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Glomerulonefritis por IGA , Glomeruloesclerosis Focal y Segmentaria , Humanos , Glomerulonefritis por IGA/patología , Glomerulonefritis por IGA/clasificación , Glomeruloesclerosis Focal y Segmentaria/patología , Glomeruloesclerosis Focal y Segmentaria/clasificación , Glomeruloesclerosis Focal y Segmentaria/diagnóstico , Glomérulos Renales/patología , BiopsiaRESUMEN
Cerebral ischemia-reperfusion injury (CIRI) is a severe pathological condition that involves oxidative stress, inflammatory response, and neuronal damage. HY-021068 belongs to a new drug of chemical class 1, which is a potential thromboxane synthase inhibitor. Our preliminary experiment found that HY-021068 has significant anti-neuroinflammatory and neuroprotective effects. However, the protective effect and mechanism of HY-021068 in CIRI remain unclear. To investigate the protective effect and mechanism of HY-021068 in CIRI mice. In mice, CIRI was induced by bilateral common carotid artery occlusion and reperfusion. Mice were treated with HY-021068 or LV-NLRP1-shRNA (lentivirus-mediated shRNA transfection to knock down NLRP1 expression). The locomotor activity, neuronal damage, pathological changes, postsynaptic density protein-95 (PSD-95) expression, NLRP1 inflammasome activation, autophagy markers, and apoptotic proteins were assessed in CIRI mice. In this study, treatment with HY-021065 and LV-NLRP1-shRNA significantly improved motor dysfunction and neuronal damage after CIRI in mice. HY-021065 and NLRP1 knockdown significantly ameliorated the pathological damage and increased PSD-95 expression in the cortex and hippocampus CA1 and CA3 regions. The further studies showed that compared with the CIRI model group, HY-021065 and NLRP1 knockdown treatment inhibited the expressions of NLRP1, ASC, caspase-1, and IL-1ß, restored the expressions of p-AMPK/AMPK, Beclin1, LC3II/LC3I, p-mTOR/m-TOR and P62, and regulated the expressions of BCL-2, Caspase3, and BAX in brain tissues of CIRI mice in CIRI mice. These results suggest that HY-021068 exerts a protective role in CIRI mice by inhibiting NLRP1 inflammasome activation and regulating autophagy function and neuronal apoptosis. HY-021068 is expected to become a new therapeutic drug for CIRI.
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Isquemia Encefálica , Daño por Reperfusión , Ratas , Ratones , Animales , Inflamasomas/metabolismo , Ratas Sprague-Dawley , Proteínas Quinasas Activadas por AMP , Daño por Reperfusión/tratamiento farmacológico , Daño por Reperfusión/patología , Apoptosis , Isquemia Encefálica/tratamiento farmacológico , Isquemia Encefálica/patología , Infarto Cerebral , Autofagia , ARN Interferente Pequeño/genética , ARN Interferente Pequeño/uso terapéutico , ARN Interferente Pequeño/farmacologíaRESUMEN
INTRODUCTION: Dysbiosis of the intestinal microbiome and related metabolites have been observed in chronic kidney disease, yet their roles in idiopathic membranous nephropathy (IMN) are poorly understood. METHODS: In this study, we describe the variation of intestinal bacteria and fecal metabolites in patients with IMN in Chinese population. Stool samples were collected from 41 IMN patients at the beginning of diagnosis confirmation and 41 gender- and age-matched healthy control (HC). Microbial communities are investigated by sequencing of 16S rRNA genes and functional profiles predicted using Tax4Fun, and the correlation between intestinal bacteria and IMN clinical characteristics is also analyzed. Untargeted metabolomic analysis is performed to explore the relationship between colon's microbiota and fecal metabolites. RESULTS: IMN gastrointestinal microbiota demonstrates lower richness and diversity compared to HC, and exhibits a marked taxonomic and inferred functional dysbiosis when compared to HC. Some genera are closely related to the clinical parameters, such as Citrobacter and Akkermansia. Twenty characteristic microbial biomarkers are selected to establish a disease prediction model with a diagnostic accuracy of 93.53%. Fecal metabolomics shows that tryptophan metabolism is reduced in IMN patients but uremic toxin accumulation in feces is not noticeable. Fecal microbiota transplantation demonstrates that gut dysbiosis impairs gut permeability in microbiota-depleted mice and induces NOD-like receptor activation in the kidneys. CONCLUSIONS: Clarifying the changes in intestinal microbiota in IMN patients will help further know the pathogenesis of this disease, and microbiota-targeted biomarkers will provide a potentially powerful tool for diagnosing and treating IMN.
