Gut microbiota-derived 5-hydroxyindoleacetic acid from pumpkin polysaccharides supplementation alleviates colitis via MAPKs-PPARγ/NF-κB inhibition.

Polysaccharides from Pumpkin (Cucurbita moschata Duchesne) (PPs) have many pharmacological activities, including anti-oxidant, immune, and intestinal microbiota regulation. These activities have provided some reminders of its potential therapeutic effect on ulcerative colitis (UC), but this has not yet been confirmed. This study preliminarily confirmed its significant anti-UC activity superior to Salicylazosulfapyridine. The average molecular weight of PPs was 3.10 × 105 Da, and PPs mainly comprised Mannose, Rhamnose, Galacturonic acid, Galactosamine, Glucose, and Xylose with molar ratios of 1.58:3.51:34.54:1.00:3.25:3.02. PPs (50, 100 mg/kg) could significantly resist dextran sodium sulfate induced UC on C57BL/6 mice by improving gut microbiota dysbiosis, such as the changes of relative abundance of Bacteroides, Culturomica, Mucispirillum, Escherichia-Shigella, Alistipes and Helicobacter. PPs also reverse the abnormal inflammatory reaction, including abnormal level changes of TNF-α, IFN-γ, IL-1ß, IL-4, IL-6, IL-10, and IL-18. Metabolomic profiling showed that PPs supplementation resulted in the participation of PPAR and MAPK pathways, as well as the increase of 5-hydroxyindole acetic acid (5-HIAA) level. 5-HIAA also exhibited individual and synergistic anti-UC activities in vivo. Furthermore, combination of PPs and 5-HIAA could also elevate the levels of PPARγ in nuclear and inhibit MAPK/NF-ĸB pathway in the colon. This study revealed that PPs and endogenous metabolite 5-HIAA might be developed to treat UC.

Isorhamnetin alleviates cisplatin-induced acute kidney injury via enhancing fatty acid oxidation.

Cisplatin is an effective chemotherapy drug widely used in the treatment of various solid tumors. However, the clinical usage of cisplatin is limited by its nephrotoxicity. Isorhamnetin, a natural flavanol compound, displays remarkable pharmacological effects, including anti-inflammatory and anti-oxidation. In this study, we aimed to investigate the potential of isorhamnetin in alleviating acute kidney injury induced by cisplatin. In vitro study showed that isorhamnetin significantly suppressed the cytotoxic effects of cisplatin on human tubular epithelial cells. Furthermore, isorhamnetin exerted significantly inhibitory effects on cisplatin-induced apoptosis and inflammatory response. In acute kidney injury mice induced by a single intraperitoneal injection with 20 mg/kg cisplatin, oral administration of isorhamnetin two days before or 2 h after cisplatin injection effectively ameliorated renal function and renal tubule injury. Transcriptomics RNA-seq analysis of the mice kidney tissues suggested that isorhamnetin treatment may protect against cisplatin-induced nephrotoxicity via PGC-1α mediated fatty acid oxidation. Isorhamnetin achieved significant enhancements in the lipid clearance, ATP level, as well as the expression of PGC-1α and its downstream target genes PPARα and CPT1A, which were otherwise impaired by cisplatin. In addition, the protection effects of isorhamnetin against cisplatin-induced nephrotoxicity were abolished by a PGC-1α inhibitor, SR-18292. In conclusion, our findings indicate that isorhamnetin could protect against cisplatin-induced acute kidney injury by inducing PGC-1α-dependent reprogramming of fatty acid oxidation, which highlights the clinical potential of isorhamnetin as a therapeutic approach for the management of cisplatin-induced nephrotoxicity.

Neuropsychological, plasma marker, and functional connectivity changes in Alzheimer's disease patients infected with COVID-19.

