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Objective: (MSU) crystals usually in the kidney tubules especially collecting ducts in the medulla. Previous animal models have not fully reproduced the impact of MSU on kidneys under non-hyperuricemic conditions. Methods: In the group treated with MSU, the upper pole of the rat kidney was injected intrarenally with 50 mg/kg of MSU, while the lower pole was injected with an equivalent volume of PBS solution. The body weight and kidney mass of the rats were observed and counted. H&E staining was used to observe the pathological damage of the kidney and to count the number of inflammatory cells. Masoon staining was used to observe the interstitial fibrosis in the kidneys of the rat model. Flow cytometric analysis was used for counting inflammatory cells in rats. ElISA was used to measure the concentration of serum and urine uric acid, creatinine and urea nitrogen in rats. Results: At the MSU injection site, a significantly higher infiltration of inflammatory cells and a substantial increase in the area of interstitial fibrosis compared to the control group and the site of PBS injection were observed. The serum creatinine level was significantly increased in the MSU group. However, there were no significant differences in the rats' general conditions or blood inflammatory cell counts when compared to the control group. Conclusion: The injection of urate crystals into the kidney compromised renal function, caused local pathological damage, and increased inflammatory cell infiltration and interstitial fibrosis. Intrarenal injection of MSU crystals may result in urate nephropathy. The method of intrarenal injection did not induce surgical infection or systemic inflammatory response.
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Modelos Animais de Doenças , Ratos Sprague-Dawley , Ácido Úrico , Animais , Ratos , Masculino , Rim/patologia , Rim/efeitos dos fármacos , Rim/metabolismo , Nefropatias/patologia , Nefropatias/induzido quimicamente , Nefropatias/metabolismo , Fibrose , Cristalização , Creatinina/sangueRESUMO
BACKGROUND: Known for its strong diuretic properties, the perennial herbaceous plant Orthosiphon stamineus Benth. is believed to preserve the kidney disease. This study compared the boiling water extract with powdered Orthosiphon stamineus Benth. and used a highly sensitive and high resolution UHPLC-Q-Exactive-Orbitrap-HRMS technology to evaluate its chemical composition. RESULTS: Furthermore, by monitoring the absorption of prototype components in rat plasma following oral treatment, the beneficial ingredients of the Orthosiphon stamineus Benth. decoction was discovered. Approximately 92 substances underwent a preliminary identification utilizing relevant databases, relevant literature, and reference standards. As the compound differences between the powdered Orthosiphon stamineus Benth. and its water decoction were analyzed, it was found that boiling produced additional compounds, 48 of which were new. 45 blood absorption prototype components and 49 OS metabolites were discovered from rat serum, and a kidney tissue homogenate revealed an additional 28 prototype components. Early differences in the distribution of ferulic acid, cis 4 coumaric acid, and rosmarinic acid were shown using spatial metabolomics. It was elucidated that the renal cortex region is where rosmarinic acid largely acts, offering a theoretical foundation for further studies on the application of OS in the prevention and treatment of illness as well as the preservation of kidney function. SIGNIFICANCE: In this study, UHPLC-Q Exactive Orbitrap-HRMS was employed to discern OS's chemical composition, and a rapid, sensitive, and broad-coverage AFADESI-MSI method was developed to visualize the spatial distribution of compounds in tissues.