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Microbioma Gastrointestinal , Glomerulonefritis Membranosa , Humanos , Ratones , Animales , Microbioma Gastrointestinal/fisiología , Disbiosis , ARN Ribosómico 16S/genética , BiomarcadoresRESUMEN
Background: As a complication of Type II Diabetes Mellitus (T2DM), the etiology, pathogenesis, and treatment of cognitive dysfunction are still undefined. Recent studies demonstrated that Ginsenoside Rg1 (Rg1) has promising neuroprotective properties, but the effect and mechanism in diabetes-associated cognitive dysfunction (DACD) deserve further investigation. Methods: After establishing the T2DM model with a high-fat diet and STZ intraperitoneal injection, Rg1 was given for 8 weeks. The behavior alterations and neuronal lesions were judged using the open field test (OFT) and Morris water maze (MWM), as well as HE and Nissl staining. The protein or mRNA changes of NOX2, p-PLC, TRPC6, CN, NFAT1, APP, BACE1, NCSTN, and Aß1-42 were investigated by immunoblot, immunofluorescence or qPCR. Commercial kits were used to evaluate the levels of IP3, DAG, and calcium ion (Ca2+) in brain tissues. Results: Rg1 therapy improved memory impairment and neuronal injury, decreased ROS, IP3, and DAG levels to revert Ca2+ overload, downregulated the expressions of p-PLC, TRPC6, CN, and NFAT1 nuclear translocation, and alleviated Aß deposition in T2DM mice. In addition, Rg1 therapy elevated the expression of PSD95 and SYN in T2DM mice, which in turn improved synaptic dysfunction. Conclusions: Rg1 therapy may improve neuronal injury and DACD via mediating PLC-CN-NFAT1 signal pathway to reduce Aß generation in T2DM mice.
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Purpose: There are increasing reports of atypical membranous nephropathy (AMN) cases with similar pathological characteristics to secondary membranous nephropathy (SMN) without definite underlying causes. Although rituximab has become a first-line option in treating idiopathic membranous nephropathy (IMN), the efficacy and safety of rituximab-based regimen for AMN is not clear. Patients and Methods: This is a retrospective, single-center study. AMN patients who received rituximab-based therapy were included. IMN patients treated with rituximab during the same period were selected as the control group matched by gender, sex, baseline urinary protein and albumin levels. Baseline data and follow-up data were collected. Results: A total of 20 AMN patients and 40 IMN patients were included. The baseline levels of urinary protein were comparable between the two groups [6.77 (IQR 3.34, 11.49) g/24 h vs 6.47 (IQR 3.4, 10.76) g/24 h, P=0.944]. The baseline levels of serum albumin were 26.15±6.71 g/L and 26.8±5.54 g/L (P=0.689) respectively. The cumulative remission rate for rituximab-based treatment at the 12th month was lower in AMN group than IMN group [13 (65%) vs 36 (90%), P=0.045]. In AMN group, non-responders showed a higher level of proteinuria and a worse renal function at baseline than those of responders. There was no significant difference in the overall adverse events or serious adverse events between the two groups. Conclusion: In our study, AMN patients obtained proteinuria remission in a lower percentage compared with IMN patients. In general, rituximab-based therapy is effective in AMN patients with an acceptable safety profile.
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Increasing evidence has shown that the NOD-like receptor protein 1 (NLRP1) inflammasome is associated with Aß generation and deposition, which contributes to neuronal damage and neuronal-inflammation in Alzheimer's disease (AD). However, the specific mechanism of NLRP1 inflammasome in the pathogenesis of AD is still unclear. It has been reported that autophagy dysfunction can aggravate the pathological symptoms of AD and plays an important role in regulating Aß generation and clearance. We hypothesized that NLRP1 inflammasome activation may induce autophagy dysfunction contributing to the progression of AD. In the present study, we observed the relationship between Aß generation and NLRP1 inflammasome activation, as well as AMPK/mTOR mediated-autophagy dysfunction in WT 9-month-old (M) mice, APP/PS1 6 M and APP/PS1 9 M mice. Additionally, we further studied the effect of NLRP1 knockdown on cognitive function, Aß generation, neuroinflammation and AMPK/mTOR mediated autophagy in APP/PS1 9 M mice. Our results indicated that NLRP1 inflammasome activation and AMPK/mTOR mediated-autophagy dysfunction are closely implicated in Aß generation and deposition in APP/PS1 9 M mice, but not in APP/PS1 6 M mice. Meanwhile, we found that knockdown of NLRP1 significantly improved learning and memory impairments, decreased the expressions of NLRP1, ASC, caspase-1, p-NF-κB, IL-1ß, APP, CTF-ß, BACE1 and Aß1-42, and decreased the level of p-AMPK, Beclin 1 and LC3 II, and increased the level of p-mTOR and P62 in APP/PS1 9 M mice. Our study suggested that inhibition of NLRP1 inflammasome activation improves AMPK/mTOR mediated-autophagy dysfunction, resulting in the decrease of Aß generation, and NLRP1 and autophagy might be important targets to delay the progression of AD.
