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Glioblastoma multiforme (GBM) is a prevalent primary brain tumor. However, no specific therapeutic drug has been developed for it. Nuclear factor erythroid 2-related factor 2 (Nrf2) is a crucial transcription factor involved in the cellular response to oxidative stress. Numerous studies have demonstrated that Nrf2 plays a pivotal role in GBM angiogenesis, and inhibiting Nrf2 can significantly enhance patient prognosis. Using virtual screening technology, we examined our in-house library and identified pinosylvin as a potential compound with high activity. Pinosylvin exhibited robust hydrogen bond and Π-Π interaction with Nrf2. Cell experiments revealed that pinosylvin effectively reduced the proliferation of U87 tumor cells by regulating Nrf2 and demonstrated greater inhibitory activity than temozolomide. Consequently, we believe that this study will offer valuable guidance for the future development of highly efficient therapeutic drugs for GBM.
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Neoplasias Encefálicas , Glioblastoma , Fitoalexinas , Estilbenos , Humanos , Glioblastoma/tratamento farmacológico , Glioblastoma/patologia , Fator 2 Relacionado a NF-E2 , Linhagem Celular Tumoral , Temozolomida , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/patologiaRESUMO
BACKGROUND: Lipid accumulation in tubular cells plays a key role in diabetic kidney disease (DKD). Targeting lipid metabolism disorders has clinical value in delaying the progression of DKD, but the precise mechanism by which molecules mediate lipid-related kidney injury remains unclear. Phosphofurin acidic cluster sorting protein 2 (PACS-2) is a multifunctional sorting protein that plays a role in lipid metabolism. This study determined the role of PACS-2 in lipid-related kidney injury in DKD. METHODS: Diabetes was induced by a high-fat diet combined with intraperitoneal injections of streptozotocin (HFD/STZ) in proximal tubule-specific knockout of Pacs-2 mice (PT-Pacs-2-/- mice) and the control mice (Pacs-2fl/fl mice). Transcriptomic analysis was performed between Pacs-2fl/fl mice and PT-Pacs-2-/- mice. RESULTS: Diabetic PT-Pacs-2-/- mice developed more severe tubule injury and proteinuria compared to diabetic Pacs-2fl/fl mice, which accompanied with increasing lipid synthesis, uptake and decreasing cholesterol efflux as well as lipid accumulation in tubules of the kidney. Furthermore, transcriptome analysis showed that the mRNA level of sterol O-acyltransferase 1 (Soat1) was up-regulated in the kidney of control PT-Pacs-2-/- mice. Transfection of HK2 cells with PACS-2 siRNA under high glucose plus palmitic acid (HGPA) condition aggravated lipid deposition and increased the expression of SOAT1 and sterol regulatory element-binding proteins (SREBPs), while the effect was blocked partially in that of co-transfection of SOAT1 siRNA. CONCLUSIONS: PACS-2 has a protective role against lipid-related kidney injury in DKD through SOAT1/SREBPs signaling.
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Diabetes Mellitus , Nefropatias Diabéticas , Hipercolesterolemia , Animais , Colesterol/metabolismo , Diabetes Mellitus/metabolismo , Nefropatias Diabéticas/etiologia , Glucose/metabolismo , Hipercolesterolemia/metabolismo , Rim/metabolismo , Camundongos , Ácido Palmítico , RNA Mensageiro/metabolismo , RNA Interferente Pequeno , Esteróis/metabolismo , Estreptozocina/metabolismoRESUMO
Cisplatin (Cis) can cause chronic kidney disease (CKD) and promote renal fibrosis, but the underlying mechanism is not fully understood. Hypoxia inducible factor-1α (HIF-1α) can promote renal fibrosis in some kidney diseases, but its role in Cis-induced CKD is still unknown. Notch-1 is a recognized molecule that promotes renal fibrosis under pathological circumstances, and evidence shows that HIF-1α and Notch-1 are closely related to each other. In the present study, mice with HIF-1α gene knockout in proximal tubular cells (PTCs) (PT-HIF-1α-KO) were generated and treated with Cis to induce CKD. A human proximal tubular cell line (HK-2) and primary mouse PTCs were used for in vitro studies. The results showed that HIF-1α was increased in the kidneys of Cis-treated wild-type mice, accompanied by elevated Notch-1, Notch-1 intracellular domain (N1ICD), Hes-1 and renal fibrosis. However, these alterations were partially reversed in PT-HIF-1α-KO mice. Similar results were observed in HK-2 cells and primary mouse PTCs. In addition, treating the cells with Cis induced a marked interaction of HIF-1α and N1ICD. Further inhibiting Notch-1 significantly reduced cellular fibrogenesis but did not affect HIF-1α expression. The data suggested that HIF-1α could promote renal fibrosis in Cis-induced CKD by activating Notch-1 both transcriptionally and post-transcriptionally and that HIF-1α may serve as a potential therapeutic target for Cis-induced CKD.