Assuntos
Orthosiphon , Extratos Vegetais , Orthosiphon/química , Animais , Cromatografia Líquida de Alta Pressão/métodos , Ratos , Extratos Vegetais/química , Masculino , Ratos Sprague-Dawley , Espectrometria de Massas/métodos , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz/métodos , Rim/metabolismoRESUMO
OBJECTIVE: Glucocorticoid (GC) administration has been associated with adverse drug reactions (ADRs) affecting multiple organ systems. While long-term use is widely recognized as a significant independent predictor of ADRs, it is important to note that even short-term use can lead to serious ADRs. The considerable inter-individual variability in ADRs occurrence may be influenced by genetic factors. This study, we present a case of a child who experienced significant weight gain and osteoporosis, following a brief administration of GC. METHODS: To comprehensively investigate the underlying mechanisms, we conducted a genomic analysis utilizing the whole exome sequencing (WES) technique. This analysis encompassed the examination of phase I and phase II metabolism, influx transport, efflux transport, and drug targeting. Additionally, a comprehensive analysis was conducted on a cohort of 52,119 children to determine their ABCB1 rs1045642 genotype, and an additional 37,884 children were tested for their CYP3A5 rs776746 genotype. RESULTS: The pharmacogenetic analysis unveiled the presence of a high-risk variant in ABCB1 rs1045642 and a slow metabolism variant in CYP3A5 rs776746, both of which have the potential to substantially contribute to ADRs. The findings of this study indicate that the prevalence of ABCB1 rs1045642 CT type among patients was 47.58%, with TT type accounting for 15.69 % and CC type accounting for 36.73 %. Furthermore, the distribution of CYP3A5 rs776746 CC genotype was observed in 50.54 % of individuals, while CT and TT genotypes were present in 41.15 % and 8.31 % of the population respectively. The distribution of ABCB1 and CYP3A5 genotypes among the pediatric population in China displays notable features. Specifically, for the ABCB1 rs1045642 genotype, less than 50 % of children exhibit intermediate metabotypes. Conversely, among children with the CYP3A5 rs776746 genotype, the predominant cause for enzyme activity is the slow metabolic type, accounting for up to 90 % of cases. CONCLUSIONS: Consequently, it is imperative to thoroughly evaluate the impact of allele mutation on the effectiveness and safety of glucocorticoid drugs or other medications metabolized by the ABCB1 and CYP3A5, particularly in the context of Chinese pediatric patients.
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Subfamília B de Transportador de Cassetes de Ligação de ATP , Citocromo P-450 CYP3A , Glucocorticoides , Humanos , Glucocorticoides/uso terapêutico , Glucocorticoides/efeitos adversos , Citocromo P-450 CYP3A/genética , Criança , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Masculino , Feminino , Sequenciamento do Exoma , Genótipo , Osteoporose/genética , Osteoporose/tratamento farmacológico , Polimorfismo de Nucleotídeo Único , Pré-Escolar , GenômicaRESUMO
Changes in lifestyle induce an increase in patients with hyperuricemia (HUA), leading to gout, gouty arthritis, renal damage, and cardiovascular injury. There is a strong inflammatory response in the process of HUA, while dysregulation of immune cells, including monocytes, macrophages, and T cells, plays a crucial role in the inflammatory response. Recent studies have indicated that urate has a direct impact on immune cell populations, changes in cytokine expression, modifications in chemotaxis and differentiation, and the provocation of immune cells by intrinsic cells to cause the aforementioned conditions. Here we conducted a detailed review of the relationship among uric acid, immune response, and inflammatory status in hyperuricemia and its complications, providing new therapeutic targets and strategies.
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Artrite Gotosa , Gota , Hiperuricemia , Humanos , Hiperuricemia/complicações , Hiperuricemia/metabolismo , Ácido Úrico/metabolismo , Gota/tratamento farmacológico , Artrite Gotosa/tratamento farmacológico , Inflamação/complicaçõesRESUMO
