RESUMEN

Lupus nephritis (LN) is an immunoinflammatory glomerulonephritis associated with renal involvement in systemic lupus erythematosus (SLE). Given the close relationship between plasma amino acids (AAs) and renal function, this study aimed to elucidate the plasma AA profiles in LN patients and identify key AAs and diagnostic patterns that distinguish LN patients from those with SLE and healthy controls. Participants were categorized into three groups: normal controls (NC), SLE, and LN. Ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) was employed to quantify AA levels in human plasma. Principal component analysis (PCA) and orthogonal partial least squares discriminant analysis (OPLS-DA) were utilized to identify key AAs. The diagnostic capacity of the models was assessed using receiver operating characteristic (ROC) curve analysis and area under the ROC curve (AUC) values. Significant alterations in plasma AA profiles were observed in LN patients compared to the SLE and NC groups. The OPLS-DA model effectively separated LN patients from the SLE and NC groups. A joint model using histidine (His), lysine (Lys), and tryptophan (Trp) demonstrated exceptional diagnostic performance, achieving an AUC of 1.0 with 100% sensitivity, specificity, and accuracy in predicting LN. Another joint model comprising arginine (Arg), valine (Val), and Trp also exhibited robust predictive performance, with an AUC of 0.998, sensitivity of 93.80%, specificity of 100%, and accuracy of 95.78% in distinguishing between SLE and LN. The joint forecasting models showed excellent predictive capabilities in identifying LN and categorizing lupus disease status. This approach provides a novel perspective for the early identification, prevention, treatment, and management of LN based on variations in plasma AA levels.

Asunto(s)

Aminoácidos , Lupus Eritematoso Sistémico , Nefritis Lúpica , Humanos , Nefritis Lúpica/sangre , Nefritis Lúpica/diagnóstico , Femenino , Adulto , Masculino , Lupus Eritematoso Sistémico/sangre , Aminoácidos/sangre , Persona de Mediana Edad , Metabolómica/métodos , Espectrometría de Masas en Tándem/métodos , Curva ROC , Triptófano/sangre , Biomarcadores/sangre , Diagnóstico Diferencial

RESUMEN

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.

RESUMEN

The precise forecasting of air quality is of great significance as an integral component of early warning systems. This remains a formidable challenge owing to the limited information of emission source and the considerable uncertainties inherent in dynamic processes. To improve the accuracy of air quality forecasting, this work proposes a new spatiotemporal hybrid deep learning model based on variational mode decomposition (VMD), graph attention networks (GAT) and bi-directional long short-term memory (BiLSTM), referred to as VMD-GAT-BiLSTM, for air quality forecasting. The proposed model initially employ a VMD to decompose original PM2.5 data into a series of relatively stable sub-sequences, thus reducing the influence of unknown factors on model prediction capabilities. For each sub-sequence, a GAT is then designed to explore deep spatial relationships among different monitoring stations. Next, a BiLSTM is utilized to learn the temporal features of each decomposed sub-sequence. Finally, the forecasting results of each decomposed sub-sequence are aggregated and summed as the final air quality prediction results. Experiment results on the collected Beijing air quality dataset show that the proposed model presents superior performance to other used methods on both short-term and long-term air quality forecasting tasks.

RESUMEN

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.

Asunto(s)

Microbioma Gastrointestinal , Hipertensión , Cloruro de Sodio Dietético , Microbioma Gastrointestinal/fisiología , Humanos , Hipertensión/microbiología , Hipertensión/fisiopatología , Cloruro de Sodio Dietético/efectos adversos , Animales , Ácidos Grasos Volátiles/metabolismo

RESUMEN

Approximately 158,500 adults and adolescents in the United States live with undiagnosed human immunodeficiency virus (HIV). Missed or delayed diagnoses adversely affect disease management and outcomes. This is particularly salient for patients receiving immunosuppressive and immunomodulatory therapy for the management of chronic inflammatory conditions, in which additional immunosuppression may increase the risk and severity of opportunistic infections. Despite this risk, comprehensive HIV testing before the initiation of immunosuppressive therapy is not yet the norm. We describe a case series containing the narratives of three patients recently treated with immunosuppressive agents, who presented with signs concerning for HIV-associated kidney diseases and who were found to have undiagnosed HIV later in the treatment course, which, unfortunately, resulted in poor outcomes. Screening for HIV or related illnesses, such as viral hepatitis or mycobacterial co-infections including tuberculosis, is essential before initiating biologic immunosuppression.

