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Acute kidney injury (AKI) is a major public health problem worldwide that still lacks effective treatments. Recent studies have suggested that ferroptosis is a key mediator of AKI due to its activation of lipid peroxidation. Therefore, we hypothesized that antiferroptosis agents might be a novel potential therapeutic strategy for AKI. Herein, we demonstrated that liquiritigenin (LG), an active ingredient of liquorice, improves renal function by inhibiting vitamin K epoxide reductase complex subunit 1 (VKORC1)-mediated ferroptosis, both in vivo and in vitro. In a folic acid-induced murine AKI model, after a single pre-treatment intravenous injection, LG markedly alleviated the loss of renal function through suppressing ferroptosis induced by iron accumulation. LG prevented mitochondrial morphological changes and upregulated glutathione and glutathione peroxidase 4 levels, while downregulating malonaldehyde and divalent iron levels. An in vitro RNA-sequence analysis suggested that the protective role of LG may involve upregulation of VKORC1. Moreover, knockdown of VKORC1 diminished the renal protective and antiferroptosis roles of LG. Collectively, our findings demonstrated that LG protected against AKI by inhibiting VKORC1-mediated ferroptosis. This suggests that inhibiting ferroptosis might be a novel therapeutic approach in the future.
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Salt-sensitivity hypertension (SSH) is an independent predictor of cardiovascular event-related death. Despite the extensiveness of research on hypertension, which covers areas such as the sympathetic nervous system, the renin-angiotensin system, the vascular system, and the immune system, its pathogenesis remains elusive, with sub-optimal blood pressure control in patients. The gut microbiota is an important component of nutritional support and constitutes a barrier in the host. Long-term high salt intake can lead to gut microbiota dysbiosis and cause significant changes in the expression of gut microbiota-related metabolites. Of these metabolites, short chain fatty acids (SCFAs), trimethylamine oxide, amino acids, bile acids, and lipopolysaccharide are essential mediators of microbe-host crosstalk. These metabolites may contribute to the incidence and development of SSH via inflammatory, immune, vascular, and nervous pathways, among others. In addition, recent studies, including those on the histone deacetylase inhibitory mechanism of SCFAs and the blood pressure-decreasing effects of H2S via vascular activation, suggest that several proteins and factors in the classical pathway elicit their effects through multiple non-classical pathways. This review summarizes changes in the gut microbiota and its related metabolites in high-salt environments, as well as corresponding treatment methods for SSH, such as diet management, probiotic and prebiotic use, antibiotic use, and fecal transplantation, to provide new insights and perspectives for understanding SSH pathogenesis and the development of strategies for its treatment.
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OBJECTIVES: Potassium supplementation reduces blood pressure and the occurrence of cardiovascular diseases, with K + -induced natriuresis playing a potential key role in this process. However, whether these beneficial effects occur in diabetes remains unknown. METHODS: In this study, we examined the impact of high-K + intake on renal Na + /K + transport by determining the expression of major apical Na + transporters, diuretics responses (as a proxy for specific Na + transporter function), urinary Na + /K + excretion, and plasma Na + /K + concentrations in db/db mice, a model of type 2 diabetes mellitus. RESULTS: Although db/m mice exhibited increased fractional excretion of sodium (FE Na ) and fractional excretion of potassium (FE K ) under high-K + intake, these responses were largely blunted in db/db mice, suggesting impaired K + -induced natriuresis and kaliuresis in diabetes. Consequently, high-K + intake increased plasma K + levels in db/db mice, which could be attributed to the abnormal activity of sodium-hydrogen exchanger 3 (NHE3), sodium-chloride cotransporter (NCC), and epithelial Na + channel (ENaC), as high-K + intake could not effectively decrease NHE3 and NCC and increase ENaC expression and activity in the diabetic group. Inhibition of NCC by hydrochlorothiazide could correct the hyperkalemia in db/db mice fed a high-K + diet, indicating a key role for NCC in K + -loaded diabetic mice. Treatment with metformin enhanced urinary Na + /K + excretion and normalized plasma K + levels in db/db mice with a high-K + diet, at least partially, by suppressing NCC activity. CONCLUSION: Collectively, the impaired K + -induced natriuresis in diabetic mice under high-K + intake may be primarily attributed to impaired NCC-mediated renal K + excretion, despite the role of NHE3.