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Fibrose/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Insuficiência Renal Crônica/etiologia , Insuficiência Renal Crônica/metabolismo , Animais , Células Epiteliais/metabolismo , Fibrose/etiologia , Hipóxia/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/deficiência , Rim/metabolismo , Túbulos Renais Proximais/patologiaRESUMO
Renal tubulointerstitial fibrosis (TIF) is a common pathological feature of aristolochic acid (AA) nephropathy (AAN). G2/M arrest of proximal tubular cells (PTCs) is implicated in renal fibrosis of AAN, but the upstream regulatory molecule remains unknown. Hypoxia inducible factor-1α (HIF-1α) promotes renal fibrosis in kidney disease, but the role of HIF-1α in AAN is unclear. Evidence shows that HIF-1α and p21, a known inducer of cellular G2/M arrest, are closely related to each other. To investigate the role of HIF-1α in renal fibrosis of AAN and its effects on p21 expression and PTCs G2/M arrest, mice with HIF-1α gene knockout PTCs (PT-HIF-1α-KO) were generated, and AAN was induced by AA. In vitro tests were conducted on the human PTCs line HK-2 and primary mouse PTCs. HIF-1α and p21 expression, fibrogenesis, and G2/M arrest of PTCs were determined. Results showed that HIF-1α was upregulated in the kidneys of wild-type (WT) AAN mice, accompanied by p21 upregulation, PTCs G2/M arrest and renal fibrosis, and these alterations were reversed in PT-HIF-1α-KO AAN mice. Similar results were observed in HK-2 cells and were further confirmed in primary PTCs from PT-HIF-1α-KO and WT mice. Inhibiting p21 in HK-2 cells and primary PTCs did not change the expression of HIF-1α, but G2/M arrest and fibrogenesis were reduced. These data indicate that HIF-1α plays a key role in renal fibrosis in AAN by inducing PTCs G2/M arrest modulated through p21. HIF-1α may serve as a potential therapeutic target for AAN.
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Inibidor de Quinase Dependente de Ciclina p21/metabolismo , Células Epiteliais/citologia , Subunidade alfa do Fator 1 Induzível por Hipóxia/fisiologia , Túbulos Renais Proximais , Nefrite Intersticial/metabolismo , Animais , Ácidos Aristolóquicos , Linhagem Celular , Fibrose/induzido quimicamente , Pontos de Checagem da Fase G2 do Ciclo Celular , Humanos , Túbulos Renais Proximais/citologia , Túbulos Renais Proximais/patologia , Camundongos , Camundongos KnockoutRESUMO
G-quadruplex-based complexes have been widely used in various analytical methods due to their outstanding capabilities of generating colorimetric, fluorescent or electrochemical signals. However, since loop sequences in traditional G-quadruplex structures are quite short, it is difficult to establish biosensors solely using G-quadruplex-based complexes. Herein, we attempted to lengthen the loop sequences of G-quadruplex structures and found that G-quadruplex-hemin DNAzymes (G-DNAzymes) with long loops (even 30 nucleotides) maintain high peroxidase activity. In addition, the peroxidase activity is not affected by the hybridization of the long loop with its complementary counterpart. Consequently, G-DNAzyme can be endowed with an additional function by taking the long loop as a recognition element, which may facilitate the construction of diverse colorimetric biosensors. Furthermore, by designing an apurinic/apyrimidinic site or a complementary sequence of microRNA-21 (miRNA-21) in long loops, bifunctional G-DNAzymes can be split in the presence of apurinic/apyrimidinic endonuclease 1 (APE1) or miRNA-21, decreasing their peroxidase activities. Accordingly, APE1 and miRNA-21 are quantified using 3,3',5,5'-tetramethylbenzidine as a chromophore. Using the G-DNAzyme, APE1 can be detected in a linear range from 2.5 to 22.5 U mL-1 with a LOD of 1.8 U mL-1. It is to be noted that benefitting from duplex-specific nuclease-induced signal amplification, the linear range of the miRNA-21 biosensor is broadened to 5 orders of magnitude, while the limit of detection is as low as 73 fM. This work demonstrates that G-DNAzymes with long loops can both generate signals and recognize targets, providing an alternative strategy to design G-quadruplex-based analytical methods.