Asunto(s)

Infecciones por VIH , Inmunosupresores , Adulto , Femenino , Humanos , Masculino , Persona de Mediana Edad , Nefropatía Asociada a SIDA/diagnóstico , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/complicaciones , Inmunosupresores/efectos adversos , Inmunosupresores/uso terapéutico

RESUMEN

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.

Asunto(s)

Hiperpotasemia , Natriuresis , Potasio , Intercambiador 3 de Sodio-Hidrógeno , Animales , Natriuresis/efectos de los fármacos , Ratones , Potasio/orina , Potasio/sangre , Potasio/metabolismo , Intercambiador 3 de Sodio-Hidrógeno/metabolismo , Masculino , Diabetes Mellitus Tipo 2/complicaciones , Suplementos Dietéticos

RESUMEN

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.

Asunto(s)

Diabetes Mellitus Experimental , Canales Epiteliales de Sodio , Potasio en la Dieta , Potasio , Animales , Diabetes Mellitus Experimental/metabolismo , Potasio/metabolismo , Potasio/orina , Masculino , Potasio en la Dieta/metabolismo , Canales Epiteliales de Sodio/metabolismo , Ratones Endogámicos C57BL , Inhibidores del Cotransportador de Sodio-Glucosa 2/farmacología , Canales de Potasio de Rectificación Interna/metabolismo , Canales de Potasio de Rectificación Interna/genética , Ratones , Nefropatías Diabéticas/metabolismo , Nefropatías Diabéticas/etiología , Nefropatías Diabéticas/fisiopatología , Riñón/metabolismo , Riñón/efectos de los fármacos , Riñón/fisiopatología , Hipopotasemia/metabolismo , Amilorida/farmacología , Eliminación Renal/efectos de los fármacos , Homeostasis , Miembro 3 de la Familia de Transportadores de Soluto 12/metabolismo , Miembro 3 de la Familia de Transportadores de Soluto 12/genética , Glucósidos/farmacología , Estreptozocina , Compuestos de Bencidrilo , Transportador 2 de Sodio-Glucosa

RESUMEN

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.

RESUMEN

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.

Asunto(s)

Diabetes Mellitus , Nefropatías Diabéticas , Glucógeno Sintasa Quinasa 3 beta , Humanos , Nefropatías Diabéticas/tratamiento farmacológico , Glucosa/metabolismo , Glucógeno Sintasa Quinasa 3 beta/metabolismo , Riñón/metabolismo

RESUMEN

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.

RESUMEN

Metal-organic frameworks (MOFs) have shown promising potential as proton-conducting materials due to their tunable structures and high porosity. In this study, two novel MOFs had been successfully synthesized, one containing sulfate groups (MOF-1; [Zn4(TIPE)2(SO4)4(H2O)]·5H2O) and the other containing sulfonate groups (MOF-2; [Zn2(TIPE)(5-sip)(NO3)0.66]·0.34NO3·17.5H2O) (TIPE = 1,1,2,2-tetrakis(4-(1H-imidazole-1-yl)phenyl)ethene, H35-sip = 5-sulfoisophthalicacid), and the effect of the two groups on the proton conductivity of Zn-based MOFs had been investigated and compared for the first time. The proton conductivity of these MOFs was systematically measured at different temperatures and humidity conditions. Remarkably, the results revealed significant differences in proton conductivity between the two sets of MOFs. At 90 °C and 98% RH, MOF-1 and MOF-2 achieved optimal proton conductivity of 4.48 × 10-3 and 5.69 × 10-2 S·cm-1, respectively. This was due to the structural differences arising from the presence of different functional groups, which subsequently affected the porosity and hydrophilicity, thereby influencing the proton conductivity. Overall, this comparative study revealed the influence of sulfate and sulfonate groups on the proton conductivity of Zn-based MOFs. This research provided a feasible idea for the development of advanced MOF materials with enhanced proton conductivity and opened up new possibilities for their application in proton devices.

