatment, total bilirubin (41.24 ± 7.35 vs 49.18 ± 8.64 µmol/L, P < 0.001), alanine aminotransferase (30.85 ± 6.23 vs 42.32 ± 7.56 U/L, P < 0.001), CD4+ (43.95 ± 5.72 vs 35.27 ± 5.56, P < 0.001), CD8+ (20.38 ± 3.91 vs 22.75 ± 4.62, P < 0.001), and CD4+/CD8+ (2.16 ± 0.39 vs 1.55 ± 0.32, P < 0.001) were significantly different between the liver cancer ablation and liver cancer resection groups. CONCLUSION: The short-term efficacy and safety of microwave ablation and laparoscopic surgery for the treatment of liver cancer are similar, but liver function recovers quickly after microwave ablation, and microwave ablation may enhance immune function.

Macrophage-Targeting DNA Nanomaterials: A Future Direction of Biological Therapy.

DNA can be used for precise construction of complex and flexible micro-nanostructures, including DNA origami, frame nucleic acids, and DNA hydrogels. DNA nanomaterials have good biocompatibility and can enter macrophages via scavenger receptor-mediated endocytosis. DNA nanomaterials can be uniquely and flexibly designed to ensure efficient uptake by macrophages, which represents a novel strategy to regulate macrophage function. With the development of nanotechnology, major advances have been made in the design and manufacturing of DNA nanomaterials for clinical therapy. In diseases accompanied by macrophage disturbances including tumor, infectious diseases, arthritis, fibrosis, acute lung injury, and atherosclerosis, DNA nanomaterials received considerable attention as potential treatments. However, we lack sufficient information to guarantee precise targeting of macrophages by DNA nanomaterials, which precludes their therapeutic applications. In this review, we summarize recent studies of macrophage-targeting DNA nanomaterials and discuss the limitations and challenges of this approach with regard to its potential use as a biological therapy.

Curcumin ameliorates focal segmental glomerulosclerosis by inhibiting apoptosis and oxidative stress in podocytes.

Focal segmental glomerulosclerosis (FSGS), a podocyte disease, is the leading cause of end-stage renal disease (ESRD). Nevertheless, the current effective treatment for FSGS is deficient. Curcumin (CUR) is a principal curcuminoid of turmeric, which is a member of the ginger family. Previous studies have shown that CUR has renoprotective effects. However, the mechanism of CUR in anti-FSGS is not clear. This study aimed to explore the mechanism of CUR against FSGS through a combination of network pharmacological methods and verification of experiments. The analysis identified 98 shared targets of CUR against FSGS, and these 98 targets formed a network of protein-protein interactions (PPI). Of these 98 targets, AKT1, TNF, IL-6, VEGFA, STAT3, MAPK3, HIF1A, CASP3, IL1B, and JUN were identified as the hub targets. Molecular docking suggested that the best binding to CUR is MAPK3 and AKT1. Apoptotic process and cell proliferation were identified as the main biological processes of CUR against FSGS by gene ontology (GO) analysis. The most enriched signaling pathway in the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis was the PI3K-AKT signaling pathway. Western blots and flow cytometry showed that CUR could inhibit adriamycin (ADR) induced apoptosis, oxidative stress damage, and attenuate podocyte epithelial-mesenchymal transition (EMT) by repressing the AKT signaling pathway. Collectively, our study demonstrates that CUR can attenuate apoptosis, oxidative stress damage, and EMT in FSGS in vitro. These results supply a compelling basis for future studies of CUR for the clinical treatment of FSGS.

Role of the SLIT-ROBO signaling pathway in renal pathophysiology and various renal diseases.

SLIT ligand and its receptor ROBO were initially recognized for their role in axon guidance in central nervous system development. In recent years, as research has advanced, the role of the SLIT-ROBO signaling pathway has gradually expanded from axonal repulsion to cell migration, tumor development, angiogenesis, and bone metabolism. As a secreted protein, SLIT regulates various pathophysiological processes in the kidney, such as proinflammatory responses and fibrosis progression. Many studies have shown that SLIT-ROBO is extensively involved in various aspects of kidney development and maintenance of structure and function. The SLIT-ROBO signaling pathway also plays an important role in different types of kidney disease. This article reviews the advances in the study of the SLIT-ROBO pathway in various renal pathophysiological and kidney disorders and proposes new directions for further research in this field.