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Técnicas Biossensoriais , DNA Catalítico , Quadruplex G , MicroRNAs , Colorimetria , DNA Catalítico/metabolismo , Endonucleases , Hemina , MicroRNAs/genéticaRESUMO
Two synthesized resveratrol analogs from our laboratory, namely pinosylvin (3,5-dihydroxy-trans-stilbene, PIN) and 4,4'-dihydroxystilbene (DHS), have been carefully evaluated for treatment of oligoasthenospermia. Recent studies have demonstrated that PIN and DHS improved sperm quality in the mouse. However, the mechanism of action of PIN and DHS on oligoasthenospermia remains unknown. Herein, we investigated the mechanistic basis for improvements in sperm parameters by PIN and DHS in a mouse model of oligoasthenospermia induced by treatment with busulfan (BUS) at 6 mg/kg b.w.. Two weeks following busulfan treatment, mice were administered different concentrations of PIN or DHS daily for 2 consecutive weeks. Thereafter, epididymal sperm concentration and motility were determined, and histopathology of the testes was performed. Serum hormone levels including testosterone (T), luteinizing hormone (LH), and follicle stimulating hormone (FSH) were measured using corresponding specific enzyme-linked immunosorbent assay (ELISA) kits. Testicular mRNA expression profiles were determined by RNA sequencing analysis. These findings were validated by quantitative real-time PCR, western blotting and ELISA. Both PIN and DHS improved the epididymal sperm concentration and motility, enhanced testosterone levels, and promoted testicular morphological recovery following BUS treatment. PIN treatment was found to significantly reduce oxidative stress via the nuclear factor erythroid 2-related factor 2 (Nrf2)-antioxidant response element (ARE)-dependent antioxidant, glutathione peroxidase 3. DHS treatment significantly reduced oxidative stress via the Nrf2-ARE-dependent antioxidants glutathione S-transferase theta 2 and glutathione S-transferase omega 2. In summary, PIN and DHS ameliorated oligoasthenospermia in this mouse model by attenuating oxidative stress via the Nrf2-ARE pathway.
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Elementos de Resposta Antioxidante/efeitos dos fármacos , Modelos Animais de Doenças , Fator 2 Relacionado a NF-E2/antagonistas & inibidores , Oligospermia/tratamento farmacológico , Estilbenos/farmacologia , Animais , Relação Dose-Resposta a Droga , Masculino , Camundongos , Camundongos Endogâmicos ICR , Estrutura Molecular , Fator 2 Relacionado a NF-E2/metabolismo , Oligospermia/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Estilbenos/química , Relação Estrutura-AtividadeRESUMO
A Ni-Al bimetallic catalyzed enantioselective cycloaddition reaction of cyclopropyl carboxamides with alkynes has been developed. A series of cyclopentenyl carboxamides were obtained in up to 99% yield and 94% ee. The bifunctional-ligand-enabled bimetallic catalysis proved to be an efficient strategy for the C-C bond cleavage of unreactive cyclopropanes.
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An ortho-selective rhodium-catalyzed direct C-H arylation of 1,1'-bi-2-naphthol (BINOL), to deliver the widely used but not easily available 3,3'-diaryl BINOL, has been developed. This highly efficient one-step synthetic approach is the shortest route to date and is greatly facilitated by the newly developed ligand system comprising tBu2 PCl, Ph2 -cod, and Cy3 Pâ HBF4 . In addition, the same procedure can facilitate the challenging syntheses of 3-bulkyaryl BINOLs in good to excellent yields.