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Enfermedad de Alzheimer , Péptidos beta-Amiloides , Ratones , Animales , Péptidos beta-Amiloides/metabolismo , Péptidos beta-Amiloides/farmacología , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Precursor de Proteína beta-Amiloide/farmacología , Inflamasomas/metabolismo , Inflamasomas/farmacología , Secretasas de la Proteína Precursora del Amiloide/farmacología , Proteínas NLR , Proteínas Quinasas Activadas por AMP/farmacología , Ratones Transgénicos , Ácido Aspártico Endopeptidasas/farmacología , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/patología , Autofagia , Serina-Treonina Quinasas TOR/metabolismo , Serina-Treonina Quinasas TOR/farmacología , Modelos Animales de EnfermedadRESUMEN
INTRODUCTION: Gitelman syndrome (GS) is a rare renal tubular salt-wasting disorder. Besides kidney electrolyte loss, proteinuria and renal dysfunction were also observed. However, their incidence, risk factors, pathological features, and prognosis were unclear. METHODS: We retrospectively reviewed 116 GS patients and analyzed their clinical, genetic, and pathological characteristics. We also systematically reviewed articles on GS with proteinuria and renal dysfunction. RESULTS: Twenty-three GS patients had proteinuria (69.6%) and renal dysfunction (43.5%) with a mean age of 35.3 ± 13.2 years, and 65.2% were male. Compared to patients without proteinuria or renal dysfunction, these patients had elevated plasma angiotensin II level (440.2 ± 351.7 vs. 253.2 ± 187.4 pg/mL, p = 0.031) and three times higher incidence of diabetes. The renal pathology of nine biopsied patients indicated hypertrophy of the juxtaglomerular apparatus (100%), chronic tubulointerstitial changes (66.7%), intrarenal vascular changes (66.7%), and glomerulopathy (55.6%). More extensive renin staining was observed in patients with GS than in the control group with glomerular minor lesion (p < 0.001). During a median of 85 months (range, 11-205 months) of follow-up for 19 out of the 23 GS-renal patients, the renal function was generally stable, except one died of cancer and one developed end-stage renal disease because of concomitant membranous nephropathy and IgA nephropathy. CONCLUSION: Proteinuria and renal dysfunction were more common than expected and might indicate glomerulopathy and vascular lesions besides a tubulointerstitial injury in GS. Renal function may maintain stable with effective therapy in most cases.
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Síndrome de Gitelman , Glomerulonefritis por IGA , Humanos , Masculino , Adulto Joven , Adulto , Persona de Mediana Edad , Femenino , Síndrome de Gitelman/complicaciones , Síndrome de Gitelman/patología , Estudios Retrospectivos , Riñón/patología , Proteinuria/complicaciones , Glomerulonefritis por IGA/complicacionesRESUMEN
Alzheimer's disease (AD) is a common neurodegenerative disorder. Amyloid ß (Aß) deposition is considered an important pathological feature of AD. Growing evidence has linked neuroinflammation and autophagy to Aß deposition in the progression of AD. However, there are few drug options for inhibiting neuroinflammation and autophagy to prevent AD. Ginsenoside Rg1 (Rg1), a steroidal saponin extracted from ginseng, has been reported to possess multiple neuroprotective effects. The present study aimed to evaluate whether Rg1 treatment could attenuate cognitive disorders and neuronal injuries by inhibiting NLRP1 inflammasome and autophagy dysfunction in an AD model of APP/PS1 mice. The results of behavioral tests indicated that Rg1 treatment for 12 weeks could significantly improve olfactory dysfunction as well as learning and memory impairments. The results of histopathological tests indicated that Rg1 treatment could reduce Aß deposition and neuronal damages in APP/PS19M mice. Additionally, the results of immunoblot, reverse transcriptionquantitative PCR or immunohistochemistry demonstrated that Rg1 treatment significantly downregulated the expression levels of inflammationrelated proteins of NLRP1, caspase1, IL1ß and TNFα, as well as autophagyrelated proteins of pAMPK/AMPK, Beclin1 and LC3 II/LC3 I, and increased the expression levels of pmTOR/mTOR and P62 in APP/PS19M mice. In addition, the molecular docking analysis showed that there was favorable binding result between Rg1 and NLRP1. The present study suggested that Rg1 may alleviate learning and memory impairments and Aß disposition by inhibiting NLRP1 inflammasome and improving autophagy dysfunction, suggesting that Rg1 may be a potential therapeutic agent for delaying AD.
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Enfermedad de Alzheimer , Péptidos beta-Amiloides , Ratones , Animales , Péptidos beta-Amiloides/metabolismo , Inflamasomas/metabolismo , Simulación del Acoplamiento Molecular , Proteínas Quinasas Activadas por AMP , Modelos Animales de Enfermedad , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/metabolismo , Trastornos de la Memoria/tratamiento farmacológico , Autofagia , Serina-Treonina Quinasas TOR , Ratones Transgénicos , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismoRESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: Ginsenoside Rg1 (Rg1) is one of the main active components in Panax ginseng C. A. Meyer (ginseng), which has been widely used to delay senescence or improve health conditions for more than 2000 years. Increasing studies have revealed that Rg1 could regulate cell proliferation and differentiation, as well as anti-inflammatory and anti-apoptotic effects, and might have protective effects on many chronic kidney diseases. AIM OF THE STUDY: Diabetic nephropathy (DN) is one of the most dangerous microvascular complications of diabetes and is the leading cause of end-stage renal disease worldwide. However, the role and mechanism of Rg1 against high-glucose and high-fat-induced glomerular fibrosis in DN are not clear. This study aimed to investigate the protective effect of Rg1 on DN and its possible mechanism. MATERIALS AND METHODS: The type 2 diabetes mellitus (T2DM) mice models were established with a high-fat diet (HFD) combined with an intraperitoneal injection of streptozotocin (STZ). Urine protein and serum biochemical indexes were detected by corresponding kits. The kidney was stained with H&E, PAS, and Masson to observe the pathological morphology, glycogen deposition, and fibrosis. The expression of CD36 and p-PLC in the kidney cortex was detected by IHC. The expressions of FN and COL4 were detected by IF. Western blot and PCR were performed to examine protein and mRNA expressions of kidney fibrosis and TRPC6/NFAT2-related pathways in DN mice. Calcium imaging was used to examine the effect of Rg1 on [Ca2+]i in PA + HG-induced human mesangial cells (HMCs). Visualization of the interaction between Rg1 and CD36 was detected by molecular docking. RESULTS: Rg1 treatment for 8 weeks could prominently decrease urinary protein, serum creatinine, and urea nitrogen and downgrade blood lipid levels and renal lipid accumulation in T2DM mice. The pathological results indicated that Rg1 treatment attenuated renal pathological injury and glomerular fibrosis. The further results demonstrated that Rg1 treatment remarkably decreased the expressions of CD36, TRPC6, p-PLC, CN, NFAT2, TGF-ß, p-Smad2/3, COL4, and FN in renal tissues from T2DM mice. Calcium imaging results found that Rg1 downgraded the base levels of [Ca2+]i and ΔRatioF340/F380 after BAPTA and CaCl2 treatment. Molecular docking results showed that Rg1 could interact with CD36 with a good affinity. CONCLUSION: These results revealed that Rg1 could ameliorate renal lipid accumulation, pathological damage, and glomerular fibrosis in T2DM mice. The mechanism may be involved in reducing the overexpression of CD36 and inhibiting the TRPC6/NFAT2 signaling pathway in renal tissues of T2DM mice.
