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Journal of the American Society of... Nov 2021Autoantibodies binding to podocyte antigens cause idiopathic membranous glomerulonephritis (iMGN). However, it remains elusive how autoantibodies reach the subepithelial...
BACKGROUND
Autoantibodies binding to podocyte antigens cause idiopathic membranous glomerulonephritis (iMGN). However, it remains elusive how autoantibodies reach the subepithelial space because the glomerular filtration barrier (GFB) is size selective and almost impermeable for antibodies.
METHODS
Kidney biopsies from patients with iMGN, cell culture, zebrafish, and mouse models were used to investigate the role of nephronectin (NPNT) regulating microRNAs (miRs) for the GFB.
RESULTS
Glomerular endothelial cell (GEC)-derived miR-192-5p and podocyte-derived miR-378a-3p are upregulated in urine and glomeruli of patients with iMGN, whereas glomerular NPNT is reduced. Overexpression of miR-192-5p and morpholino-mediated npnt knockdown induced edema, proteinuria, and podocyte effacement similar to podocyte-derived miR-378a-3p in zebrafish. Structural changes of the glomerular basement membrane (GBM) with increased lucidity, splitting, and lamellation, especially of the lamina rara interna, similar to ultrastructural findings seen in advanced stages of iMGN, were found. IgG-size nanoparticles accumulated in lucidity areas of the lamina rara interna and lamina densa of the GBM in npnt-knockdown zebrafish models. Loss of slit diaphragm proteins and severe structural impairment of the GBM were further confirmed in podocyte-specific Npnt knockout mice. GECs downregulate podocyte NPNT by transfer of miR-192-5p-containing exosomes in a paracrine manner.
CONCLUSIONS
Podocyte NPNT is important for proper glomerular filter function and GBM structure and is regulated by GEC-derived miR-192-5p and podocyte-derived miR-378a-3p. We hypothesize that loss of NPNT in the GBM is an important part of the initial pathophysiology of iMGN and enables autoantigenicity of podocyte antigens and subepithelial immune complex deposition in iMGN.
Topics: Animals; Antigen-Antibody Complex; Autoantigens; Cells, Cultured; Coculture Techniques; Endothelial Cells; Exosomes; Extracellular Matrix Proteins; Gene Expression Regulation; Gene Targeting; Glomerular Basement Membrane; Glomerulonephritis, Membranous; Gold Sodium Thiosulfate; Humans; Kidney Glomerulus; Metal Nanoparticles; Mice; MicroRNAs; Paracrine Communication; Permeability; Podocytes; Proteinuria; Transfection; Zebrafish; Zebrafish Proteins
PubMed: 34716242
DOI: 10.1681/ASN.2020121699 -
Frontiers in Immunology 2021In the immunology of sepsis microcirculatory and mitochondrial dysfunction in the gastrointestinal system are important contributors to mortality. Hydrogen sulfide (HS)...
INTRODUCTION
In the immunology of sepsis microcirculatory and mitochondrial dysfunction in the gastrointestinal system are important contributors to mortality. Hydrogen sulfide (HS) optimizes gastrointestinal oxygen supply and mitochondrial respiration predominantly K(ATP)-channels. Therefore, we tested the hypothesis that sodium thiosulfate (STS), an inducer of endogenous HS, improves intestinal and hepatic microcirculation and mitochondrial function K(ATP)-channels in sepsis.
METHODS
In 40 male Wistar rats colon ascendens stent peritonitis (CASP) surgery was performed to establish sepsis. Animals were randomized into 4 groups (1: STS 1 g • kg i.p., 2: glibenclamide (GL) 5 mg • kg i.p., 3: STS + GL, 4: vehicle (VE) i.p.). Treatment was given directly after CASP-surgery and 24 hours later. Microcirculatory oxygenation (µHBO) and flow (µflow) of the colon and the liver were continuously recorded over 90 min using tissue reflectance spectrophotometry. Mitochondrial oxygen consumption in tissue homogenates was determined with respirometry. Statistic: two-way ANOVA + Dunnett´s and Tukey post - hoc test (microcirculation) and Kruskal-Wallis test + Dunn's multiple comparison test (mitochondria). p < 0.05 was considered significant.