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Hiperpotassemia , Natriurese , Potássio , Trocador 3 de Sódio-Hidrogênio , Animais , Natriurese/efeitos dos fármacos , Camundongos , Potássio/urina , Potássio/sangue , Potássio/metabolismo , Trocador 3 de Sódio-Hidrogênio/metabolismo , Masculino , Diabetes Mellitus Tipo 2/complicações , Suplementos NutricionaisRESUMO
Diabetes is closely associated with K+ disturbances during disease progression and treatment. However, it remains unclear whether K+ imbalance occurs in diabetes with normal kidney function. In this study, we examined the effects of dietary K+ intake on systemic K+ balance and renal K+ handling in streptozotocin (STZ)-induced diabetic mice. The control and STZ mice were fed low or high K+ diet for 7 days to investigate the role of dietary K+ intake in renal K+ excretion and K+ homeostasis and to explore the underlying mechanism by evaluating K+ secretion-related transport proteins in distal nephrons. K+-deficient diet caused excessive urinary K+ loss, decreased daily K+ balance, and led to severe hypokalemia in STZ mice compared with control mice. In contrast, STZ mice showed an increased daily K+ balance and elevated plasma K+ level under K+-loading conditions. Dysregulation of the NaCl cotransporter (NCC), epithelial Na+ channel (ENaC), and renal outer medullary K+ channel (ROMK) was observed in diabetic mice fed either low or high K+ diet. Moreover, amiloride treatment reduced urinary K+ excretion and corrected hypokalemia in K+-restricted STZ mice. On the other hand, inhibition of SGLT2 by dapagliflozin promoted urinary K+ excretion and normalized plasma K+ levels in K+-supplemented STZ mice, at least partly by increasing ENaC activity. We conclude that STZ mice exhibited abnormal K+ balance and impaired renal K+ handling under either low or high K+ diet, which could be primarily attributed to the dysfunction of ENaC-dependent renal K+ excretion pathway, despite the possible role of NCC.NEW & NOTEWORTHY Neither low dietary K+ intake nor high dietary K+ intake effectively modulates renal K+ excretion and K+ homeostasis in STZ mice, which is closely related to the abnormality of ENaC expression and activity. SGLT2 inhibitor increases urinary K+ excretion and reduces plasma K+ level in STZ mice under high dietary K+ intake, an effect that may be partly due to the upregulation of ENaC activity.
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Diabetes Mellitus Experimental , Canais Epiteliais de Sódio , Potássio na Dieta , Potássio , Animais , Diabetes Mellitus Experimental/metabolismo , Potássio/metabolismo , Potássio/urina , Masculino , Potássio na Dieta/metabolismo , Canais Epiteliais de Sódio/metabolismo , Camundongos Endogâmicos C57BL , Inibidores do Transportador 2 de Sódio-Glicose/farmacologia , Canais de Potássio Corretores do Fluxo de Internalização/metabolismo , Canais de Potássio Corretores do Fluxo de Internalização/genética , Camundongos , Nefropatias Diabéticas/metabolismo , Nefropatias Diabéticas/etiologia , Nefropatias Diabéticas/fisiopatologia , Rim/metabolismo , Rim/efeitos dos fármacos , Rim/fisiopatologia , Hipopotassemia/metabolismo , Amilorida/farmacologia , Eliminação Renal/efeitos dos fármacos , Homeostase , Membro 3 da Família 12 de Carreador de Soluto/metabolismo , Membro 3 da Família 12 de Carreador de Soluto/genética , Glucosídeos/farmacologia , Estreptozocina , Compostos Benzidrílicos , Transportador 2 de Glucose-SódioRESUMO
Ferroptosis is a novel form of lipid peroxidation-driven, iron-dependent programmed cell death. Various metabolic pathways, including those involved in lipid and iron metabolism, contribute to ferroptosis regulation. The gut microbiota not only supplies nutrients and energy to the host, but also plays a crucial role in immune modulation and metabolic balance. In this review, we explore the metabolic pathways associated with ferroptosis and the impact of the gut microbiota on host metabolism. We subsequently summarize recent studies on the influence and regulation of ferroptosis by the gut microbiota and discuss potential mechanisms through which the gut microbiota affects ferroptosis. Additionally, we conduct a bibliometric analysis of the relationship between the gut microbiota and ferroptosis in the context of chronic kidney disease. This analysis can provide new insights into the current research status and future of ferroptosis and the gut microbiota.