TOPK Activation Exerts Protective Effects on Cisplatin-induced Acute Kidney Injury.

OBJECTIVE: T-LAK-cell-originated protein kinase (TOPK), a PSD95-Disc large-ZO1 (PDZ) binding kinase (PBK), is a novel member of the mitogen-activated protein kinase (MAPK) family. Studies have shown that TOPK plays a critical role in the function of tumor cells, including apoptosis and mitosis. However, little is known on the effect of TOPK in cisplatin-induced acute kidney injury (CP-AKI). This study aimed to investigate the role and mechanism of TOPK in CP-AKI. METHODS: Cisplatin was administered to C57BL/6 mice and cultured kidney tubular epithelial cells (TECs) to establish the CP-AKI murine or cellular models. TECs were then stimulated with the specific inhibitor of TOPK OTS514 or transfected with the recombinant-activated plasmid TOPK-T9E to inhibit or activate TOPK. The TECs were treated with AKT inhibitor VIII following stimulation with OTS514 or cisplatin. Western blotting and flow cytometry were used to evaluate the cell cycle and apoptosis of TECs. RESULTS: The analysis revealed that the TOPK activity was significantly suppressed by cisplatin, both in vivo and in vitro. Furthermore, the pharmacological inhibition of TOPK by OTS514, a specific inhibitor of TOPK, exacerbated the cisplatin-induced cell cycle arrest in the G2/M phase and apoptosis of cultured TECs. Moreover, the TOPK activation via the TOPK-T9E plasmid transfection could partially reverse the cell cycle arrest at the G2/M phase and apoptosis of cisplatin-treated TECs. In addition, AKT/protein kinase B (PKB), as a TOPK target protein, was inhibited by cisplatin in cultured TECs. The pharmaceutical inhibition of AKT further aggravated the apoptosis of TECs induced by cisplatin or TOPK inhibition. TOPK systematically mediated the apoptosis via the AKT pathway in the CP-AKI cell model. CONCLUSION: These results indicate that TOPK activation protects against CP-AKI by ameliorating the G2/M cell cycle arrest and cell apoptosis.

Mechanistic insights into the renoprotective role of curcumin in cisplatin-induced acute kidney injury: network pharmacology analysis and experimental validation.

Cisplatin-induced acute kidney injury (CP-AKI) is a severe complication in patients receiving CP chemotherapy. However, effective therapies for CP-AKI are currently lacking. Curcumin (CUR), a natural polyphenol, is extracted from the rhizome of turmeric and has been reported to have nephroprotective activity. However, the role of CUR in CP-AKI remains unclear. This study aimed to explore the mechanism of CUR in CP-AKI by combining a network pharmacology approach with experimental validations. The analysis revealed 176 potential targets of CUR based on the HERB database and 1,286 related targets of CP-AKI from the GeneCards, DrugBank, and OMIM databases. Further, 106 common targets of CUR against CP-AKI were obtained, and these common targets constructed a protein-protein interaction (PPI) network. In addition, the core targets were screened from the PPI network using Cytoscape. Molecular docking revealed that CUR displayed the best binding to AKT1. Gene Ontology (GO) analysis indicated that the primary biological processes of CUR against CP-AKI included cellular response to chemical stress and apoptotic regulation. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis suggested that the PI3K-Akt signaling pathway was most significantly enriched in CUR against CP-AKI. Western blotting and flow cytometry showed that CUR inhibited apoptosis induced by CP by activating the Akt signaling pathway in human kidney tubular epithelial cells (HK-2). Altogether, our findings demonstrated that CUR alleviated apoptosis by activating the Akt signaling pathway in CP-AKI in vitro. These data provide a scientific basis for future investigations into the clinical application of CUR against CP-AKI.

Pseudothrombus deposition accompanied with minimal change nephrotic syndrome and chronic kidney disease in a patient with Waldenström's macroglobulinemia: A case report.