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Diabetes Mellitus Tipo 2 , Nefropatías Diabéticas , Animales , Humanos , Ratones , Calcio/metabolismo , Antígenos CD36/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Nefropatías Diabéticas/patología , Fibrosis , Riñón , Simulación del Acoplamiento Molecular , Transducción de Señal , Canal Catiónico TRPC6/metabolismoRESUMEN
Glucocorticoid (GC) exposure can lead to deterioration of the structure and function of hippocampal neurons and is closely involved in Alzheimer's disease (AD). Amyloid-ß (Aß) overproduction is an important aspect of AD pathogenesis. Our study mainly investigated the mechanism of chronic GC exposure in accelerating Aß production in primary cultured hippocampal neurons from APP/PS1 mice. The results indicated that chronic dexamethasone (DEX, 1 µM) significantly accelerated neuronal damage and Aß accumulation in hippocampal neurons from APP/PS1 mice. Meanwhile, DEX exposure markedly upregulated APP, NCSTN, BACE1 and p-Tau/Tau expression in hippocampal neurons from APP/PS1 mice. Our study also indicated that chronic DEX exposure significantly increased intracellular Ca2+ ([Ca2+]i) levels and the expressions of p-PLC, CN and NFAT1 in hippocampal neurons from APP/PS1 mice. We further found that stabilizing intracellular calcium homeostasis with 2-APB (50 µM) and SKF-96365 (10 µM) significantly alleviated neuronal damage and Aß accumulation in chronic DEX-induced hippocampal neurons from APP/PS1 mice. Additionally, dual luciferase assays showed that NFAT1 upregulated NCSTN transactivation, which was further increased upon DEX treatment. This study suggests that chronic DEX exposure accelerates Aß accumulation by activating calcium-mediated CN-NFAT1 signaling in hippocampal neurons from APP/PS1 mice, which may be closely related to the acceleration of AD.
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Enfermedad de Alzheimer , Péptidos beta-Amiloides , Glucocorticoides , Enfermedad de Alzheimer/metabolismo , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Péptidos beta-Amiloides/metabolismo , Péptidos beta-Amiloides/toxicidad , Precursor de Proteína beta-Amiloide/genética , Animales , Ácido Aspártico Endopeptidasas/metabolismo , Calcio/metabolismo , Dexametasona/toxicidad , Modelos Animales de Enfermedad , Glucocorticoides/efectos adversos , Glucocorticoides/toxicidad , Hipocampo/metabolismo , Ratones , Ratones Transgénicos , Factores de Transcripción NFATC/efectos de los fármacos , Factores de Transcripción NFATC/metabolismo , Neuronas/metabolismo , Síndromes de Neurotoxicidad/metabolismoRESUMEN
Background: The incidence of ischemic cerebrovascular disease is increasing in recent years and has been one of the leading causes of neurological dysfunction and death. Ginsenoside Rg1 has been found to protect against neuronal damage in many neurodegenerative diseases. However, the effect and mechanism by which Rg1 protects against cerebral ischemia-reperfusion injury (CIRI) are not fully understood. Here, we report the neuroprotective effects of Rg1 treatment on CIRI and its possible mechanisms in mice. Methods: A bilateral common carotid artery ligation was used to establish a chronic CIRI model in mice. HT22 cells were treated with Rg1 after OGD/R to study its effect on [Ca2+]i. The open-field test and pole-climbing experiment were used to detect behavioral injury. The laser speckle blood flowmeter was used to measure brain blood flow. The Nissl and H&E staining were used to examine the neuronal damage. The Western blotting was used to examine MAP2, PSD95, Tau, p-Tau, NOX2, PLC, p-PLC, CN, NFAT1, and NLRP1 expression. Calcium imaging was used to test the level of [Ca2+]i. Results: Rg1 treatment significantly improved cerebral blood flow, locomotion, and limb coordination, reduced ROS production, increased MAP2 and PSD95 expression, and decreased p-Tau, NOX2, p-PLC, CN, NFAT1, and NLRP1 expression. Calcium imaging results showed that Rg1 could inhibit calcium overload and resist the imbalance of calcium homeostasis after OGD/R in HT22 cells. Conclusion: Rg1 plays a neuroprotective role in attenuating CIRI by inhibiting oxidative stress, calcium overload, and neuroinflammation.