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Diabetic kidney disease (DKD), a major microvascular complication of diabetes, is characterized by its complex pathogenesis, high risk of chronic renal failure, and lack of effective diagnosis and treatment methods. GSK3ß (glycogen synthase kinase 3ß), a highly conserved threonine/serine kinase, was found to activate glycogen synthase. As a key molecule of the glucose metabolism pathway, GSK3ß participates in a variety of cellular activities and plays a pivotal role in multiple diseases. However, these effects are not only mediated by affecting glucose metabolism. This review elaborates on the role of GSK3ß in DKD and its damage mechanism in different intrinsic renal cells. GSK3ß is also a biomarker indicating the progression of DKD. Finally, the protective effects of GSK3ß inhibitors on DKD are also discussed.
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Diabetes Mellitus , Nefropatias Diabéticas , Glicogênio Sintase Quinase 3 beta , Humanos , Nefropatias Diabéticas/tratamento farmacológico , Glucose/metabolismo , Glicogênio Sintase Quinase 3 beta/metabolismo , Rim/metabolismoRESUMO
The global prevalence of diabetes mellitus (DM) has led to widespread multi-system damage, especially in cardiovascular and renal functions, heightening morbidity and mortality. Emerging antidiabetic drugs sodium-glucose cotransporter 2 inhibitors (SGLT2i), glucagon-like peptide-1 receptor agonists (GLP-1RAs), and dipeptidyl peptidase-4 inhibitors (DPP-4i) have demonstrated efficacy in preserving cardiac and renal function, both in type 2 diabetic and non-diabetic individuals. To understand the exact impact of these drugs on cardiorenal protection and underlying mechanisms, we conducted a comprehensive review of recent large-scale clinical trials and basic research focusing on SGLT2i, GLP-1RAs, and DPP-4i. Accumulating evidence highlights the diverse mechanisms including glucose-dependent and independent pathways, and revealing their potential cardiorenal protection in diabetic and non-diabetic cardiorenal disease. This review provides critical insights into the cardiorenal protective effects of SGLT2i, GLP-1RAs, and DPP-4i and underscores the importance of these medications in mitigating the progression of cardiovascular and renal complications, and their broader clinical implications beyond glycemic management.
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Dry eye disease (DED) is a common disorder of tear secretion on the ocular surface caused by multiple factors with dry eyes as the main symptom, but until now studies focusing on relationship between local meteorological factors and ocular surface diseases in Urumqi are very limited. Besides, the effects of long-term and extreme meteorological factors on DED and the lag effect have not been fully evaluated. Electronic case information of 9970 DED outpatients from the Ophthalmology Department of the First Affiliated Hospital of Xinjiang Medical University (Urumqi, Xinjiang, China) between January 1, 2013, and December 31, 2020, was screened and analyzed. We used a time-series analysis design and a quasi-Poisson generalized linear regression model combined with a distributed lagged nonlinear model (DLNM) to fit the effects of exposure to different meteorological factors and extreme weather on DED outpatient visits. Subgroup analyses were further performed for gender, age, and season. The results showed that exposure to extremely low mean temperature (P1:RR = 1.18), atmospheric pressure (P1:RR = 1.11), and extremely high relative humidity (P99:RR = 1.35) were the risk factors, while extremely high atmospheric pressure (P90:RR = 0.883) and extremely low humidity (P10:RR = 0.856) appeared to have a positive effect on reduced risk of DED. Relative humidity exhibited a 1-day lag effect (RR = 1.06). Increased mean temperature positively affected female DED patients (RR = 0.761) with similar effects in the cold season (RR = 0.926). However, elevated relative humidity had a negative effect on female patients (RR = 1.14). We conducted the first large sample size time-series analysis study in this major city at the farthest distance from the ocean in the world and in northwest China, confirming the association of DED outpatient visits with the remaining three meteorological factors except wind speed in Urumqi, and a larger sample size multi-center epidemiological study with a longer duration is still needed.