Introduction: Patients with COVID-19 may experience various neurological conditions, including cognitive impairment, encephalitis, and stroke. This is particularly significant in individuals who already have Alzheimer's disease (AD), as the cognitive impairments can be more pronounced in these cases. However, the extent and underlying mechanisms of cognitive impairments in COVID-19-infected AD patients have yet to be fully investigated through clinical and neurophysiological approaches. Methods: This study included a total of 77 AD patients. Cognitive functions were assessed using neuropsychiatric scales for all participants, and plasma biomarkers of amyloid protein and tau protein were measured in a subset of 25 participants. To investigate the changes in functional brain connectivity induced by COVID-19 infection, a cross-sectional neuroimaging design was conducted involving a subset of 37 AD patients, including a control group of 18 AD participants without COVID-19 infection and a COVID-19 group consisting of 19 AD participants. Results: For the 77 AD patients between the stages of pre and post COVID-19 infection, there were significant differences in cognitive function and psychobehavioral symptoms on the Montreal Scale (MoCA), the neuropsychiatric inventory (NPI), the clinician's global impression of change (CIBIC-Plus), and the activity of daily living scale (ADL). The COVID-19 infection significantly decreased the plasma biomarker level of Aß42 and increased the plasma p-tau181 level in AD patients. The COVID-19-infected AD patients show decreased local coherence (LCOR) in the anterior middle temporal gyrus and decreased global correlation (GCOR) in the precuneus and the medial prefrontal cortex. Conclusion: The findings suggest clinical, cognitive, and neural alterations following COVID-19 infection in AD patients and emphasize the need for close monitoring of symptoms in AD patients who have had COVID-19 and further exploration of the underlying mechanisms.

Sanguinarine ameliorates DSS induced ulcerative colitis by inhibiting NLRP3 inflammasome activation and modulating intestinal microbiota in C57BL/6 mice.

BACKGROUND: Sanguinarine (SAN) is an important natural anti-inflammatory constitutes and dietary supplementation with SAN could improve the relative length of the intestine, alter gut microbiota, and enhance growth performance of pigs, broiler chickens, and cattle. However, it is unclear whether it has the therapeutic effect on ulcerative colitis (UC). PURPOSE: This study aimed to investigate the therapeutic effect of SAN on UC and explore its mechanisms of action. STUDY DESIGN AND METHODS: Several efficacy indexes of SAN on dextran sulfate sodium (DSS)-induced C57BL/6 mice were evaluated. ELISA kit and western blot analysis were used to evaluate it's anti-inflammatory effect and the mechanism of action. 16S rDNA sequencing detection was used to determine the impact of SAN on gut microbiota. RESULTS: SAN and Sulfasalazine could significantly improve the colon length, the weight loss, the symptoms and the pathological injury of colon in DSS-induced mice. Meanwhile, SAN could decrease the levels of pro-inflammatory cytokines (TNF-α, IFN-γ, IL-1ß, IL-6, IL-13 and IL-18) and increase the levels of anti-inflammatory cytokines (IL-4 and IL-10) in colon, and suppress DSS-induced high expressions of NLRP3, caspase-1 and IL-1ß. In addition, SAN (0.5, 1 µM) could inhibit the expression level of NLRP3 and the activation of caspase-1 and IL-1ß in lipopolysaccharide-stimulated THP-1 cells in non-cytotoxic doses, which was similar to that of MCC950, a specific inhibitor of NLRP3 inflammasome activation. The abundance changes of many genera such as Muribaculaceae_unclassified, Escherichia-Shigella, Lachnospiraceae_NK4A136_group and Helicobacter were also closely related to the improvement of SAN on intestinal inflammatory response. CONCLUSION: SAN exhibited therapeutic effect on DSS-induced colitis by blocking NLRP3-(Caspase-1)/IL-1ß pathway and improving intestinal microbial dysbiosis. SAN might be developed to treat UC and other disorders associated with microbial dysbiosis.

Elevated D-Dimer levels correlate with the development of hepatorenal syndrome and a poor outcome in patients with cirrhosis.

OBJECTIVES: Whether hemostatic status was correlated with the diverse types of acute kidney injury in cirrhotic patients is unclear. The present study aimed to investigate the relationship between hemostatic markers and the diverse types of acute kidney injury (AKI) in liver cirrhosis. PATIENTS AND METHODS: Cirrhotic patients with consecutive treatment at the First Affiliated Hospital of Medicine School, Zhejiang University, were pooled in a cohort. Their demographic and clinical data, biochemistry parameters and hemostatic markers were assessed to identify risk factors for the development and prognosis of AKI. RESULTS: A total of 773 cirrhotic patients were included in this cohort. Patients with hepatorenal syndrome (HRS) had significantly higher D-Dimer than those with the other types of AKI. In univariate COX regression, APTT, TT, INR, D-Dimer and Fib were correlated with the development of AKI, HRS and acute tubular necrosis (ATN), however, only D-Dimer remained independently associated with the development of AKI and HRS in multivariate COX regression. The area under the ROC curve of D-Dimer was 0.755 (95%CI, 0.718-0.793) in predicting the development of AKI, 0.879 (95%CI, 0.791-0.967) in predicting the development of HRS, respectively. D-Dimer was used for diagnosis of HRS with a sensitivity of 87.3% and specificity of 72.9% at the cutoff of 3.7 (mg/L FEU). Survival rates differed significantly between groups by D-Dimer level. CONCLUSIONS: Hemostatic markers were significantly associated with the diverse types of AKI. D-Dimer was an independent risk factor for HRS and correlated with a poor outcome in cirrhotic patients.