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The level of lipopolysaccharide (LPS) is higher in the blood and brains of patients with Alzheimer's disease (AD), and this phenomenon is strongly linked to AD-related neuronal damage and ß-amyloid (Aß) generation. However, the mechanism by which LPS causes neuronal damage has still not been fully clarified. Oxidative stress, neuroinflammation, and Ca2+ overload are regarded as important factors influencing AD. NADPH oxidase 2 (NOX2) and the NOD-like receptor family protein 1 (NLRP1) inflammasome play important roles in promoting oxidative stress and inflammation in neurons. Ca2+ overload can activate calcineurin (CN), which further dephosphorylates nuclear factor of activated T cells (NFAT), leading to its translocation into the nucleus to regulate gene transcription. In the present study, LPS (250 µg/kg) exposure for 14 days was used to induce cognitive dysfunction in mice and LPS (20 µg/ml) exposure for 48 h was used to induce neuronal damage in HT22 cells. The results showed that LPS exposure activated phospholipase C (PLC), CN, and NFAT1; increased the expressions of NOX2- and NLRP1-related proteins; and promoted neuronal damage and Aß deposition in mice and HT22 cells. However, treatment with 2-APB (SOCE inhibitor), apocynin (NOX inhibitor), or tempol (reactive oxygen species scavenger) significantly reversed these LPS-induced changes, and improved neuronal damage and Aß deposition. Moreover, LPS exposure promoted PLC phosphorylation, increased the level of inositol-1,4,5-triphosphate, elevated the intracellular Ca2+ concentration ([Ca2+]i), and disrupted [Ca2+]i homeostasis in HT22 cells. These data indicated that the activation of SOCE-mediated NFAT1-NOX2-NLRP1 inflammasome involves in LPS-induced neuronal damage and Aß generation.
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Enfermedad de Alzheimer , Inflamasomas , Enfermedad de Alzheimer/metabolismo , Animales , Calcineurina/metabolismo , Humanos , Inflamasomas/metabolismo , Lipopolisacáridos/farmacología , Ratones , NADPH Oxidasa 2/metabolismo , Proteínas NLR/metabolismo , Neuronas/metabolismo , Transducción de Señal , Sinapsinas/metabolismoRESUMEN
Ginsenoside Rg_1, one of the main active components of precious traditional Chinese medicine Ginseng Radix et Rhizoma, has the anti-oxidative stress, anti-inflammation, anti-aging, neuroprotection, and other pharmacological effects. Diabetic retinopathy(DR), the most common complication of diabetes, is also the main cause of impaired vision and blindness in the middle-aged and the elderly. The latest research shows that ginsenoside Rg_1 can protect patients against DR, but the protection and the mechanism are rarely studied. This study mainly explored the protective effect of ginsenoside Rg_1 against DR in type 2 diabetic mice and the mechanism. High fat diet(HFD) and streptozotocin(STZ) were used to induce type 2 diabetes in mice, and hematoxylin-eosin(HE) staining was employed to observe pathological changes in the retina of mice. The immunohistochemistry was applied to study the localization and expression of nucleotide-binding oligomerization domain-like receptors 3(NLRP3) and vascular endothelial growth factor(VEGF) in retina, and Western blot was used to detect the expression of nuclear factor-kappa B(NF-κB), p-NF-κB, NLRP3, caspase-1, interleukin-1ß(IL-1ß), transient receptor potential channel protein 6(TRPC6), nuclear factor of activated T-cell 2(NFAT2), and VEGF in retina. The results showed that ginsenoside Rg_1 significantly alleviated the pathological injury of retina in type 2 diabetic mice. Immunohistochemistry results demonstrated that ginsenoside Rg_1 significantly decreased the expression of NLRP3 and VEGF in retinal ganglion cells, middle plexiform layer, and outer plexiform layer in type 2 diabetic mice. According to the Western blot results, ginsenoside Rg_1 significantly lowered the expression of p-NF-κB, NLRP3, caspase-1, IL-1ß, TRPC6, NFAT2, and VEGF in retina of type 2 diabetic mice. These findings suggest that ginsenoside Rg_1 can significantly alleviate DR in type 2 diabetic mice, which may be related to inhibition of NLRP3 inflammasome and VEGF. This study provides experimental evidence for the clinical application of ginsenoside Rg_1 in the treatment of DR.