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OBJECTIVE: To evaluate the impact of preoperative dual antiplatelet therapy of aspirin and clopidogrel on perioperative blood loss and blood transfusion requirements. METHODS: A total of 60 patients underwent off-pump coronary artery bypass grafting (OPCABG) performed by the same surgeons. And they were assigned to receive dual antiplatelet therapy of aspirin and clopidogrel (group AC, n = 30) and discontinue antiplatelet therapy more than 5 days before surgery (group control, n = 30). RESULTS: No significant inter-group differences existed in basic clinical characteristics (all P > 0.05). Itraoperative blood loss volume was similar for two groups (637 ± 257 vs 635 ± 196 ml, P = 0.978). No significant inter-group difference existed in 24 h chest drainage volume (522 ± 160 vs 524 ± 204 ml, P = 0.961) or total volume of chest drainage (1044 ± 337 vs 1118 ± 198 ml, P = 0.306). CONCLUSION: Preoperative dual antiplatelet therapy of aspirin and clopidogrel does not increase the total volume of postoperative chest drainage.
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Ponte de Artéria Coronária sem Circulação Extracorpórea , Hemorragia , Aspirina , Transfusão de Sangue , Clopidogrel , Humanos , Inibidores da Agregação Plaquetária , Ticlopidina/análogos & derivadosRESUMO
Endoplasmic reticulum (ER) degradation via autophagy is a process that maintains ER homeostasis when cells are in a state of stress and is associated with many diseases; however, the role of hypoxia inducible factor-1α (HIF-1α)-mediated ER degradation and the related regulatory pathway in acute kidney injury (AKI) still needs to be further established. In the present study, an in vivo AKI model was induced in mice via the ischemiaâreperfusion (IR) method. The results revealed that HIF-1α and BNIP3 were increased, and autophagy and ER degradation were activated in the kidneys of AKI mice, whereas HIF-1α knockout significantly inhibited BNIP3, autophagy and ER degradation, accompanied by aggravated kidney injury. Overexpression of HIF-1α in vitro significantly increased BNIP3, autophagy and ER degradation, whereas inhibition of BNIP3 significantly reversed the effects of HIF-1α. In addition, the in vitro inhibition of autophagy with chloroquine significantly reversed the effects of HIF-1α on cell apoptosis. Moreover, selectively overexpressing BNIP3 on the ER membrane significantly increased ER degradation via autophagy and decreased cell apoptosis in vitro. These data indicate that HIF-1α/BNIP3-mediated ER degradation via autophagy in tubular cells protects against IR-induced AKI.
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Aims: To determine the bioactive components of Hedyotis Diffusae Herba (HDH) and the targets in treating lupus nephritis (LN), and so as to elucidate the protective mechanism of HDH against LN. Methods and results: An aggregate of 147 drug targets and 162 LN targets were obtained from online databases, with 23 overlapped targets being determined as potential therapeutic targets of HDH against LN. Through centrality analysis, TNF, VEGFA and JUN were screened as core targets. And the bindings of TNF with stigmasterol, TNF with quercetin, and VEGFA with quercetin were further validated by molecular docking. By conducting Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) enrichment analyses for drug targets, disease targets and the shared targets, TNF signaling pathway, Toll-like receptor signaling pathway, NF-kappa B signaling pathway and HIF-1 signaling pathway, etc., were found in all these three lists, indicating the potential mechanism of HDH in the treatment of LN. Conclusion: HDH may ameliorate the renal injury in LN by targeting multi-targets and multi-pathways, including TNF signaling pathway, NF-kappa B signaling pathway, HIF-1 signaling pathway and so on, which provided novel insights into further researches of the drug discovery in LN.