The Love-Hate Relationship Between TGF-ß Signaling and the Immune System During Development and Tumorigenesis.

Since TGF-ß was recognized as an essential secreted cytokine in embryogenesis and adult tissue homeostasis a decade ago, our knowledge of the role of TGF-ß in mammalian development and disease, particularly cancer, has constantly been updated. Mounting evidence has confirmed that TGF-ß is the principal regulator of the immune system, as deprivation of TGF-ß signaling completely abrogates adaptive immunity. However, enhancing TGF-ß signaling constrains the immune response through multiple mechanisms, including boosting Treg cell differentiation and inducing CD8+ T-cell apoptosis in the disease context. The love-hate relationship between TGF-ß signaling and the immune system makes it challenging to develop effective monotherapies targeting TGF-ß, especially for cancer treatment. Nonetheless, recent work on combination therapies of TGF-ß inhibition and immunotherapy have provide insights into the development of TGF-ß-targeted therapies, with favorable outcomes in patients with advanced cancer. Hence, we summarize the entanglement between TGF-ß and the immune system in the developmental and tumor contexts and recent progress on hijacking crucial TGF-ß signaling pathways as an emerging area of cancer therapy.

Clinical Efficacy and Safety of Massage for the Treatment of Restless Leg Syndrome in Hemodialysis Patients: A Meta-Analysis of 5 Randomized Controlled Trials.

Aim: We conducted this meta-analysis to evaluate the clinical efficacy and safety of massage for the treatment of hemodialysis patients with restless leg syndrome (RLS). Methods: A comprehensive literature search was performed using the PubMed database, EMBASE database (via OVID), and the Cochrane Library in order to identify eligible randomized controlled trials (RCTs) published before August 31, 2021. After extracted essential data and assessed risk of bias of each eligible study, we calculated the pooled estimate of RLS score and safety after treatment. Statistical analysis was performed by using Review Manager 5.3. Results: Five studies involving 369 hemodialysis patients with RLS were analyzed. The RLS score after treatment [mean difference (MD), -12.01; 95% confidence interval (CI), -14.91 to -9.11] and mean difference of RLS score at the beginning and end of treatment [mean difference (MD), -11.94; 95% confidence interval (CI), -15.45 to -8.43] in a massage group was significantly better than that in route care group. Subgroup analysis suggested that massage with lavender oil also significantly reduced the RLS score after treatment (MD, -14.22; 95% CI, -17.81 to -10.63) and mean difference of RLS score at the beginning and end of treatment (MD, -14.87; 95% CI, -18.29 to -11.45) compared with route care. Meanwhile, massage regime significantly relieved RLS severity compared with route care but did not increase adverse events. Conclusion: Massage may be a preferred treatment modality for hemodialysis patients with RLS because it effectively reduces RLS symptoms, relieves RLS severity, and does not increase the risk of adverse events. However, future study with a larger sample size is warranted due to the fact that only limited number of eligible studies with small sample size are enrolled.

Evaluating the treatment outcomes of repetitive transcranial magnetic stimulation in patients with moderate-to-severe Alzheimer's disease.