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Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 2 , Retinopatía Diabética , Ginsenósidos , Anciano , Animales , Diabetes Mellitus Experimental/tratamiento farmacológico , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/genética , Retinopatía Diabética/tratamiento farmacológico , Retinopatía Diabética/genética , Ginsenósidos/farmacología , Humanos , Inflamasomas/metabolismo , Ratones , Persona de Mediana Edad , FN-kappa B/genética , FN-kappa B/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/genética , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Transducción de Señal , Factor A de Crecimiento Endotelial Vascular/genéticaRESUMEN
PURPOSE: Urinary stone disease (USD) has been associated with an increased risk of chronic kidney disease (CKD) and end-stage renal disease in Western populations. However, the metabolic disorders associated with unilateral and bilateral renal stones and the association of these types of stones with CKD and kidney tubular injury markers, such as urine N-acetyl-ß-D-glucosaminidase (NAG) and alpha-1-microglobulin (α1-MG), have not been fully examined. MATERIALS AND METHODS: We performed a cross-sectional study of 10,281 participants in rural China in 2014. All the subjects underwent renal ultrasound to detect USD; stone formers were divided into groups with unilateral or bilateral renal stones by ultrasound examinations. CKD was defined as a decreased estimated glomerular filtration rate (eGFR, <60 mL/minute/1.73 m2) and/or albuminuria (albumin-to-creatinine ratio ≥30 mg/gm). Increased urine NAG and α1-MG levels were defined as their values above the 75th percentile of the sample distribution. RESULTS: Among all the participants, 4.9% (507) had unilateral renal stones, and 0.7% (75) had bilateral renal stones. The proportion of CKD in the nonstone, unilateral and bilateral renal stone formers was 11.0%, 19.2% and 29.7%, respectively (p for trend <0.001). Individuals with bilateral renal stones had the highest proportion of metabolic components, such as elevated blood pressure and serum glucose. In multivariate analyses after adjustment for multiple confounders, bilateral renal stones were significantly associated with an increased risk of decreased eGFR (OR 3.38; 95% CI 1.05-10.90), albuminuria (OR 3.01; 95% CI 1.76-5.13), CKD (OR 3.18; 95% CI 1.88-5.36), increased urine NAG-to-creatinine ratio (OR 1.95; 95% CI 1.21-3.16) and α1-MG-to-creatinine ratio levels (OR 2.54; 95% CI 1.56-4.12) compared with the lack of stones. CONCLUSIONS: Bilateral renal stones were associated with a higher risk of CKD and higher levels of kidney tubular injury markers. Clinicians should pay attention to metabolic disorders in bilateral renal stone formers.
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Cálculos Renales/complicaciones , Cálculos Renales/metabolismo , Insuficiencia Renal Crónica/etiología , Anciano , Biomarcadores/orina , Estudios Transversales , Femenino , Humanos , Cálculos Renales/patología , Cálculos Renales/orina , Masculino , Persona de Mediana Edad , Insuficiencia Renal Crónica/orinaRESUMEN
Aging is often accompanied by liver injury and fibrosis, eventually leading to the decline in liver function. However, the mechanism of aginginduced liver injury and fibrosis is still not fully understood, to the best of our knowledge, and there are currently no effective treatment options available for liver aging. Ginsenoside Rg1 (Rg1) has been reported to exert potent antiaging effects due to its potential antioxidant and antiinflammatory activity. The present study aimed to investigate the protective effect and underlying mechanism of action of Rg1 in aginginduced liver injury and fibrosis in senescenceaccelerated mouse prone 8 (SAMP8) mice treated for 9 weeks. The histopathological results showed that the arrangement of hepatocytes was disordered, vacuolelike degeneration occurred in the majority of cells, and collagen IV and TGFß1 expression levels, that were detected via immunohistochemistry, were also significantly upregulated in the SAMP8 group. Rg1 treatment markedly improved aginginduced liver injury and fibrosis, and significantly downregulated the expression levels of collagen IV and TGFß1. In addition, the dihydroethylene staining and western blotting results showed that Rg1 treatment significantly reduced the levels of reactive oxygen species (ROS) and IL1ß, and downregulated the expression levels of NADPH oxidase 4 (NOX4), p47phox, p22phox, phosphorylatedNFκB, caspase1, apoptosisassociated specklike protein containing a Cterminal caspase recruitment domain and the NLR family pyrin domain containing 3 (NLRP3) inflammasome, which were significantly upregulated in the liver tissues of elderly SAMP8 mice. In conclusion, the findings of the present study suggested that Rg1 may attenuate aginginduced liver injury and fibrosis by reducing NOX4mediated ROS oxidative stress and inhibiting NLRP3 inflammasome activation.
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Ginsenósidos/farmacología , NADPH Oxidasa 4/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Envejecimiento/efectos de los fármacos , Animales , Animales no Consanguíneos , Antioxidantes/farmacología , Apoptosis/efectos de los fármacos , Caspasa 1/metabolismo , China , Ginsenósidos/metabolismo , Inflamasomas/metabolismo , Hígado/metabolismo , Cirrosis Hepática/tratamiento farmacológico , Cirrosis Hepática/metabolismo , Masculino , Ratones , NADPH Oxidasa 4/efectos de los fármacos , Proteína con Dominio Pirina 3 de la Familia NLR/efectos de los fármacos , Oxidación-Reducción , Estrés Oxidativo/efectos de los fármacos , Especies Reactivas de Oxígeno/metabolismo , Factor de Crecimiento Transformador beta1/metabolismoRESUMEN
BACKGROUND: The clinical use of serum creatine (sCr) and cystatin C (CysC) in kidney function evaluation of critically ill patients has been in continuous discussion. The difference between estimated glomerular filtration rate calculated by sCr (eGFRcr) and CysC (eGFRcysc) of critically ill COVID-19 patients were investigated in this study. METHODS: This is a retrospective, single-center study of critically ill patients with COVID-19 admitted in intensive care unit (ICU) at Wuhan, China. Control cases were moderate COVID-19 patients matched in age and sex at a ratio of 1:1. The eGFRcr and eGFRcysc were compared. The association between eGFR and death were analyzed in critically ill cases. The potential factors influencing the divergence between eGFRcr and eGFRcysc were explored. RESULTS: A total of 76 critically ill COVID-19 patients were concluded. The mean age was 64.5 ± 9.3 years. The eGFRcr (85.45 (IQR 60.58-99.23) ml/min/1.73m2) were much higher than eGFRcysc (60.6 (IQR 34.75-79.06) ml/min/1.73m2) at ICU admission. About 50 % of them showed eGFRcysc < 60 ml/min/1.73 m2 while 25% showed eGFRcr < 60 ml/min/1.73 m2 (χ2 = 10.133, p = 0.001). This divergence was not observed in moderate group. The potential factors influencing the divergence included serum interleukin-6 (IL-6), tumor necrosis factor (TNF-α) level as well as APACHEII, SOFA scores. Reduced eGFRcr (<60 mL/min/1.73 m2) was associated with death (HR = 1.939, 95%CI 1.078-3.489, p = 0.027). CONCLUSIONS: The eGFRcr was generally higher than eGFRcysc in critically ill COVID-19 cases with severe inflammatory state. The divergence might be affected by inflammatory condition and illness severity. Reduced eGFRcr predicted in-hospital death. In these patients, we advocate for caution when using eGFRcysc.