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Like tuberculosis and Acquired Immune Deficiency Syndrome (AIDS), hepatitis B is a globally recognized major public health threat. Although there are many small-molecule drugs for the treatment of hepatitis B, the approved drugs cannot eradicate the pathogenic culprit covalently closed circular DNA in patients, so the patients need long-term medication to control HBV amplification. Driven by a high unmet medical need, many pharmaceutical companies and research institutions have been engaged in the development of anti-HBV drugs to achieve a functional cure for chronic hepatitis B as soon as possible. This review summarizes the pathogenesis of hepatitis B virus and the research progress in the development of anti-HBV small molecule drugs, and introduces the cccDNA formation and transcription inhibitors and core inhibitors in detail, especially emphasizes the role of chinese herbal medicine in the treatment of chronic hepatitis B. Furthermore, this review proposes three potential strategies for cccDNA eradication in the future. We believe this review will provide meaningful guidance to achieve a functional cure for viral hepatitis B in the future.
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Hepatite B Crônica , Hepatite B , Humanos , Hepatite B Crônica/tratamento farmacológico , Hepatite B Crônica/genética , Antivirais/farmacologia , Antivirais/uso terapêutico , Replicação Viral , DNA Viral , Vírus da Hepatite B , Hepatite B/tratamento farmacológicoRESUMO
Alzheimer's disease (AD) is the most common neurodegenerative disease among the elderly, and the morbidity increases with the aging population aggravation. The clinical symptoms of AD mainly include cognitive impairment and memory loss, which undoubtedly bring a huge burden to families and society. Currently, the drugs in clinical use only improve the symptoms of AD but do not cure or prevent the progression of the disease. Therefore, it is urgent for us to develop novel therapeutic strategies for effective AD treatment. To provide a better theoretical basis for exploring novel therapeutic strategies in future AD treatment, this review introduces the recent AD treatment technologies from three aspects, including nanoparticle (NP) based drug therapy, biological therapy and physical therapy. The nanoparticle-mediated therapeutic approaches at the nanomaterial-neural interface and biological system are described in detail, and in particular the magneto-regulated strategies by magnetic field actuating magnetic nanoparticles are highlighted. Promising application of magneto-mechanical force regulated strategy in future AD treatment is also addressed, which offer possibilities for the remote manipulation in a precise manner. In the future, it may be possible for physicians to realize a remote, precise and effective therapy for AD using magneto-mechanical force regulated technology based on the combination of magnetic nanoparticles and an external magnetic field.
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Doença de Alzheimer , Doenças Neurodegenerativas , Humanos , Idoso , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/diagnósticoRESUMO
As the engine that maintains blood circulation, the heart is also an endocrine organ that regulates the function of distant target organs by secreting a series of cardiokines. As endocrine factors, cardiokines play an indispensable role in maintaining the homeostasis of the heart and other organs. Here, we summarize some of the cardiokines that have been defined thus far and explore their roles in heart and kidney diseases. Finally, we propose that cardiokines may be a potential therapeutic target for kidney diseases.
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The increasing incidence of metabolic diseases, including obesity and diabetes, is a serious social public problem. Therefore, there is an urgent need to find effective prevention and treatment measures for these diseases. DsbA-L is a protein that is widely expressed in many tissues and is closely related to metabolism. Emerging evidence shows that DsbA-L plays an important role in antioxidative stress, promoting the synthesis and secretion of adiponectin and maintaining mitochondrial homeostasis, and the abnormalities of these functions are also closely related to the occurrence and development of metabolic diseases. Here, we reviewed the tissue expression patterns and regulatory factors of DsbA-L, summarized its biological functions and the current research progress of DsbA-L in metabolic diseases, and found that DsbA-L may be a promising target for metabolic diseases.
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Autophagy of endoplasmic reticulum (ER-phagy) selectively removes damaged ER through autophagy-lysosome pathway, acting as an adaptive mechanism to alleviate ER stress and restore ER homeostasis. However, the role and precise mechanism of ER-phagy in tubular injury of diabetic kidney disease (DKD) remain obscure. In the present study, we demonstrated that ER-phagy of renal tubular cells was severely impaired in streptozocin (STZ)-induced diabetic mice, with a decreased expression of phosphofurin acidic cluster sorting protein 2 (PACS-2), a membrane trafficking protein which was involved in autophagy, and a reduction of family with sequence similarity 134 member B (FAM134B), one ER-phagy receptor. These changes were further aggravated in mice with proximal tubule specific knockout of Pacs-2 gene. In vitro, transfection of HK-2 cells with PACS-2 overexpression plasmid partially improved the impairment of ER-phagy and the reduction of FAM134B, both of which were induced in high glucose ambience; while the effect was blocked by FAM134B siRNA. Mechanistically, PACS-2 interacted with and promoted the nuclear translocation of transcription factor EB (TFEB), which was reported to activate the expression of FAM134B. Collectively, these data unveiled that PACS-2 deficiency aggravates renal tubular injury in DKD via inhibiting ER-phagy through TFEB/FAM134B pathway.