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Síndromes do Olho Seco , Clima Extremo , Humanos , Feminino , Pacientes Ambulatoriais , Conceitos Meteorológicos , Estações do Ano , China , Síndromes do Olho Seco/epidemiologia , TemperaturaRESUMO
Objective: This study aimed to elucidate the relationship between retinopathy status or severity and the all-cause and specific-cause mortality risk based on the updated National Health and Nutrition Examination Survey (NHANES) database and 2019 Public Access Link mortality file. Methods: In this prospective cohort study, a total of 6,797 participants aged over 40 years based on NHANES 2005-2008 were analyzed. The severity of retinopathy was classified into 4 grades-no retinopathy, mild non-proliferative retinopathy (NPR), moderate to severe NPR, and proliferative retinopathy (PR). Multiple covariate-adjusted Cox proportional hazards regression models and Fine and Gray competing risk regression models were used to assess the all-cause and cause-specific mortality risks, respectively. The propensity score matching (PSM) approach was also applied additionally to adequately balance between-group covariates to validate our findings. Results: A final total of 4,808 participants representing 18,282,772 United States (US) non-hospitalized participants were included for analysis, 50.27% were male (n = 2,417), 55.32% were non-hispanic white (n = 2,660), and mean [SE] age, 56.10 [0.40] years. After a median follow-up of 12.24 years (interquartile range, 11.16-13.49 years), 1,164 participants died of all-cause mortality, of which 941 (80.84%) died without retinopathy and 223 (19.16%) died with retinopathy at baseline. The presence of retinopathy was associated with increased all-cause mortality, cardiovascular disease (CVD), and diabetes mellitus (DM)-specific mortality, and the results remain consistent after PSM. Severity analysis showed that only mild NPR was associated with an increased all-cause mortality risk (hazard ratio (HR) = 2.01; 95% confidence interval (CI), 1.00-4.03), while increased CVD and DM-specific mortality risk were associated with all grades of retinopathy and were exponentially greater with increasing retinopathy severity, and the trend test was also significant (P for trend 0.004 and 0.04, respectively). Discussion: Our findings suggest that the diagnosis of retinopathy is an independent risk factor for all-cause mortality in people over 40 years old. Retinopathy grading is significantly associated with the survival risk of patients with CVD or DM, it can be a valuable predictor in the stratified management and risk warning of CVD or DM patients, as well as in the monitoring of systemic vasculopathy status.
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Doenças Cardiovasculares , Retinopatia Diabética , Humanos , Masculino , Adulto , Pessoa de Meia-Idade , Feminino , Inquéritos Nutricionais , Estudos Prospectivos , Retinopatia Diabética/epidemiologia , Doenças Cardiovasculares/epidemiologia , Bases de Dados FactuaisRESUMO
OBJECTIVES: Functional impairment of renal sodium handling and blood pressure (BP) homeostasis is an early characteristic manifestation of type 1 diabetes. However, the underlying mechanisms remain unclear. METHODS: Metabolic cages, radio-telemetry, immunoblotting, and electrophysiology were utilized to examine effects of high salt (8% NaCl, HS) intake on Na + /K + balance, BP, Na + -Cl - cotransporter (NCC) function, and basolateral K + channel activity in the distal convoluted tubule (DCT) under diabetic conditions. RESULTS: Improper Na + balance, hypernatremia, and a mild but significant increase in BP were found in streptozotocin (STZ)-induced diabetic mice in response to HS intake for 7 days. Compared to the vehicle, STZ mice showed increased Kir4.1 expression and activity in the DCT, a more negative membrane potential, higher NCC abundance, and enhanced hydrochlorothiazide-induced natriuretic effect. However, HS had no significant effect on basolateral Kir4.1 expression/activity and DCT membrane potential, or NCC activity under diabetic conditions, despite a downregulation in phosphorylated NCC abundance. In contrast, HS significantly downregulated the expression of Na + -H + exchanger 3 (NHE3) and cleaved epithelial sodium channel-γ in STZ mice, despite an increase in NHE3 abundance after STZ treatment. Kir4.1 deletion largely abolished STZ-induced upregulation of NCC expression and prevented BP elevation during HS intake. Interestingly, HS causes severe hypokalemia in STZ-treated kidney-specific Kir4.1 knockout (Ks-Kir4.1 KO) mice and lead to death within a few days, which could be attributed to a higher circulating aldosterone level. CONCLUSIONS: We concluded that Kir4.1 is required for upregulating NCC activity and may be essential for developing salt-sensitive hypertension in early STZ-induced diabetes.