Asunto(s)
COVID-19/fisiopatología , Creatina/sangre , Cistatina C/sangre , Tasa de Filtración Glomerular , Insuficiencia Renal Crónica/diagnóstico , Anciano , Biomarcadores/sangre , COVID-19/complicaciones , COVID-19/mortalidad , China/epidemiología , Enfermedad Crítica/terapia , Femenino , Mortalidad Hospitalaria , Humanos , Pruebas de Función Renal , Masculino , Persona de Mediana Edad , Insuficiencia Renal Crónica/sangre , Insuficiencia Renal Crónica/etiología , Estudios Retrospectivos , Análisis de SupervivenciaRESUMEN
OBJECTIVE: The aim of this study was to investigate the role of prophylactic use of statin in venous thromboembolism (VTE) in patients with primary membranous nephropathy (PMN). METHODS: A total of 734 patients with PMN were consecutively enrolled in this retrospective study. 564 patients had received statins prescription, while 170 patients did not. Kaplan-Meier methods were used for cumulative incidence plots of thromboembolic events and Cox proportional hazards regression models were used to assess risk factors. Finally, the effects of different potency of statins were evaluated. RESULTS: In the cohort, 37 patients (5.0%) experienced VTE. In a univariate Cox proportional hazard model, the hazard ratio (HR) for VTE in statin users versus statin non-users was 0.5 (95% CI 0.3-0.8, p = .03). Multivariable model proportional-hazards analysis corrected for co-medications and risk factors revealed that adjusted HR was 0.4 (95% CI 0.1-0.7, p = .03). According to the type and dose, statin users were assigned into 3 groups: high-intensity group (n = 278), moderate-intensity group (n = 186), and low-intensity group (n = 49). In comparison, incidences of VTEs in the three groups were similar (2.9% vs 4.8% vs 2.0%, p = .45). CONCLUSIONS: The prophylactic use of statins could effectively decrease the occurrence of VTE in patients with PMN, and the benefits have no difference in different potency of statins.
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Glomerulonefritis Membranosa/tratamiento farmacológico , Inhibidores de Hidroximetilglutaril-CoA Reductasas/administración & dosificación , Tromboembolia Venosa/epidemiología , Adulto , Biopsia , Relación Dosis-Respuesta a Droga , Femenino , Estudios de Seguimiento , Membrana Basal Glomerular/patología , Glomerulonefritis Membranosa/complicaciones , Glomerulonefritis Membranosa/diagnóstico , Glomerulonefritis Membranosa/patología , Humanos , Incidencia , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Medición de Riesgo/estadística & datos numéricos , Factores de Riesgo , Tromboembolia Venosa/etiología , Tromboembolia Venosa/prevención & controlRESUMEN
BACKGROUND: Pemphigus is a group of rare and severe autoimmune blistering disease mediated by pathogenic autoantibodies against desmogleins. Plasmapheresis can directly remove autoantibodies from circulation, which has been applied to the treatment of pemphigus as an adjuvant therapy. But the results of the researches are controversial. This study aims to evaluate the efficacy and safety of double filtration plasmapheresis (DFPP) combined with immunosuppressive treatment for patients with severe pemphigus in our single center. METHODS: We retrospectively analyzed 17 patients with severe pemphigus who were unresponsive to high-dose corticosteroid and received DFPP treatment between January 2010 and January 2020. The information on demographic characteristics, clinical and laboratory data, treatment regimens, and clinical outcomes were collected. RESULTS: All the patients were diagnosed as severe pemphigus and had a period of at least 1 week of high-dose prednisone (1-1.5 mg/kg/day), but they were unresponsive to corticosteroid and immunosuppressants treatment. They received DFPP treatment as an adjuvant therapy. After DFPP treatment, the titers of desmogleins antibodies significantly decreased (P < .001), Nikolsky's sign became negative and no new blisters appeared. The dosage of corticosteroid could begin to taper down rapidly in 9 ± 4 days. On discharge, the dosage of prednisone decreased significantly (51 ± 3 mg/day, P < .001). No major adverse events happened that could lead to the termination of DFPP treatment. CONCLUSION: Double filtration plasmapheresis combined with immunosuppressive treatment is an effective and safe therapeutic regimen for severe pemphigus. DFPP can also contribute to the dosage reduction of steroid to avoid more drug-related side effect.