BACKGROUND: Chronic kidney disease (CKD) is an increasing public health issue. Anemia, which is a complication of CKD, is associated with reduced quality of life and increased morbidity and mortality. Currently quite a few clinical studies have been conducted to compare roxadustat with epoetin alfa [all for dialysis-dependent (DD) patients] or placebo [all for nondialysis-dependent (NDD) patients]. Our meta-analysis aimed to investigate the efficacy and safety of roxadustat for anemia in patients with CKD. METHODS: We thoroughly searched eight electronic resource databases for randomized controlled trials (RCTs) comparing the efficacy and safety between roxadustat versus epoetin alfa or placebo for the treatment of anemia in patients with CKD. RESULTS: Four Phase 2 and two Phase 3 studies with 1010 participants were included. Hemoglobin (Hb) and transferrin levels were increased significantly in the roxadustat group versus those in the placebo {standard mean difference [SMD] 1.57 [95% confidence interval (CI) 1.17-1.98]; SMD 1.81 [95% CI 1.53-2.08]; respectively, both low-quality evidence} or epoetin alfa group [SMD 0.47 (95% CI 0.02-0.93), very low-quality evidence; SMD 1.05 (95% CI 0.81-1.29), low-quality evidence; respectively]. Hepcidin levels were reduced significantly in the roxadustat group versus those in the placebo [SMD -1.72 (95% CI -3.03 to -0.41), very low-quality evidence] or epoetin alfa group [SMD -0.23 (95% CI -0.43 to -0.02), low-quality evidence]. Ferritin and serum transferrin saturation (TSAT) levels were reduced significantly in the roxadustat group versus those in the placebo group [SMD -0.82 (95% CI -1.31 to -0.33); SMD -0.54 (95% CI -0.76 to -0.32), respectively; both low-quality evidence] and ferritin and TSAT levels in the roxadustat group were comparable to those in the epoetin alfa group [SMD 0.02 (95% CI -0.18-0.21); SMD 0.15 (95% CI -0.04-0.35), respectively, both low-quality evidence]. As for safety, the incidence of adverse events (AEs) in the roxadustat group was insignificantly different from that of the placebo group [risk ratio (RR) 0.99 (95% CI 0.83-1.18); P = 0.89, very low-quality evidence]. But the incidence of AEs in the roxadustat group was significantly higher than that in the epoetin alfa group [RR 1.25 (95% CI 1.01-1.54); P = 0.04, low-quality evidence]. There was no significant association between roxadustat and the incidence of serious AEs (SAEs) for both NDD and DD patients [RR 1.08 (95% CI 0.51-2.28) and RR 1.43 (95% CI 0.85-2.40), respectively, both very low-quality evidence]. CONCLUSION: In this meta-analysis of RCTs, we found evidence that after the oral administration of roxadustat, NDD patients' Hb levels were increased effectively and DD patients' Hb levels were maintained effectively. The risk of SAEs was not observed with the short-term use of roxadustat. These findings support roxadustat for the treatment of anemia in patients with CKD.
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Anemia , Glicina/uso terapêutico , Isoquinolinas/uso terapêutico , Insuficiência Renal Crônica , Anemia/tratamento farmacológico , Anemia/etiologia , Glicina/análogos & derivados , Humanos , Ensaios Clínicos Controlados Aleatórios como Assunto , Diálise Renal , Insuficiência Renal Crônica/complicaçõesRESUMO
Hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHIs) are a new class of oral medicines being developed for the treatment of anemia in chronic kidney disease (CKD) patients. This study aimed to compare the efficacy and safety of HIF-PHI vs epoetin and darbepoetin in CKD patients with anemia not undergoing dialysis. The PubMed, Embase, Cochrane Library, Web of Science, and clinicaltrials.gov databases were searched from inception to October 2019 for randomized controlled trials investigating different agents (six HIF-PHIs, epoetin, darbepoetin, and placebo) for treating CKD patients with anemia that did not undergo dialysis. The outcomes included a change in hemoglobin (Hb) levels and all-cause mortality. A total of 19 studies were included. Compared with the placebo, except for vadadustat (mean differences: 1.12, 95 % confidence interval [CI]: â0.11-2.35), the other drugs significantly increased Hb levels, with mean differences of 2.46 (95 % CI: 0.93-3.99) for desidustat, 1.81 (0.87-2.75) for enarodustat, 1.68 (0.64-2.72) for molidustat, 1.66 (0.89-2.44) for epoetin, 1.63 (0.69-2.56) for darbepoetin, 1.61 (0.99-2.22) for roxadustat, and 1.55 (0.74-2.36) for daprodustat. No differences were found in the Hb level elevations among these eight drugs. Compared with the placebo, there also was no significant association between the drugs and all-cause mortality (molidustat of RR, 0.39 [95 % CI, 0.06-2.59]; roxadustat, 0.40 (0.06-2.84); enarodustat, 0.33 (0.01-16.25); desidustat, 0.34 (0.01-17.00); epoetin, 0.50 (0.18-1.42); daprodustat, 0.54 (0.09-3.31); darbepoetin, 1.03 (0.65-1.65); and vadadustat, 1.43 (0.15-13.27)). No differences were observed in the all-cause mortality among the drugs. In conclusion, these HIF-PHIs are effective and relatively tolerant for treating anemia patients with CKD not undergoing dialysis. Further research should consider the limitations of our study to evaluate the value of these HIF-PHIs in clinical settings.