BACKGROUND: Waldenström's macroglobulinemia (WM) is a rare lymphoid neoplasia, which can have renal complications. These rarely occur, and most common renal manifestations are mild proteinuria and microscopic hematuria. Herein we describe a case of WM that presented with pseudothrombi depositing in capillaries associated with minimal change nephrotic syndrome and chronic kidney disease (CKD). CASE SUMMARY: A 52-year-old man presented with features suggesting nephrotic syndrome. Extensive workups were done, and there were elevated serum levels of interleukin-6 and vascular endothelial growth factor (VEGF), capillary pseudothrombus accumulation associated with minimal change nephrotic syndrome, CKD, and WM. Treatment was directed at the patient's WM with bortezomib, thalidomide, and dexamethasone whereby serum immunoglobulin M (IgM) decreased. The damage of IgM on the kidney was corrected; thus, the patient's proteinuria and serum creatinine had improved. The patient is still under clinical follow-up. CONCLUSION: It is essential for clinicians to promptly pay more attention to patients presenting with features of nephrotic syndrome and do extensive workups to come up with a proper therapy strategy.

Novel role for SGK3 in glucose homeostasis revealed in SGK3/Akt2 double-null mice.

The phosphatidylinositol-3-kinase-dependent kinase, Akt2, plays a central role in mediating insulin effects in glucose-metabolizing tissues. Akt2 knockout mice display insulin resistance with a reactive increase in pancreatic islet mass and hyperinsulinemia. The related phosphatidylinositol-3-kinase-dependent kinase, serum- and glucocorticoid-regulated kinase 3 (SGK3), is essential for normal postnatal hair follicle development but plays no apparent role in glucose homeostasis. We report here an unexpected role of SGK3 in islet ß-cell function, which is revealed in Akt2/SGK3 double-knockout (DKO) mice. DKO mice have markedly worse glucose homeostasis than Akt2 single-null animals, including greater baseline glucose, and greater rise in blood glucose after glucose challenge. However, surprisingly, our data strongly support the idea that this exacerbation of the glucose-handling defect is due to impaired ß-cell function, rather than increased insulin resistance in peripheral tissues. DKO mice had lower plasma insulin and C-peptide levels, lower ß-cell mass, reduced glucose-stimulated insulin secretion, and greater sensitivity to exogenous insulin than Akt2 single nulls. We further demonstrated that SGK3 is strongly expressed in normal mouse islets and, interestingly, that ß-catenin expression is dramatically lower in the islets of DKO mice than in those of Akt2(-/-)/SGK3(+/+) or Akt2(-/-)/SGK3(+/-) mice. Taken together, these data strongly suggest that SGK3 plays a previously unappreciated role in glucose homeostasis, likely through direct effects within ß-cells, to stimulate proliferation and insulin release, at least in part by controlling the expression and activity of ß-catenin.

mTOR complex-2 activates ENaC by phosphorylating SGK1.

The serum- and glucocorticoid-induced kinase 1 (SGK1) plays a central role in hormone regulation of epithelial sodium (Na+) channel (ENaC)-dependent Na+ transport in the distal nephron. Phosphorylation within a carboxy-terminal domain, designated the hydrophobic motif (HM), determines the activity of SGK1, but the identity of the HM kinase is unknown. Here, we show that the highly conserved serine-threonine kinase mammalian target of rapamycin (mTOR) is essential for the phosphorylation of the HM of SGK1 and the activation of ENaC. We observed that mTOR, in conjunction with rictor (mTORC2), phosphorylated SGK1 and stimulated ENaC. In contrast, when mTOR assembled with raptor in the rapamycin-inhibited complex (mTORC1), it did not phosphorylate SGK1 or stimulate ENaC. Inhibition of mTOR blocked both SGK1 phosphorylation and ENaC-mediated Na+ transport, whereas specific inhibition of mTORC1 had no effect. Similarly, small hairpin RNA-mediated knockdown of rictor inhibited SGK1 phosphorylation and Na+ current, whereas knockdown of raptor had no effect. Finally, in co-immunoprecipitation experiments, SGK1 interacted selectively with rictor but not with raptor, suggesting selective recruitment of SGK1 to mTORC2. We conclude that mTOR, specifically mTORC2, is the HM kinase for SGK1 and is required for ENaC-mediated Na+ transport, thereby extending our understanding of the molecular mechanisms underlying Na+ balance.