The repetitive transcranial magnetic stimulation (rTMS) shows great potential in the treatment of Alzheimer's disease (AD). However, its treatment efficacy for AD patients in moderate to severe stage is relatively evaluated. Here, we proposed a randomized, sham-controlled, clinical trial of rTMS among 35 moderate-to-severe AD patients. A high frequency (10 Hz) stimulation of the left dorsal lateral prefrontal cortex (DLPFC), 60-session long treatment lasting for 3 months procedure was adopted in the trial. Each participant completed a battery of neuropsychological tests at baseline and post-treatment for evaluation of the rTMS therapeutic effect. Twelve of them completed baseline resting-state functional magnetic resonance imaging (fMRI) for exploration of the underlying neural contribution to individual difference in treatment outcomes. The result showed that the rTMS treatment significantly improved cognitive performance on the severe impairment battery (SIB), reduced psychiatric symptoms on the neuropsychiatric inventory (NPI), and improved the clinician's global impression of change (CIBIC-Plus). Furthermore, the result preliminarily proposed resting-state multivariate functional connectivity in the (para) hippocampal region as well as two clusters in the frontal and occipital cortices as a pre-treatment neuroimaging marker for predicting individual differences in treatment outcomes. The finding could brought some enlightenment and reference for the rTMS treatment of moderate and severe AD patients.

Using Cell Type-Specific Genes to Identify Cell-Type Transitions Between Different in vitro Culture Conditions.

In vitro differentiation or expansion of stem and progenitor cells under chemical stimulation or genetic manipulation is used for understanding the molecular mechanisms of cell differentiation and self-renewal. However, concerns around the cell identity of in vitro-cultured cells exist. Bioinformatics methods, which rely heavily on signatures of cell types, have been developed to estimate cell types in bulk samples. The Tabula Muris Senis project provides an important basis for the comprehensive identification of signatures for different cell types. Here, we identified 46 cell type-specific (CTS) gene clusters for 83 mouse cell types. We conducted Gene Ontology term enrichment analysis on the gene clusters and revealed the specific functions of the relevant cell types. Next, we proposed a simple method, named CTSFinder, to identify different cell types between bulk RNA-Seq samples using the 46 CTS gene clusters. We applied CTSFinder on bulk RNA-Seq data from 17 organs and from developing mouse liver over different stages. We successfully identified the specific cell types between organs and captured the dynamics of different cell types during liver development. We applied CTSFinder with bulk RNA-Seq data from a growth factor-induced neural progenitor cell culture system and identified the dynamics of brain immune cells and nonimmune cells during the long-time cell culture. We also applied CTSFinder with bulk RNA-Seq data from reprogramming induced pluripotent stem cells and identified the stage when those cells were massively induced. Finally, we applied CTSFinder with bulk RNA-Seq data from in vivo and in vitro developing mouse retina and captured the dynamics of different cell types in the two development systems. The CTS gene clusters and CTSFinder method could thus serve as promising toolkits for assessing the cell identity of in vitro culture systems.

Case Report of a pathologically confirmed vascular parkinsonism with early cognitive impairment and Behavioral disturbance.

BACKGROUND: Vascular Parkinsonism(VaP) is defined as parkinsonism resulting from cerebral vascular disease(CVD), with presence of variable motor and non-motor signs that are corroborated by clinical, anatomic or imaging findings of cerebrovascular disease. Overlapping syndromes with mixed pathologies make VaP difficult to distinguish from primary neurodegenerative parkinsonism.To understand the clinical and pathological features of VaP,we report a case of autopsy confirmed vascular Parkinsonism that was clinical misdiagnosed as idiopathic Parkinson's disease.Clinical features include early mixed symptoms of dementia,behavioral disturbance and parkinsonism that were similar to Dementia with lewy Body(DLB) and Parkinson disease Dementia(PDD). CASE PRESENTATION: A 84-year-old man presented progressive parkinsonism with prominent postural instability, gait impairment, pseudobulbar, early cognitive impairment, irritability, hallucination, urinary symptoms and poor responsiveness to dopaminergic drugs. He was clinically diagnosed as Parkinson disease(PD). In the post-mortem study, we examined Aß and phospho-tau as pathological biomarker for Alzheimer's disease(AD), α-synucleing in medulla, pons and midbrain for PD and DLB. Hematoxylin and eosin staining in cerebral cortex, cerebellum and brainstem examines vascular pathological changes and microvascular lesion.Neither Lewy bodies in the substantia nigra ,locus ceruleus and cerebrumnor accumulation of Aß, neurofibrillary tangles were noted. Instead, there were many cerebral infarctions and widespread arteriosclerosis in the brain. The final brain autopsy supported a diagnosis of VaP not PD. CONCLUSIONS: This case of pathologically confirmed VaP misdiagnosed as idiopathic PD suggested that we must be vigilant about the possibility of VaP for patients with parkinsonisms, cognitive impairments, early behavioral and psychological symptoms,imaging performances of cerebral small vessel disease and other vascular damages.