Assuntos
Anemia/tratamento farmacológico , Darbepoetina alfa/uso terapêutico , Inibidores Enzimáticos/uso terapêutico , Epoetina alfa/uso terapêutico , Hematínicos/uso terapêutico , Hemoglobinas/metabolismo , Prolina Dioxigenases do Fator Induzível por Hipóxia/antagonistas & inibidores , Insuficiência Renal Crônica/complicações , Idoso , Idoso de 80 Anos ou mais , Anemia/enzimologia , Anemia/etiologia , Anemia/mortalidade , Biomarcadores/sangue , Darbepoetina alfa/efeitos adversos , Inibidores Enzimáticos/efeitos adversos , Epoetina alfa/efeitos adversos , Feminino , Hematínicos/efeitos adversos , Humanos , Prolina Dioxigenases do Fator Induzível por Hipóxia/metabolismo , Masculino , Pessoa de Meia-Idade , Metanálise em Rede , Ensaios Clínicos Controlados Aleatórios como Assunto , Insuficiência Renal Crônica/mortalidade , Medição de Risco , Fatores de Risco , Fatores de Tempo , Resultado do TratamentoRESUMO
OBJECTIVE: This study is aimed at investigating the efficacy of a very low-energy diet (VLED) in overweight and obese individuals with type 2 diabetes mellitus (T2DM). METHODS: We thoroughly searched eight electronic resource databases of controlled studies concerning the efficacy and acceptability of intermittent or continuous VLEDs in patients with T2DM compared with other energy restriction interventions. RESULTS: Eighteen studies (11 randomized and seven nonrandomized controlled trials) with 911 participants were included. The meta-analyses showed that compared with a low-energy diet (LED) and mild energy restriction (MER), VLED is superior in the reduction of body weight (mean difference (MD) MDLED = -2.77, 95% confidence interval (CI) CILED = -4.81 to - 0.72, P LED = 0.008; MDMER = -6.72, 95%CIMER = -10.05 to - 3.39, P LED = 0.008; MDMER = -6.72, 95%CIMER = -10.05 to - 3.39, P LED = 0.008; MDMER = -6.72, 95%CIMER = -10.05 to - 3.39, P LED = 0.008; MDMER = -6.72, 95%CIMER = -10.05 to - 3.39, P LED = 0.008; MDMER = -6.72, 95%CIMER = -10.05 to - 3.39, P LED = 0.008; MDMER = -6.72, 95%CIMER = -10.05 to - 3.39, P LED = 0.008; MDMER = -6.72, 95%CIMER = -10.05 to - 3.39, I 2 = 0%) and TG level (MD = -0.25, 95%CI = -0.55 to 0.06, P LED = 0.008; MDMER = -6.72, 95%CIMER = -10.05 to - 3.39, I 2 = 0%) and TG level (MD = -0.25, 95%CI = -0.55 to 0.06, P LED = 0.008; MDMER = -6.72, 95%CIMER = -10.05 to - 3.39, P LED = 0.008; MDMER = -6.72, 95%CIMER = -10.05 to - 3.39, P LED = 0.008; MDMER = -6.72, 95%CIMER = -10.05 to - 3.39, P LED = 0.008; MDMER = -6.72, 95%CIMER = -10.05 to - 3.39, P LED = 0.008; MDMER = -6.72, 95%CIMER = -10.05 to - 3.39. CONCLUSION: Dietary intervention through VLEDs is an effective therapy for rapid weight loss, glycemic control, and improved lipid metabolism in overweight and obese individuals with T2DM. Thus, VLEDs should be encouraged in overweight and obese individuals with T2DM who urgently need weight loss and are unsuitable or unwilling to undergo surgery. As all outcome indicators have low or extremely low quality after GRADE evaluation, further clinical trials that focus on the remission effect of VLEDs on T2DM are needed.