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Diabetes Mellitus Experimental , Hipertensão , Animais , Camundongos , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/metabolismo , Hipertensão/metabolismo , Túbulos Renais Distais/metabolismo , Camundongos Knockout , Sódio/metabolismo , Cloreto de Sódio/farmacologia , Cloreto de Sódio na Dieta/farmacologia , Trocador 3 de Sódio-Hidrogênio/metabolismo , Trocador 3 de Sódio-Hidrogênio/farmacologia , Membro 3 da Família 12 de Carreador de Soluto/genética , Membro 3 da Família 12 de Carreador de Soluto/metabolismo , Estreptozocina/metabolismo , Estreptozocina/farmacologiaRESUMO
Conjunctivitis is an inflammatory disease of the conjunctival tissue caused by a variety of causes; despite the conjunctiva being directly exposed to the external atmospheric environment, the important role of air pollution is not fully evaluated, especially in areas with poor air quality undergoing rapid economic and industrial development. Information on 59,731 outpatient conjunctivitis visits from 1 January 2013 to 31 December 2020 was obtained from the Ophthalmology Department of the First Affiliated Hospital of Xinjiang Medical University (Urumqi, Xinjiang, China), and data on six air pollutants including particulate matter with a median aerometric diameter of less than 10 and 2.5 mm (PM10 and PM2.5, respectively), carbon monoxide (CO), sulfur dioxide (SO2), nitrogen dioxide (NO2), and ozone (O3) from eleven standard urban background fixed air quality monitors were also recorded. A time-series analysis design and a quasi-Poisson generalized linear regression model combined with a distributed lagged nonlinear model (DLNM) were used to fit the effect of exposure to air pollutants on the risk of conjunctivitis outpatient visits. Further subgroup analyses were conducted for gender, age, and season, as well as the type of conjunctivitis. Single and multi-pollutant models showed that exposure to PM2.5, PM10, NO2, CO, and O3 was associated with increased risk of outpatient conjunctivitis visits on the lag 0 day and various other lag days. Variations in the effect estimates on direction and magnitude were found in different subgroup analyses. We conducted the first time-series analysis with the longest duration as well as the largest sample size in Northwest China, which provides evidence that outpatient conjunctivitis visits is significantly associated with air pollution in Urumqi, China. Meanwhile, our results demonstrate the effectiveness of SO2 reduction in reducing the risk of outpatient conjunctivitis visits in the Urumqi region and reaffirm the need to implement special air pollution control measures.
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Poluentes Atmosféricos , Poluição do Ar , Conjuntivite , Humanos , Pacientes Ambulatoriais , Dióxido de Nitrogênio/análise , Poluição do Ar/análise , Poluentes Atmosféricos/análise , Material Particulado/análise , China/epidemiologia , Conjuntivite/induzido quimicamenteRESUMO
AIM: Cyclosporin A (CsA) is a widely used immunosuppressive drug that causes hypertension and hyperkalemia. Moreover, CsA-induced stimulation of the thiazide-sensitive NaCl cotransporter (NCC) in the kidney has been shown to be responsible for the development of hyperkalemic hypertension. In this study, we tested whether CsA induces the activation of NCC by stimulating the basolateral Kir4.1/Kir5.1 channel in the distal convoluted tubule (DCT). METHODS: Electrophysiology, immunoblotting, metabolic cages, and radio-telemetry methods were used to examine the effects of CsA on Kir4.1/Kir5.1 activity in the DCT, NCC function, and blood pressure in wild-type (WT) and kidney-specific Kir4.1 knockout (KS-Kir4.1 KO) mice. RESULTS: The single-channel patch clamp experiment demonstrated that CsA stimulated the basolateral 40 pS K+ channel in the DCT. Whole-cell recording showed that short-term CsA administration (2 h) not only increased DCT K+ currents but also shifted the K+ current (IK ) reversal potential to the negative range (hyperpolarization). Furthermore, CsA administration increased phosphorylated NCC (pNCC) levels and inhibited renal Na+ and K+ excretions in WT mice but not in KS-Kir4.1 KO mice, suggesting that Kir4.1 is required to mediate CsA effects on NCC function. Finally, long-term CsA infusion (14 days) increased blood pressure, plasma K+ concentration, and total NCC or pNCC abundance in WT mice, but these effects were blunted in KS-Kir4.1 KO mice. CONCLUSION: We conclude that CsA stimulates basolateral K+ channel activity in the DCT and that Kir4.1 is essential for CsA-induced NCC activation and hyperkalemic hypertension.