The association between IL-1 family gene polymorphisms and colorectal cancer: A meta-analysis.

BACKGROUND: Colorectal cancer (CRC) is a major public health problem given its high incidence and mortality. This study focuses on examining the associations between IL-1α, IL-1ß, and IL-1RN polymorphisms and colorectal cancer susceptibility. METHODS: A systematic literature search of PubMed, Embase, Web of Science, CNKI (China National Knowledge Infrastructure) and Wan Fang databases was conducted to identify relevant studies. Relevant data were extracted from the original included studies. The correlation was demonstrated based on the odds ratio (OR) and corresponding 95% confidence intervals (95% CIs). Publication bias was investigated by Egger's line regression test and Begg's funnel plot. RESULTS: Eighteen independent studies involving 6218 cases and 10160 controls were eligible for this pooled analysis. Overall, the result revealed that the IL-1α rs3783553 polymorphism was significantly associated with an increased risk of CRC (G vs. C, OR = 1.02, 95% CI = 0.90-1.15, I2 = 51%, P = 0.78; GG vs. CC, OR = 1.97, 95% CI = 1.04-3.74, I2 = 70%, P = 0.04; GC vs. CC, OR = 1.75, 95% CI = 1.12-2.75, I2 = 42%, P = 0.01; GG + GC vs. CC, OR = 1.85, 95% CI = 1.08-3.18, I2 = 63%, P = 0.03; and GG vs. GC + CC, OR = 1.28, 95% CI = 1.04-1.58, I2 = 39%, P = 0.02), and significance was also noted for IL-1RN VNTR under the dominant model (22 + 2L vs. LL, OR = 1.49, 95% CI = 1.01-2.19, I2 = 77%, P = 0.045) and allelic contrast model (2 vs. L, OR = 1.28, 95% CI = 1.00-1.64, I2 = 58.6%, P = 0.047). For IL-1ß + 31C/T, significance was observed in the dominant model (CC + CT vs. TT, OR = 0.83, 95% CI = 0.69-0.99, I2 = 52%, P = 0.034) and the heterozygous model (CT vs. TT, OR = 0.80, 95% CI = 0.65-0.98, I2 = 60%, P = 0.04). For IL-1ß + 511 C/T, a significant association was noted in four gene models (CT vs. TT, OR = 0.72, 95% CI = 0.63-0.83, I2 = 0%, P < 0.001; CC + CT vs. TT, OR = 0.74, 95% CI = 0.65-0.84, I2 = 0%, P < 0.001; CC vs. TT, OR = 0.77, 95% CI = 0.65-0.91, I2 = 30.9%, P = 0.003; C vs. T, OR = 0.87, 95% CI = 0.80-0.95, I2 = 38%, P = 0.001), but a significant relationship was not found in the recessive model (CC vs. CT + TT, OR = 1.09, 95% CI = 0.86-1.38, I2 = 57.1%, P = 0.25). In addition, borderline statistical significance was noted between IL-1ß + 3954 Ins/Del and CRC in the homozygous model, but no significance was identified for IL-1ß + 3737 G/A, Il-1ß + 1464 G/C, and IL-1RN + 2018 T/C under all five genetic models. In the subgroup analysis of ethnic groups, significant associations with CRC were found for IL-1ß + 31 (CC vs. TT: OR = 0.82, 95% CI = 0.67-0.99, I2 = 20.2%, P = 0.04; CT vs. TT: OR = 0.62, 95% CI = 0.47-0.82, I2 = 0%, P < 0.001; CC + CT vs. TT: OR = 0.69, 95% CI = 0.55-0.87, I2 = 29.7%, P = 0.001), IL-1ß + 511 (CT vs. TT, OR = 0.65, 95% CI = 0.55-0.77, I2 = 0%, P < 0.001; CC + CT vs. TT, OR = 0.67, 95% CI = 0.58-0.78, I2 = 0%, P < 0.001; C vs. T, OR = 0.83, 95% CI = 0.75-0.92, I2 = 49.6%, P < 0.001) and IL-1RN + 2018 T/C in the allelic contrast model (T vs. C, OR = 0.66, 95% CI = 0.44-0.98, I2 = 0%, P = 0.04) among Asians but not in Caucasians. A significant association between IL-1ß + 1464 G/C polymorphisms in Caucasians was observed under the recessive model (OR = 0.87, 95% CI = 0.77-0.98, I2 = 45%, P = 0.03). CONCLUSION: The current meta-analysis demonstrated that IL-1α rs3783553, IL-1ß + 31C/T, IL-1ß + 511C/T, and IL-1RN VNTR are critical genes for CRC susceptibility.