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Diabetes Mellitus Experimental , Nefropatias Diabéticas , Animais , Camundongos , Autofagia/genética , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/genética , Nefropatias Diabéticas/genética , Estresse do Retículo Endoplasmático , Peptídeos e Proteínas de Sinalização Intracelular , Proteínas de Membrana/metabolismoRESUMO
Alzheimer's disease (AD) is an irreversible, progressive neurodegenerative brain disorder with no effective therapeutic drugs currently. The complicated pathophysiology of AD is not well understood, although beta-amyloid (Aß) cascade and hyperphosphorylated tau protein were regarded as the two main causes of AD. Other mechanisms, such as oxidative stress, deficiency of central cholinergic neurotransmitters, mitochondrial dysfunction, and inflammation, were also proposed and studied as targets in AD. This review aims to summarize the small-molecule drugs that were developed based on the pathogenesis and gives a deeper understanding of the AD. We hope that it could help scientists find new and better treatments to gradually conquer the problems related to AD in future.
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In recent years, the incidence of non-alcoholic fatty liver disease (NAFLD) has been increasing worldwide. Hepatic lipid deposition is a major feature of NAFLD, and insulin resistance is one of the most important causes of lipid deposition. Insulin resistance results in the disruption of lipid metabolism homeostasis characterized by increased lipogenesis and decreased lipolysis. Estrogen receptor α (ERα) has been widely reported to be closely related to lipid metabolism. Activating ERa may be a promising strategy to improve lipid metabolism. Here, we used computer-aided drug design technology to discover a highly active compound, YRL-03, which can effectively reduce lipid accumulation. Cellular experimental results showed that YRL-03 could effectively reduce lipid accumulation by targeting ERα, thereby achieving alleviation of insulin resistance. We believe this study provides meaningful guidance for future molecular development of drugs to prevent and treat NAFLD.
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Diabetic nephropathy (DN) is a serious complication of diabetes, and its pathogenesis has not been fully elucidated. Recently, communication between organs has gradually become a new focus in the study of diseases pathogenesis, and abnormal interorgan communication has been proven to be involved in the occurrence and progression of many diseases. As an important metabolic organ in the human body, the liver plays an important role in maintaining homeostasis in humans. The liver secretes a series of proteins called hepatokines that affect adjacent and distal organs through paracrine or endocrine signaling pathways. In this review, we summarize some of the hepatokines identified to date and describe their roles in DN to discuss the possibility that the liver-renal axis is potentially useful as a therapeutic target for DN. We summarize the important hepatokines identified thus far and discuss their relationship with DN. We propose for the first time that the "liver-renal axis" is a potential therapeutic target in individuals with DN.
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Diabetes Mellitus , Nefropatias Diabéticas , Fenômenos Fisiológicos Celulares , Diabetes Mellitus/metabolismo , Nefropatias Diabéticas/patologia , Humanos , Rim/patologia , Fígado/metabolismoRESUMO
Diabetic nephropathy (DN) is the leading cause of end-stage renal disease (ESRD). However, its pathogenesis remains unclear, and effective prevention and treatment strategies are lacking. Recently, organ-to-organ communication has become a new focus of studies on pathogenesis. Various organs or tissues (the liver, muscle and adipose tissue) secrete a series of proteins or peptides to regulate the homeostasis of distal organs in an endocrine manner. Bone, an important part of the body, can also secrete bone-derived proteins or peptides that act on distal organs. As an organ with high metabolism, the kidney is responsible for signal and material exchange with other organs at any time through circulation. In this review, we briefly discussed bone composition and changes in bone structure and function in DN and summarized the current status of bone-derived proteins and their role in the progression of DN. We speculated that the "bone-kidney axis" is a potential target for early diagnosis and treatment of DN.