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Hiperpotassemia , Hipertensão , Animais , Camundongos , Membro 3 da Família 12 de Carreador de Soluto/metabolismo , Hiperpotassemia/metabolismo , Ciclosporina/farmacologia , Cloreto de Sódio/metabolismo , Cloreto de Sódio/farmacologia , Camundongos Knockout , Túbulos Renais Distais , Hipertensão/induzido quimicamente , Hipertensão/metabolismoRESUMO
Global climate change will increase surface soil temperature, with consequences on plant seedling growth and population dynamics. In this study, we carried out a field experiment to investigate the effects of 2 â soil warming on the growth and physiological characteristics of 1- and 2-year-old seedlings of a dominant tree species in broadleaved Korean pine forest, Juglans mandshurica. The results showed that soil warming significantly increased basal diameter, root length, total leaf area, leaf dry weight, root dry weight, total biomass, apparent photosynthetic electron transfer rate (ETR), PSâ ¡ actual photochemical efficiency (ΦPSâ ¡), and apparent photosynthetic electrophotochemical quenching coefficient (qP) of 1-year-old seedlings by 18.3%, 66.7%, 94.4%, 105.9%, 95.8%, 37.8%, 89.5%, 100.0%, and 71.4%, respectively. Soil warming significantly increased basal diameter, total leaf area, leaf dry weight, total biomass, leaf superoxide dismutase activity, peroxidase activity, catalase activity and free proline content, ETR, ΦPSâ ¡, and qP of 2-year-old seedlings by 12.5%, 180.5%, 97.3%, 42.5%, 23.9%, 20.4%, 14.9%, 20.7%, 66.7%, 283.3% and 284.6%, respectively. There was an interaction between seedling age and soil warming on the root-shoot ratio and the ΦPSâ ¡ and qP in chlorophyll fluorescence parameters, in that soil warming significantly reduced the root-shoot ratio of 2-year-old seedlings and that the increase of chlorophyll fluorescence parameters of 2-year-old seedlings (4.1-4.6 times) was much higher than that of 1-year-old seedlings (1.5-1.8 times). Soil warming of 2 â was beneficial to the growth of 1- and 2-year-old J. mandshurica seedlings and increased their regeneration potential. In particular, 2-year-old J. mandshurica seedlings responded to soil warming by increasing leaf area, improving leaf photochemical efficiency, and enhancing protective enzyme activity to increase resistance.
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Juglans , Plântula , Clorofila , Fotossíntese , Folhas de Planta , SoloRESUMO
Diabetic kidney disease (DKD) is one of the major microvascular complications of diabetes mellitus and is also one of the serious risk factors in cardiovascular events, end-stage renal disease, and mortality. DKD is associated with the diversified, compositional, and functional alterations of gut microbiota. The interaction between gut microbiota and host is mainly achieved through metabolites, which are small molecules produced by microbial metabolism from exogenous dietary substrates and endogenous host compounds. The gut microbiota plays a critical role in the pathogenesis of DKD by producing multitudinous metabolites. Nevertheless, detailed mechanisms of gut microbiota and its metabolites involved in the occurrence and development of DKD have not been completely elucidated. This review summarizes the specific classes of gut microbiota-derived metabolites, aims to explore the molecular mechanisms of gut microbiota in DKD pathophysiology and progression, recognizes biomarkers for the screening, diagnosis, and prognosis of DKD, as well as provides novel therapeutic strategies for DKD.