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Inmunosupresores/uso terapéutico , Pénfigo/terapia , Plasmaféresis/métodos , Corticoesteroides/efectos adversos , Adulto , Autoanticuerpos/sangre , Desmogleína 1/inmunología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Pénfigo/inmunología , Plasmaféresis/efectos adversos , Estudios RetrospectivosRESUMEN
BACKGROUND: Cryoglobulinemic glomerulonephritis (CryoGn) caused by hepatitis B virus (HBV) infection was rarely reported. Our study aimed to investigate the clinical features, renal pathology findings, and prognosis in patients with HBV related CryoGn. METHODS: This was a retrospective study including seven Chinese patients with HBV related CryoGn in a tertiary referral hospital from April 2016 to March 2019. The clinical and pathological data were collected and analyzed. RESULTS: Age at renal biopsy was 47 ± 12 years, with female/male ratio 3/4. Urine protein was 5.6 (3.0, 6.6) g/d and five cases presented with nephrotic syndrome. The baseline eGFR was 23.5 (20.2, 46.3) ml/min per 1.73m2. The extrarenal manifestations included purpura (n = 6), arthralgia (n = 1), peripheral neuropathy (n = 1), and cardiomyopathy (n = 1). Six cases had type II cryoglobulinemia with IgMκ, the other one had type III. The median cryocrit was 4.0 (1.0, 15.0) %. Renal pathologic findings on light microscopy: endocapillary proliferative glomerulonephritis (Gn) (n = 3), membranoproliferative Gn (n = 3), and mesangial proliferative Gn (n = 1). On immunofluorescence microscopy, the predominant type of immunoglobulin deposits was IgM (n = 5). HBsAg and HBcAg deposits were found in one case. Ultrastructural studies showed granular subendothelial and mesangial electron-dense deposits in all patients and microtubules in one case. All patients received antiviral medications. They were given corticosteroid alone (n = 2) or combined with cyclophosphamide (n = 4) or mycophenolate mofetil (n = 1). Two patients received plasmapheresis. The median follow-up time was 18 (6, 37) months. Four patients got remission, two patients died of pneumonia, and one progressed to end-stage renal disease (ESRD). At endpoint of follow-up, 24hUP was 2.1 (0.8-5.2) g/d, and eGFR was 55.3 (20.7, 111.8) ml/min per 1.73m2. The median cryocrit decreased to 1.0 (0, 5.75) %. CONCLUSIONS: The etiology of mixed CryoGn should be screened for HBV infection. Endocapillary proliferative Gn and membranoproliferative Gn were the common pathologic patterns. Diagnosis and treatment in early stage benefit patients' renal outcomes. Immunosuppressive therapy should be considered for severe renal disease, based on efficient antiviral therapy.
Asunto(s)
Crioglobulinemia/patología , Glomerulonefritis/patología , Hepatitis B Crónica/metabolismo , Inmunoglobulina M/metabolismo , Síndrome Nefrótico/patología , Adulto , Anciano , Artralgia/etiología , Artralgia/fisiopatología , Cardiomiopatías/etiología , Cardiomiopatías/fisiopatología , Crioglobulinemia/etiología , Crioglobulinemia/metabolismo , Crioglobulinemia/fisiopatología , Femenino , Tasa de Filtración Glomerular , Glomerulonefritis/etiología , Glomerulonefritis/metabolismo , Glomerulonefritis/fisiopatología , Hepatitis B Crónica/complicaciones , Humanos , Cadenas kappa de Inmunoglobulina/metabolismo , Masculino , Microscopía Fluorescente , Persona de Mediana Edad , Síndrome Nefrótico/etiología , Síndrome Nefrótico/metabolismo , Síndrome Nefrótico/fisiopatología , Enfermedades del Sistema Nervioso Periférico/etiología , Enfermedades del Sistema Nervioso Periférico/fisiopatología , Púrpura/etiología , Púrpura/fisiopatología , Estudios Retrospectivos , Carga ViralRESUMEN
BACKGROUND: Renal Fanconi syndrome (FS) is rare in primary SjÓ§gren's syndrome (pSS). We aimed to describe the clinicopathological characteristics of pSS associated FS (pSS-FS) and its responses to treatment. METHODS: We reported 25 cases of pSS-FS patients and retrospectively reviewed their clinical records, kidney pathology and follow-up data. RESULTS: The 25 pSS-FS patients were mainly female (92.0%) and the mean age at diagnosis was 43.6±11.3 years. They showed different degrees of proximal tubular dysfunctions and eGFR decline (60.9±32.3 ml/min/1.73m2). Kidney pathology of pSS-FS patients showed tubulo-interstitial nephritis with defective brush border and lymphoplasmacytic infiltrates. After glucocorticoid treatment, the eGFR levels were significantly improved from 48.3±20.6 ml/min/1.73m2 to 55.0±19.9 ml/min/1.73m2 (P = 0.012) at the third month of follow-up. They also acquired good tubular (88.2%) and immunological (90.0%) responses. pSS-FS patients with young-onset pSS presented with a higher prevalence of positive anti-SSB antibody and hypocomplementemia, more severe hypokalemia, and better eGFR levels. CONCLUSIONS: In pSS-FS patients, use of glucocorticoids could improve eGFR and tubular functions. The young-onset pSS group presented with a particular pattern in immunological features and kidney involvement.