RESUMEN

OBJECTIVE: The aim of this research was to assess the therapeutic drug monitoring (TDM) of clozapine (CLO) and norclozapine (NCLO). METHODS: TDM results of CLO and NCLO in patients obtained from the Xi'an Mental Health Center were retrospectively analyzed. RESULTS: TDM of CLO and NCLO was typically conducted only once in the majority of patients, particularly those receiving outpatient care. The CLO plasma concentrations were higher in inpatients and female patients. The interquartile (25th-75th) CLO concentrations ranged from 129.83 to 397.53 ng/mL, nearly 68.63% of the samples had subtherapeutic concentrations (<350 ng/mL). Receiver operating characteristic curve analysis showed that inpatients achieved the therapeutic level concentration of 350-600 ng/mL when their daily CLO dose was > 125 mg. CONCLUSIONS: It was surprising to find such a large number of patients with CLO levels below the therapeutic range, there is still a window of improvement for optimizing pharmacological treatments in clinical practice.

Asunto(s)

Antipsicóticos , Clozapina , Esquizofrenia , Humanos , Femenino , Clozapina/uso terapéutico , Esquizofrenia/tratamiento farmacológico , Estudios Retrospectivos , Antipsicóticos/uso terapéutico , Monitoreo de Drogas/métodos

RESUMEN

Anions play a significant role in the construction of metal-organic frameworks (MOFs). Anions can affect coordination between metal ions and organic ligands, and the formation of crystal structures, thereby affecting the structure and properties of MOFs. Two novel 3D porous MOFs ({[Cd3(TIPE)2(SO4)1.6(H2O)2.4]·2.8OH·6.2H2O}n (MOF-1) and {[Cd3(TIPE)2(SO4)3(H2O)2]·10H2O}n (MOF-2)) were successfully synthesized, by introducing SO42- to design and adjust their structure and properties, in which the sulfate ions not only participated in coordination but also played a bridging role. Both MOF-1 and MOF-2 exhibited high stability and strong fluorescence properties, and their fluorescence properties also changed compared to those of previously reported 2D nonporous MOF-3 ({[Cd2(TIPE)2Cl3(ACN)]·CdCl3·3H2O}n) with an identical ligand. They could also be used in combination with MOF-3 to distinguish between Fe3+ and Cr2O72- ions, due to a change in their fluorescence properties. In this work, the structure was reshaped by introducing sulfate ions, and the role and function of the sulfate ions in the structure were studied, providing a feasible idea for the design and precise regulation of MOFs.

RESUMEN

We report here a robust and practical strategy for chemical protein synthesis using an o-nitrobenzyl group as a temporary protective group for an N-terminal cysteine residue of intermediate hydrazide fragments. By reinvestigating the photoremoval of an o-nitrobenzyl group, we establish a robust and reliable strategy for its quantitative photodeprotection. The o-nitrobenzyl group is completely stable to oxidative NaNO2 treatment and has been applied to the convergent chemical synthesis of programmed death ligand 1 fragment, providing a practical avenue for hydrazide-based native chemical ligation.

Asunto(s)

Cisteína , Proteínas , Cisteína/química , Ligadura , Nitrito de Sodio/química

RESUMEN

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.