Assuntos
Glicemia/metabolismo , Restrição Calórica/métodos , Diabetes Mellitus Tipo 2/terapia , Dieta Redutora/métodos , Obesidade/dietoterapia , Redução de Peso , Cirurgia Bariátrica , Índice de Massa Corporal , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/metabolismo , Humanos , Resistência à Insulina , Obesidade/complicações , Obesidade/metabolismo , Sobrepeso/complicações , Sobrepeso/dietoterapia , Sobrepeso/metabolismo , Aceitação pelo Paciente de Cuidados de Saúde , Pacientes Desistentes do Tratamento , Resultado do Tratamento , Triglicerídeos/metabolismoRESUMO
Objective: Daprodustat is a novel oral agent in treating anemia of chronic kidney disease (CKD), and several clinical trials have been conducted to compare daprodustat with recombinant human erythropoietin (rhEPO) or placebo. Our systematic review aimed to investigate the efficacy and safety of daprodustat for anemia treatment in both dialysis-dependent (DD) and non-dialysis-dependent (NDD) patients. Methods: Six databases were searched for randomized controlled trials (RCTs) reporting daprodustat vs. rhEPO or placebo for anemia patients in CKD. The outcome indicators were focused on hemoglobin (Hb), ferritin, transferrin saturation (TSAT), total iron-binding capacity (TIBC), vascular endothelial growth factor (VEGF), and serious adverse events (SAEs). Results: Eight eligible studies with 1,516 participants were included. For both NDD and DD patients, changes in Hb levels from baseline were significantly higher in daprodustat group than that in the placebo (mean difference (MD) = 1.73, [95% confidence interval (CI), 0.34 to 3.12], p = 0.01; MD = 1.88, [95% CI, 0.68 to 3.09], p = 0.002; respectively), and there was no significant difference between daprodustat and rhEPO group (MD = 0.05, [95% CI, -0.49 to 0.59], p = 0.86; MD = 0.12, [95% CI, -0.28 to 0.52], p = 0.55; respectively). The indexes of iron metabolism were improved significantly in the daprodustat group compared to placebo- or rhEPO-treated patients, while there was no similar change in terms of TSAT for DD patients. Furthermore, no trend of increasing plasma VEGF was observed in daprodustat-treated subjects. As for safety, there was no significant difference in the incidence of SAEs between daprodustat and placebo treatment, while the incidence of SAEs in the daprodustat group was significantly lower than that in the rhEPO group. Conclusion: Daprodustat was efficacious and well tolerated for anemia in both NDD and DD patients in the short term based on current RCTs. And daprodustat may become an effective alternative for treatment of anemia with CKD. Since the application of daprodustat is still under exploration, future researches should consider the limitations of our study to evaluate the value of daprodustat.
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The emerging connected, low-cost, and easy-to-use air quality monitoring systems have enabled a paradigm shift in the field of air pollution monitoring. These systems are increasingly being used by local government and non-profit organizations to inform the public, and to support decision making related to air quality. However, data integrity and system security are rarely considered during the design and deployment of such monitoring systems, and such ignorance leaves tremendous room for undesired and damaging cyber intrusions. The collected measurement data, if polluted, could misinform the public and mislead policy makers. In this paper, we demonstrate such issues by using a.com, a popular low-cost air quality monitoring system that provides an affordable and continuous air quality monitoring capability to broad communities. To protect the air quality monitoring network under this investigation, we denote the company of interest as a.com. Through a series of probing, we are able to identify multiple security vulnerabilities in the system, including unencrypted message communication, incompetent authentication mechanisms, and lack of data integrity verification. By exploiting these vulnerabilities, we have the ability of "impersonating" any victim sensor in the a.com system and polluting its data using fabricated data. To the best of our knowledge, this is the first security analysis of low-cost and connected air quality monitoring systems. Our results highlight the urgent need in improving the security and data integrity design in these systems.