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Diabetes Mellitus , Nefropatias Diabéticas , Microbioma Gastrointestinal , Falência Renal Crônica , Humanos , Nefropatias Diabéticas/etiologia , Nefropatias Diabéticas/terapia , Nefropatias Diabéticas/metabolismo , Falência Renal Crônica/complicações , Fatores de Risco , BiomarcadoresRESUMO
AIMS: The aim of this study was to develop a population pharmacokinetic (PK) model to simultaneously describe both total and unbound concentrations of ciprofol and its major glucuronide metabolite, M4, and to link it to the population pharmacodynamics (PD) model in subjects with various renal functions. METHODS: A total of 401 and 459 pairs of total and unbound plasma concentrations of ciprofol and M4, respectively, as well as 2190 bispectral index (BIS) data from 24 Chinese subjects with various renal functions were available. Covariates that may potentially contribute to the PK and PD variability of ciprofol were screened using a stepwise procedure. The optimal ciprofol induction dosing regimen was determined by model-based simulations. RESULTS: The PK of unbound ciprofol could best be described by a three-compartment model, while a two-compartment model could adequately describe unbound M4 PK. The concentrations of total and unbound ciprofol and M4 were linked using a linear protein binding model. The relationship between plasma concentrations of ciprofol and BIS data was best described by an inhibitory sigmoidal Emax model with a two-compartment biophase distribution compartment. Hemoglobin was the identified covariate determining the central compartment clearance of ciprofol; uric acid was a covariate affecting the central compartment clearance of M4 and protein binding rate, kB . The included covariates had no effect on the PD of ciprofol. Simulation results indicated that the label-recommended dose regimen was adequate for anaesthesia induction. CONCLUSIONS: The developed model fully characterized the population PK and PD profiles of ciprofol. No dose adjustment is required in patients with mild and moderate renal impairment.
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Rim , Modelos Biológicos , Humanos , Relação Dose-Resposta a Droga , Rim/fisiologiaRESUMO
BACKGROUND: LncRNA AK044604 (regulator of insulin sensitivity and autophagy, Risa) and autophagy-related factors Sirt1 and GSK3ß play important roles in diabetic nephropathy (DN). In this study, we sought to explore the effect of Risa on Sirt1/GSK3ß-induced podocyte injury. METHODS: Diabetic db/db mice received Risa-inhibition adeno-associated virus (AAV) via tail vein injection, and intraperitoneal injection of lithium chloride (LiCl). Blood, urine, and kidney tissue samples were collected and analyzed at different time points. Immortalized mouse podocyte cells (MPCs) were cultured and treated with Risa-inhibition lentivirus (LV), EX-527, and LiCl. MPCs were collected under different stimulations as noted. The effects of Risa on podocyte autophagy were examined by qRT-PCR, Western blotting analysis, transmission electron microscopy, Periodic Acid-Schiff staining, and immunofluorescence staining. RESULTS: Risa and activated GSK3ß were overexpressed, but Sirt1 was downregulated in DN mice and high glucose-treated MPCs (P < 0.001, db/m vs. db/db, NG or HM vs. HG), which was correlated with poor prognosis. Risa overexpression attenuated Sirt1-mediated downstream autophagy levels and aggravated podocyte injury by inhibiting the expression of Sirt1 (P < 0.001, db/m vs. db/db, NG or HM vs. HG). In contrast, Risa suppression enhanced Sirt1-induced autophagy and attenuated podocyte injury, which could be abrogated by EX-527 (P < 0.001, db/db + Risa-AAV vs. db/db, HG + Risa-LV vs. HG). Furthermore, LiCl treatment could restore GSK3ß-mediated autophagy of podocytes (P < 0.001, db/db + LiCl vs. db/db, HG + LiCl vs. HG), suggesting that Risa overexpression aggravated podocyte injury by decreasing autophagy. CONCLUSION: Risa could inhibit autophagy by regulating the Sirt1/GSK3ß axis, thereby aggravating podocyte injury in DN. Risa may serve as a therapeutic target for the treatment of DN.