[Protein kinase C-betaI, betaII in mouse diabetic nephropathy kidney and its relation to nephroprotective actions of the angiotensin receptor blocker telmisartan].

OBJECTIVE: To investigate the localization and expression of protein kinase C (PKC)-betaI, betaII in diabetic nephropathy (DN) mouse kidney and its relation to angiotensin receptor blocker telmisartan (Micardis). METHODS: Eighteen mice were divided into three groups: normal group, DN group and Micardis-treated group (n = 6, each group). The expression of PKC-betaI, betaII, transforming growth factor- beta 1 (TGF-beta1) and vascular endothelial growth factor (VEGF) in glomeruli was measured by semiquantitative immunofluorescence histochemistry, the localization of PKC-betaI, betaII was detected by confocal immunofluorescence laser scanning microscopy and the expression of PKC-betaI, betaII in renal cortex, outer and inner medulla were evaluated by semiquantitative Western blotting. RESULTS: Compared to normal mice, the expression of PKC-betaI and betaII on apical membrane of proximal tubule epithelial cells of DN mice was significantly increased, whereas the expression of PKC-betaII on cortical and inner medullary collecting duct was decreased. Western blotting detected increasing expression of PKC-betaI in the renal cortex and outer medulla (P < 0.01), and decreasing expression of PKC-betaII in renal cortex of DN mice (P < 0.01). Enhanced expression of PKC-betaI as well as TGF-beta1 and VEGF (P < 0.01) were shown in the glomeruli of DN mice, where the expression of PKC-betaII was decreased (P < 0.05). Meanwhile, PKC-betaI exhibited a positive correlation to TGF-beta1 (r = 0.649, P = 0.030), but no correlation to VEGF (r = 0.387, P = 0.079). Micardis could partly attenuate above changes. CONCLUSION: The localization and expression of PKC-betaI, betaII are altered in DN mice, PKC-betaI, betaII may change the function of proximal tubule and PKC-betaI may contribute to glomerular hypertrophy through influencing the expression of glomerular TGF-beta1. Treatment with Micardis can partly improve the abnormal expression and distribution of PKC-betaI, betaII in kidneys of DN mice, which suggests that renin-angiotensin-system is implicated in the pathogenesis of DN by regulating the expression and activation of PKC-betaI, betaII isoforms.

Effect of telmisartan on expression of protein kinase C-alpha in kidneys of diabetic mice.

AIM: To investigate the effects of angiotensin receptor blocker (ARB) telmisartan on the expression and distribution of protein kinase C (PKC)-alpha in the kidneys of diabetic mice. METHODS: Diabetic mice were induced with streptozotocin and a group of them were randomly selected for treatment with telmisartan. After 6 weeks, the expression and localization of PKC-alpha in the renal cortex, and the outer and inner medulla were assessed by immunohistochemistry and semiquantitative Western blotting. In addition, expressions of PKC-alpha, transforming growth factor-beta1 (TGF-beta1), and vascular endothelial growth factor (VEGF) in glomeruli were measured by semiquantitative immunohistochemistry. RESULTS: Diabetic and normal mice showed similar distributions of PKC-alpha in the kidneys. The expression of PKC-alpha was found in glomeruli, epithelial cells of proximal tubules, and medullary-collecting duct, while not in the medullary and cortical thick ascending limb, and was different in the epithelial cells of proximal tubules of diabetic nephropathy (DN) mice, PKC-alpha was mostly translocated from the basement membrane to the apical membrane, whereas it was largely translocated from the apical membrane to the basement membrane in epithelial cells of the inner medullary-collecting duct. Western blotting detected increased expression of PKC-alpha in the renal cortex and outer medulla, but not in the inner medulla of DN mice. Enhanced expressions of PKC-alpha, TGF-beta1, and VEGF were shown in the glomeruli of DN mice, where PKC-alpha exhibited a correlation to VEGF, but no correlation to TGF-beta1. ARB telmisartan attenuated alterations of PKC-alpha as mentioned earlier in the DN mice. CONCLUSION: Our findings suggest that PKC-alpha may play a role in the pathogenesis of DN, and that the nephroprotective effects of ARB telmisartan may be partly associated with its influence on PKC-alpha.