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Urinary tract infection (UTI) in traditional Chinese medicine (TCM) belongs to the category of stranguria. This article describes the unsatisfactory situations in clinical practice such as antibiotics abuse, increasing of drug-resistant bacteria, high recurrence rate, etc. According to evidence-based medicine, literatures as evidence are collected for summarizing and analyzing and the result shows the advantages of TCM of relieving symptoms, reducing the dosage of antibiotics, less side effects, lower recurrence rate, etc. In the field of fundamental research, literatures associated with UTI are also summarized and analysed from several perspectives, such as causes, pathogenesis, syndrome differentiation, pharmacological effects of Chinese herbal medicine, working mechanism of non-drug therapy, etc and the result presents that integrated treatment of TCM in UTI has significant advangtages and its own characteristic.
Assuntos
Medicina Tradicional Chinesa , Infecções Urinárias/prevenção & controle , Infecções Urinárias/terapia , Medicamentos de Ervas Chinesas/uso terapêutico , Medicina Baseada em Evidências , HumanosRESUMO
We address issues related to establishing a defender's reputation in anomaly detection against two types of attackers: 1) smart insiders, who learn from historic attacks and adapt their strategies to avoid detection/punishment, and 2) naïve attackers, who blindly launch their attacks without knowledge of the history. In this paper, we propose two novel algorithms for reputation establishment--one for systems solely consisting of smart insiders and the other for systems in which both smart insiders and naïve attackers are present. The theoretical analysis and performance evaluation show that our reputation-establishment algorithms can significantly improve the performance of anomaly detection against insider attacks in terms of the tradeoff between detection and false positives.
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Algoritmos , Segurança Computacional , Técnicas de Apoio para a Decisão , Fraude/prevenção & controle , Teoria dos Jogos , Modelos TeóricosRESUMO
BACKGROUND: The antigen reducing ability of dendritic cells (DCs), a kind of antigen presenting cells (APCs) initiating immune response, is associated with the specific immune tolerance of chronic hepatitis B (CHB) patients. However, the dysfunction of DCs can be possibly reversed by the stimulation of antigen peptides. In this study, DCs were cultured from peripheral blood monocytes (PBMCs) in patients with CHB in vitro, and the expression of phenotypic molecules on DCs loaded by different concentrations of HBsAg was observed. METHODS: Forty patients with CHB were divided randomly into 4 groups (10 patients in each group). PBMCs were isolated, and DCs were cultured after addition of granulocyte/macrophage colony-stimulating factor (GM-CSF) and interleukin 4 (IL-4). On the 9th day, DCs of the experimental groups were loaded at HBsAg concentrations of 2.5 mg/L, 5 mg/L and 10 mg/L for 24 hours, whereas those of the control group were not loaded. An electron microscope was used to analyze the morphological changes of the DCs. The expression of phenotypic molecules on DCs in different groups was detected with flow cytometry. RESULTS: A combination of GM-CSF and IL-4 produced DCs from PBMCs in patients with CHB after being cultured for 9 days, whose morphological changes were tested by an electron microscope. The expression of phenotypic molecules on DCs in the control group was as low as CD83 (8.02+/-3.99)%, CD80 (8.77+/-2.06)%, and MHC-DR (14.05+/-2.66)%. Loaded by different concentrations of HBsAg, the up-regulation of phenotypic molecules on DCs was found, with CD83 (18.35+/-2.93)%, CD80 (42.63+/-7.15)% and MHC-DR (47.49+/-6.59)% in 2.5 mg/L HBsAg loading group, CD83 (17.88+/-3.12)%, CD80 (45.24+/-10.93)% and MHC-DR (47.07+/-8.52)% in 5 mg/L HBsAg loading group and CD83 (16.74+/-2.86)%, CD80 (44.59+/-6.99)% and MHC-DR (48.59+/-7.42)% in 10 mg/L HBsAg loading group, respectively. Compared with the control group, the phenotypic molecules in the experimental groups were all different significantly (P<0.01), but among them, there were no differences (P>0.05). CONCLUSIONS: DCs cultured from PBMCs in the patients with CHB under the conditions of GM-CSF and IL-4 present on the typical dendritic morphology but are immature for expressing low phenotypic molecules. Loaded by different concentrations of HBsAg, the immature DCs can differentiate to mature DCs for expressing increasing phenotypic molecules.