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Diabetes Mellitus , Nefropatias Diabéticas , Glicogênio Sintase Quinase 3 beta , Podócitos , RNA Longo não Codificante , Sirtuína 1 , Animais , Autofagia/genética , Nefropatias Diabéticas/genética , Nefropatias Diabéticas/metabolismo , Regulação para Baixo , Glicogênio Sintase Quinase 3 beta/genética , Glicogênio Sintase Quinase 3 beta/metabolismo , Glicogênio Sintase Quinase 3 beta/farmacologia , Camundongos , Podócitos/metabolismo , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , RNA Longo não Codificante/farmacologia , Sirtuína 1/genética , Sirtuína 1/metabolismo , Sirtuína 1/farmacologiaRESUMO
ABSTRACT: We aimed to evaluate the quality of life of Chinese patients after immediate reconstruction surgery on individuals with oral cavity cancer. In addition, we compared the differences between radial forearm free flap and pectoralis major myocuta- neous flap. Using the University of Washington quality of life v4 questionnaire, 1:1 matched research was performed on patients received PMM or RFF flap. Chi-square test was used to analyze the variables. One hundred twenty four of 179 questionnaires were returned (69.3%). Age, N stage, and postoperative radiotherapy were similar for both groups. However, there were significant differences between two groups in gender, T stage, operation duration, and complication rate. Oral cavity cancer patients reconstructed with radial forearm free flap had better shoulder and speech functions but worse appearance domains. The results of our research provide important information for patients and physicians during their discussion of treatment programs for oral cavity cancers.
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Retalhos de Tecido Biológico , Neoplasias Bucais , Retalho Miocutâneo , Procedimentos de Cirurgia Plástica , Antebraço/cirurgia , Retalhos de Tecido Biológico/cirurgia , Humanos , Neoplasias Bucais/cirurgia , Retalho Miocutâneo/cirurgia , Qualidade de Vida , Procedimentos de Cirurgia Plástica/métodosRESUMO
The kidney is a complex organ comprising various functional partitions and special cell types that play important roles in maintaining homeostasis in the body. Diabetic kidney disease (DKD) is the leading cause of end-stage renal disease and is an independent risk factor for cardiovascular diseases. Owing to the complexity and heterogeneity of kidney structure and function, the mechanism of DKD development has not been fully elucidated. Single-cell sequencing, including transcriptomics, epigenetics, metabolomics, and proteomics etc., is a powerful technology that enables the analysis of specific cell types and states, specifically expressed genes or pathways, cell differentiation trajectories, intercellular communication, and regulation or co-expression of genes in various diseases. Compared with other omics, RNA sequencing is a more developed technique with higher utilization of tissues or samples. This article reviewed the application of single-cell transcriptomics in the field of DKD and highlighted the key signaling pathways in specific tissues or cell types involved in the occurrence and development of DKD. The comprehensive understanding of single-cell transcriptomics through single-cell RNA-seq and single-nucleus RNA-seq will provide us new insights into the pathogenesis and treatment strategy of various diseases including DKD.
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Background: Accumulating evidence indicates that mitophagy is crucial for the development of diabetic nephropathy (DN). However, little is known about the key genes involved. The present study is to identify the potential mitophagy-related genes (MRGs) in DN. Methods: Five datasets were obtained from the Gene Expression Omnibus (GEO) database and were split into the training and validation set. Then the differentially expressed MRGs were screened and further analyzed for GO and KEGG enrichment. Next, three algorithms (SVM-RFE, LASSO and RF) were used to identify hub genes. The ROC curves were plotted based on the hub genes. We then used the CIBERSORT algorithm to assess the infiltration of 22 types of immune cells and explore the correlation between hub genes and immune cells. Finally, the Nephroseq V5 tool was used to analyze the correlation between hub genes and GFR in DN patients. Results: Compared with the tubulointerstitium, the expression of MRGs was more noticeably varied in the glomeruli. Twelve DE-MRGs were identified in glomerular samples, of which 11 genes were down-regulated and only MFN1 was up-regulated. GO and KEGG analysis indicated that several enrichment terms were associated with changes in autophagy. Three genes (MFN1, ULK1 and PARK2) were finally determined as potential hub genes by three algorithms. In the training set, the AUROC of MFN1, ULK1 and PARK2 were 0.839, 0.906 and 0.842. However, the results of the validation set demonstrated that MFN1 and PARK2 had no significant difference in distinguishing DN samples from healthy controls, while the AUROC of ULK1 was 0.894. Immune infiltration analysis using CIBERSORT showed that ULK1 was positively related to neutrophils, whereas negatively related to M1 and M2 macrophages. Finally, ULK1 was positively correlated with GFR in Nephroseq database. Conclusions: ULK1 is a potential biomarker for DN and may influence the development of diabetic nephropathy by regulating mitophagy.