Drug rash with eosinophilia and systemic symptoms and severe renal injury induced by proton pump inhibitor therapy: A case report.

INTRODUCTION: Proton pump inhibitors (PPIs) are widely prescribed and generally well tolerated but can rarely cause severe allergic reactions, such as drug rash with eosinophilia and systemic symptoms (DRESS). We report a case of DRESS and renal injury induced by PPIs, and describe the therapeutic process. PATIENT CONCERNS: The patient was a 66-year-old female who complained of fever, pruritus, desquamation, erythema multiforme, and anuria caused by omeprazole taken for 2 weeks to treat abdominal distention. DIAGNOSIS: The clinical history revealed a similar episode of PPI-induced fever, eosinophilia, and acute kidney injury more than 1 year ago. The present laboratory tests revealed eosinophilia and oliguric renal failure. The renal biopsy was performed subsequently and proved the diagnosis of PPI-induced DRESS. INTERVENTIONS: After the suspected diagnosis of PPI-induced DRESS, omeprazole was discontinued and methylprednisolone infusion (40 mg qd) was initiated. Because of oliguric renal failure, the patient received intermittent hemodialysis. OUTCOMES: The patient initially responded to omeprazole discontinuation, hemodialysis, and glucocorticoids but later died from severe infection during the tapering of glucocorticoid therapy. CONCLUSION: Clinicians should remain on high alert for potential life-threatening complications when prescribing PPIs. If unexplained renal injury develops in a patient taking a PPI, renal biopsy may help in identifying the pathogenesis and might facilitate timely intervention.

Critically ill patients with COVID-19 with ECMO and artificial liver plasma exchange: A retrospective study.

COVID-19 is an emerging infectious disease capable of causing severe pneumonia. We aimed to characterize a group of critically ill patients in a single-center study.This was a retrospective case series of 23 patients with confirmed COVID-19-related critical illness in the intensive care unit (ICU) of a hospital in Hangzhou Zhejiang Province between January 22 and March 20, 2020.Of the 23 critically ill patients, the median age was 66 years (interquartile range [IQR] 59-80 years). The median time from disease onset to ICU admission was 10 days (IQR 6-11 days), to mechanical ventilation (MV) was 11 days (IQR 7.75-13 days), to artificial liver plasma exchange was 12 days (IQR 9.75-14.75 days), and to extracorporeal membrane oxygenation (ECMO) was 22 days (IQR 17.5-30 days). Nine patients required high flow oxygen. Fourteen patients received MV. Six required ECMO. Nine received artificial liver plasma exchange. Mortality was 0 at day 28.Mortality was 0 at day 28 in our single-center study. Extracorporeal membrane oxygenation reduced the requirements for ventilator support. Artificial liver plasma exchange significantly reduced inflammatory cytokine levels. These supportive therapies helped to extend the patients' survival times and increase the chance of follow-up treatments.

The interactions between cGAS-STING pathway and pathogens.

Cytosolic DNA is an indicator of pathogen invasion or DNA damage. The cytosolic DNA sensor cyclic guanosine monophosphate-adenosine monophosphate (cGAMP) synthase (cGAS) detects DNA and then mediates downstream immune responses through the molecule stimulator of interferon genes (STING, also known as MITA, MPYS, ERIS and TMEM173). Recent studies focusing on the roles of the cGAS-STING pathway in evolutionary distant species have partly sketched how the mammalian cGAS-STING pathways are shaped and have revealed its evolutionarily conserved mechanism in combating pathogens. Both this pathway and pathogens have developed sophisticated strategies to counteract each other for their survival. Here, we summarise current knowledge on the interactions between the cGAS-STING pathway and pathogens from both evolutionary and mechanistic perspectives. Deeper insight into these interactions might enable us to clarify the pathogenesis of certain infectious diseases and better harness the cGAS-STING pathway for antimicrobial methods.

