Role of mitochondria in pathogenesis and therapy of renal fibrosis.

Renal fibrosis, specifically tubulointerstitial fibrosis, represents the predominant pathological consequence observed in the context of progressive chronic kidney conditions. The pathogenesis of renal fibrosis encompasses a multifaceted interplay of mechanisms, including but not limited to interstitial fibroblast proliferation, activation, augmented production of extracellular matrix (ECM) components, and impaired ECM degradation. Notably, mitochondria, the intracellular organelles responsible for orchestrating biological oxidation processes in mammalian cells, assume a pivotal role within this intricate milieu. Mitochondrial dysfunction, when manifest, can incite a cascade of events, including inflammatory responses, perturbed mitochondrial autophagy, and associated processes, ultimately culminating in the genesis of renal fibrosis. This comprehensive review endeavors to furnish an exegesis of mitochondrial pathophysiology and biogenesis, elucidating the precise mechanisms through which mitochondrial aberrations contribute to the onset and progression of renal fibrosis. We explored how mitochondrial dysfunction, mitochondrial cytopathy and mitochondrial autophagy mediate ECM deposition and renal fibrosis from a multicellular perspective of mesangial cells, endothelial cells, podocytes, macrophages and fibroblasts. Furthermore, it succinctly encapsulates the most recent advancements in the realm of mitochondrial-targeted therapeutic strategies aimed at mitigating renal fibrosis.

Peroxisome proliferator-activated receptors: A key link between lipid metabolism and cancer progression.

Lipids represent the essential components of membranes, serve as fuels for high-energy processes, and play crucial roles in signaling and cellular function. One of the key hallmarks of cancer is the reprogramming of metabolic pathways, especially abnormal lipid metabolism. Alterations in lipid uptake, lipid desaturation, de novo lipogenesis, lipid droplets, and fatty acid oxidation in cancer cells all contribute to cell survival in a changing microenvironment by regulating feedforward oncogenic signals, key oncogenic functions, oxidative and other stresses, immune responses, or intercellular communication. Peroxisome proliferator-activated receptors (PPARs) are transcription factors activated by fatty acids and act as core lipid sensors involved in the regulation of lipid homeostasis and cell fate. In addition to regulating whole-body energy homeostasis in physiological states, PPARs play a key role in lipid metabolism in cancer, which is receiving increasing research attention, especially the fundamental molecular mechanisms and cancer therapies targeting PPARs. In this review, we discuss how cancer cells alter metabolic patterns and regulate lipid metabolism to promote their own survival and progression through PPARs. Finally, we discuss potential therapeutic strategies for targeting PPARs in cancer based on recent studies from the last five years.

Mapping the tumor microenvironment in clear cell renal carcinoma by single-cell transcriptome analysis.

Introduction: Clear cell renal cell carcinoma (ccRCC) is associated with unfavorable clinical outcomes. To identify viable therapeutic targets, a comprehensive understanding of intratumoral heterogeneity is crucial. In this study, we conducted bioinformatic analysis to scrutinize single-cell RNA sequencing data of ccRCC tumor and para-tumor samples, aiming to elucidate the intratumoral heterogeneity in the ccRCC tumor microenvironment (TME). Methods: A total of 51,780 single cells from seven ccRCC tumors and five para-tumor samples were identified and grouped into 11 cell lineages using bioinformatic analysis. These lineages included tumor cells, myeloid cells, T-cells, fibroblasts, and endothelial cells, indicating a high degree of heterogeneity in the TME. Copy number variation (CNV) analysis was performed to compare CNV frequencies between tumor and normal cells. The myeloid cell population was further re-clustered into three major subgroups: monocytes, macrophages, and dendritic cells. Differential expression analysis, gene ontology, and gene set enrichment analysis were employed to assess inter-cluster and intra-cluster functional heterogeneity within the ccRCC TME. Results: Our findings revealed that immune cells in the TME predominantly adopted an inflammatory suppression state, promoting tumor cell growth and immune evasion. Additionally, tumor cells exhibited higher CNV frequencies compared to normal cells. The myeloid cell subgroups demonstrated distinct functional properties, with monocytes, macrophages, and dendritic cells displaying diverse roles in the TME. Certain immune cells exhibited pro-tumor and immunosuppressive effects, while others demonstrated antitumor and immunostimulatory properties. Conclusion: This study contributes to the understanding of intratumoral heterogeneity in the ccRCC TME and provides potential therapeutic targets for ccRCC treatment. The findings emphasize the importance of considering the diverse functional roles of immune cells in the TME for effective therapeutic interventions.

Role of extracellular vesicles in pathogenesis and therapy of renal ischemia-reperfusion injury.

Renal ischemia-reperfusion injury (RIRI) is a complex disorder characterized by both intrinsic damage to renal tubular epithelial cells and extrinsic inflammation mediated by cytokines and immune cells. Unfortunately, there is no cure for this devastating condition. Extracellular vesicles (EVs) are nanosized membrane-bound vesicles secreted by various cell types that can transfer bioactive molecules to target cells and modulate their function. EVs have emerged as promising candidates for cell-free therapy of RIRI, owing to their ability to cross biological barriers and deliver protective signals to injured renal cells. In this review, we provide an overview of EVs, focusing on their functional role in RIRI and the signaling messengers responsible for EV-mediated crosstalk between various cell types in renal tissue. We also discuss the renoprotective role of EVs and their use as therapeutic agents for RIRI, highlighting the advantages and challenges encountered in the therapeutic application of EVs in renal disease.

Key events in cancer: Dysregulation of SREBPs.

Lipid metabolism reprogramming is an important hallmark of tumor progression. Cancer cells require high levels of lipid synthesis and uptake not only to support their continued replication, invasion, metastasis, and survival but also to participate in the formation of biological membranes and signaling molecules. Sterol regulatory element binding proteins (SREBPs) are core transcription factors that control lipid metabolism and the expression of important genes for lipid synthesis and uptake. A growing number of studies have shown that SREBPs are significantly upregulated in human cancers and serve as intermediaries providing a mechanistic link between lipid metabolism reprogramming and malignancy. Different subcellular localizations, including endoplasmic reticulum, Golgi, and nucleus, play an indispensable role in regulating the cleavage maturation and activity of SREBPs. In this review, we focus on the relationship between aberrant regulation of SREBPs activity in three organelles and tumor progression. Because blocking the regulation of lipid synthesis by SREBPs has gradually become an important part of tumor therapy, this review also summarizes and analyzes several current mainstream strategies.

The role of transketolase in human cancer progression and therapy.

Transketolase (TKT) is an enzyme that is ubiquitously expressed in all living organisms and has been identified as an important regulator of cancer. Recent studies have shown that the TKT family includes the TKT gene and two TKT-like (TKTL) genes; TKTL1 and TKTL2. TKT and TKTL1 have been reported to be involved in the regulation of multiple cancer-related events, such as cancer cell proliferation, metastasis, invasion, epithelial-mesenchymal transition, chemoradiotherapy resistance, and patient survival and prognosis. Therefore, TKT may be an ideal target for cancer treatment. More importantly, the levels of TKTL1 were detected using EDIM technology for the early detection of some malignancies, and TKTL1 was more sensitive and specific than traditional tumor markers. Detecting TKTL1 levels before and after surgery could be used to evaluate the surgery's effect. While targeted TKT suppresses cancer in multiple ways, in some cases, it has detrimental effects on the organism. In this review, we discuss the role of TKT in different tumors and the detailed mechanisms while evaluating its value and limitations in clinical applications. Therefore, this review provides a basis for the clinical application of targeted therapy for TKT in the future, and a strategy for subsequent cancer-related research.