Asunto(s)

Diabetes Mellitus Experimental , Hipertensión , Animales , Ratones , Diabetes Mellitus Experimental/complicaciones , Diabetes Mellitus Experimental/metabolismo , Hipertensión/metabolismo , Túbulos Renales Distales/metabolismo , Ratones Noqueados , Sodio/metabolismo , Cloruro de Sodio/farmacología , Cloruro de Sodio Dietético/farmacología , Intercambiador 3 de Sodio-Hidrógeno/metabolismo , Intercambiador 3 de Sodio-Hidrógeno/farmacología , Miembro 3 de la Familia de Transportadores de Soluto 12/genética , Miembro 3 de la Familia de Transportadores de Soluto 12/metabolismo , Estreptozocina/metabolismo , Estreptozocina/farmacología

RESUMEN

BACKGROUND: A patient, with a mental disorder caused by an intracranial infection, treated with olanzapine, fluvoxamine, and buspirone. The plasma exposure of olanzapine was too high at standard doses, with evidence indicating that it was caused by drug-drug interactions. METHODS: Using pharmacogenomics and therapeutic drug monitoring to guide drug dose adjustment for a patient in clinical practice. RESULTS: The patient underwent pharmacogenetic testing in addition to therapeutic drug monitoring as part of a pharmacist-led comprehensive evaluation of medication therapy management in a clinical setting, resulting in improved clinical efficacy that allowed discharge from a psychiatric hospital. CONCLUSIONS: This case study demonstrates that therapeutic drug monitoring combined with pharmacogenetic-guided dose adjustment can aid in the management of patients receiving complex pharmacological treatments.

Asunto(s)

Buspirona , Fluvoxamina , Humanos , Olanzapina , Fluvoxamina/uso terapéutico , Buspirona/uso terapéutico , Farmacogenética , Monitoreo de Drogas/métodos , Benzodiazepinas

RESUMEN

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.

Asunto(s)

Hiperpotasemia , Hipertensión , Animales , Ratones , Miembro 3 de la Familia de Transportadores de Soluto 12/metabolismo , Hiperpotasemia/metabolismo , Ciclosporina/farmacología , Cloruro de Sodio/metabolismo , Cloruro de Sodio/farmacología , Ratones Noqueados , Túbulos Renales Distales , Hipertensión/inducido químicamente , Hipertensión/metabolismo

RESUMEN

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.

Asunto(s)

Diabetes Mellitus , Nefropatías Diabéticas , Microbioma Gastrointestinal , Fallo Renal Crónico , Humanos , Nefropatías Diabéticas/etiología , Nefropatías Diabéticas/terapia , Nefropatías Diabéticas/metabolismo , Fallo Renal Crónico/complicaciones , Factores de Riesgo , Biomarcadores

RESUMEN

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.

Asunto(s)

Riñón , Modelos Biológicos , Humanos , Relación Dosis-Respuesta a Droga , Riñón/fisiología

RESUMEN

BACKGROUND: Various types of drug-induced liver injury are induced by Polygonum multiflorum (PM); however, it rarely causes neutropenia. Herein, we report the case of a 65-year-old woman with concurrent severe hepatotoxicity and agranulocytosis induced by PM. CASE SUMMARY: A 65-year-old woman reported with severe hepatotoxicity and agranulocytosis 17 d after ingestion of PM. The results of the Roussel Uclaf Causality Assessment Method demonstrated a highly probable relationship between hepatotoxicity and PM, with a total score of 10. The Naranjo algorithm results indicated that agranulocytosis had a probable relationship with PM, with an overall score of 6. Granulocyte colony-stimulating factor (for once), a steroid, compound glycyrrhizin, and polyene phosphatidylcholine therapy were initiated. After 15 d of treatment, there was a gradual improvement in liver biochemistry, leukocytes, and neutrophils levels. CONCLUSION: Concurrent hepatotoxicity and agranulocytosis are rare and critical adverse drug reactions of PM, which should be highly valued.