Severe mental disorders following anti-retroviral treatment in a patient on peritoneal dialysis: A case report and literature review.

BACKGROUND: Antiviral drugs are widely used in populations with viral infection caused by immunologic inadequacy. Because these drugs are mainly metabolized by the kidneys, patients with renal failure undergoing renal replacement therapy are prone to drug adverse effects and poisoning. Severe neurotoxicity caused by antiviral drugs is a rare but life-threatening complication. CASE SUMMARY: This study reported one male patient on peritoneal dialysis who suffered from severe mental disorders after receiving an overdose of acyclovir and valacyclovir for the treatment of herpes zoster. The literature review suggested that hemodialysis is better than peritoneal dialysis to clear acyclovir from the circulation. The patient died after his consciousness deteriorated despite peritoneal dialysis and continuous blood purification. CONCLUSION: This case emphasizes cautiousness when using anti-retroviral drugs in patients with uremia. Hemodialysis is optimal method to remove the drugs.

NMDA receptors participate in the progression of diabetic kidney disease by decreasing Cdc42-GTP activation in podocytes.

Podocytes play important roles in the progression of diabetic kidney disease (DKD) and these roles are closely associated with cytoskeletal actin dynamics. N-Methyl-d-aspartate receptors (NMDARs), which consist of two functional NR1 subunits and two regulatory NR2 subunits, are widely expressed in the brain but are also found in podocytes. Here, we found increased NR1 expression in two diabetic mouse models and in podocytes incubated in high glucose (HG). In diabetic mice, knockdown of NR1 using lentivirus carrying NR1-shRNA ameliorated the pathological features associated with DKD, and reversed the decreased expression of synaptopodin and Wilms' tumour-1. In podocytes incubated with HG, NR1 was secreted from the endoplasmic reticulum and this was blocked by bisindolylmaleimide I. NR1 knockdown decreased the cell shape remodelling, cell collapse, bovine serum albumin permeability, and migration induced by HG. After HG incubation, levels of cell division control protein 42 (Cdc42) and its active form increased, and a significantly higher Cdc42-GTP level, increased Cdc42 translocation onto the leading edges, and lower migration ability were found in podocytes with NR1 knockdown. Increases in the number and length of filopodia were found in podocytes with NR1 knockdown but these were abolished by Cdc42-GTP blockade with ML141. In conclusion, the activation of NMDARs plays an important role in DKD by reducing Cdc42-GTP activation. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

[SPIO-labeled rat bone marrow mesenchymal stem cells: alterations of biological activity and labeling efficiency assay in vitro].

This study aimed to characterize and magnetic resonance imaging (MRI) track the mesenchymal stem cells labeled with polylysine-coated superparamagnetic iron oxide (PLL-SPIO). Rat bone marrow derived mesenchymal stem cells (rMSCs) were labeled with 25, 50 and 100 microg/mL PLL-SPIO for 24 hours. The labeling efficiency was assessed by iron content, Prussian blue staining, electron microscopy and in vitro MR imaging. The labeled cells were also analyzed for cytotoxicity and differentiation potential. Electron microscopic observations and Prussian blue staining revealed that 75% -100% of cells were labeled with iron particles. PLL-SPIO did not show any cytotoxicity up to 100 microg/mL concentration. Both 25 microg/mL and 50 microg/mL PLL-SPIO labeled stem cells did not exhibit any significant alterations in the adipo/osteo/chondrogenic differentiation potential compared to unlabeled control cells. The lower concentration of 25 microg/mL iron labeled cells emitted an obvious dark signal in T1W, T2WI and T2 * WI MR image. The novel PLL-SPIO enables to label and track rMSCs for in vitro MRI without cellular alteration. Therefore PLL-SPIO may potentially become a better MR contrast agent especially in tracking the transplanted stem cells and other cells without compromising cell functional quality.

Effect of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers on all-cause mortality, cardiovascular deaths, and cardiovascular events in patients with diabetes mellitus: a meta-analysis.

IMPORTANCE: Angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs) may have different effects on cardiovascular (CV) events in patients with diabetes mellitus (DM). OBJECTIVE: To conduct a meta-analysis to separately evaluate the effects of ACEIs and ARBs on all-cause mortality, CV deaths, and major CV events in patients with DM. DATA SOURCES Data sources included MEDLINE (1966-2012), EMBASE (1988-2012), the Cochrane Central Register of Controlled Trials, conference proceedings, and article reference lists. STUDY SELECTION: We included randomized clinical trials reporting the effects of ACEI and ARB regimens for DM on all-cause mortality, CV deaths, and major CV events with an observation period of at least 12 months. Studies were excluded if they were crossover trials. DATA EXTRACTION AND SYNTHESIS: Dichotomous outcome data from individual trials were analyzed using the risk ratio (RR) measure and its 95% CI with random-effects models. We estimated the difference between the estimates of the subgroups according to tests for interaction. We performed meta-regression analyses to identify sources of heterogeneity. MAIN OUTCOMES AND MEASURES: Primary end points were all-cause mortality and death from CV causes. Secondary end points were the effects of ACEIs and ARBs on major CV events. RESULTS: Twenty-three of 35 identified trials compared ACEIs with placebo or active drugs (32,827 patients) and 13 compared ARBs with no therapy (controls) (23,867 patients). When compared with controls (placebo/active treatment), ACEIs significantly reduced the risk of all-cause mortality by 13% (RR, 0.87; 95% CI, 0.78-0.98), CV deaths by 17% (0.83; 0.70-0.99), and major CV events by 14% (0.86; 0.77-0.95), including myocardial infarction by 21% (0.79; 0.65-0.95) and heart failure by 19% (0.81; 0.71-0.93). Treatment with ARBs did not significantly affect all-cause mortality (RR, 0.94; 95% CI, 0.82-1.08), CV death rate (1.21; 0.81-1.80), and major CV events (0.94; 0.85-1.01) with the exception of heart failure (0.70; 0.59-0.82). Both ACEIs and ARBs were not associated with a decrease in the risk for stroke in patients with DM. Meta-regression analysis showed that the ACEI treatment effect on all-cause mortality and CV death did not vary significantly with the starting baseline blood pressure and proteinuria of the trial participants and the type of ACEI and DM. CONCLUSIONS AND RELEVANCE: Angiotensin-converting enzyme inhibitors reduced all-cause mortality, CV mortality, and major CV events in patients with DM, whereas ARBs had no benefits on these outcomes. Thus, ACEIs should be considered as first-line therapy to limit excess mortality and morbidity in this population.

Tacrolimus as rescue therapy for adult-onset refractory minimal change nephrotic syndrome with reversible acute renal failure.

BACKGROUND: Some adult patients with minimal change nephrotic syndrome (MCNS) who are refractory to steroid treatment or combination with immunosuppressive drug developed reversible acute renal failure (ARF) due to persistent severe hypoalbuminemia and proteinuria. It is a challenge to find rescue therapies that are effective and safe in treating such difficult patients. METHODS: In this prospective observational study, 13 patients with adult-onset MCNS, all unresponsive to treatment with a steroid or a steroid with other immunosuppressive drugs, were studied from January 2005 to February 2009. All patients developed ARF before enrollment. Oral tacrolimus (TAC) was started at 1 mg/day (target trough levels of 3-6 ng/mL) before serum creatinine (SCr) decreased to ≤133 µmol/L, and then increased doses were given (target trough level of 5-10 ng/mL) when SCr decreased to ≤133 µmol/L. Primary outcome variables were remission, and recovery from ARF. Secondary outcome variables were time to recovery from ARF, time to remission, relapse rate, changes in SCr and estimated glomerular filtration rate (eGFR). RESULTS: One patient discontinued TAC due to deterioration of ARF, and 12 patients recovered from ARF. The mean time to recovery from ARF was 15.8 ± 4.4 days. Nine patients (69.2%) experienced complete remission (CR) and two patients (15.4%) experienced partial remission (PR). The mean time to PR and CR was 4.8 ± 2.7 and 9.4 ± 2.3 weeks, respectively. After a mean follow-up of 69.6 months, 36.4% (4/11) of patients who had remission experienced relapses. One patient who was resistant to TAC therapy had a doubling of serum creatinine concentration during follow-up. CONCLUSIONS: TAC may be a suitable therapeutic option for treatment of adult-onset refractory MCNS with reversible ARF.