RESULTS
STS increased µHbO (colon: 90 min: + 10.4 ± 18.3%; liver: 90 min: + 5.8 ± 9.1%; p < 0.05 vs. baseline). Furthermore, STS ameliorated µflow (colon: 60 min: + 51.9 ± 71.1 aU; liver: 90 min: + 22.5 ± 20.0 aU; p < 0.05 vs. baseline). In both organs, µHbO and µflow were significantly higher after STS compared to VE. The combination of STS and GL increased colonic µHbO and µflow (µHbO 90 min: + 8.7 ± 11.5%; µflow: 90 min: + 41.8 ± 63.3 aU; p < 0.05 vs. baseline), with significantly higher values compared to VE. Liver µHbO and µflow did not change after STS and GL. GL alone did not change colonic or hepatic µHbO or µflow. Mitochondrial oxygen consumption and macrohemodynamic remained unaltered.
CONCLUSION
The beneficial effect of STS on intestinal and hepatic microcirculatory oxygenation in sepsis seems to be mediated by an increased microcirculatory perfusion and not by mitochondrial respiratory or macrohemodynamic changes. Furthermore, the effect of STS on hepatic but not on intestinal microcirculation seems to be K(ATP)-channel-dependent.
Topics: Animals; Antioxidants; Colon; Disease Models, Animal; Liver; Male; Microcirculation; Mitochondria; Rats; Rats, Wistar; Sepsis; Thiosulfates
PubMed: 34163476
DOI: 10.3389/fimmu.2021.671935 -
International Journal of Preventive... 2017Children with cancer treated with cytotoxic drugs are frequently at risk of developing renal dysfunction. The cytotoxic drugs that are widely used for cancer treatment... (Review)
Review
Children with cancer treated with cytotoxic drugs are frequently at risk of developing renal dysfunction. The cytotoxic drugs that are widely used for cancer treatment in children are cisplatin (CPL), ifosfamide (IFO), carboplatin, and methotrexate (MTX). Mechanisms of anticancer drug-induced renal disorders are different and include acute kidney injury (AKI), tubulointerstitial disease, vascular damage, hemolytic uremic syndrome (HUS), and intrarenal obstruction. CPL nephrotoxicity is dose-related and is often demonstrated with hypomagnesemia, hypokalemia, and impaired renal function with rising serum creatinine and blood urea nitrogen levels. CPL, mitomycin C, and gemcitabine treatment cause vascular injury and HUS. High-dose IFO, streptozocin, and azacitidine cause renal tubular dysfunction manifested by Fanconi syndrome, rickets, and osteomalacia. AKI is a common adverse effect of MTX, interferon-alpha, and nitrosourea compound treatment. These strategies to reduce the cytotoxic drug-induced nephrotoxicity should include adequate hydration, forced diuresis, and urinary alkalization. Amifostine, sodium thiosulfate, and diethyldithiocarbamate provide protection against CPL-induced renal toxicity.
PubMed: 29114374
DOI: 10.4103/ijpvm.IJPVM_40_17 -
The Lancet. Child & Adolescent Health Aug 2019The identification of preventive interventions that are safe and effective for cisplatin-induced ototoxicity is important, especially in children because hearing loss... (Review)
Review
The identification of preventive interventions that are safe and effective for cisplatin-induced ototoxicity is important, especially in children because hearing loss can impair speech-language acquisition development. Previous randomised trials assessed systemic drugs such as amifostine, sodium diethyldithiocarbamate or disulfiram, and sodium thiosulfate. Amifostine, sodium diethyldithiocarbamate, and disulfiram did not show hearing preservation. Paediatric trials assessing sodium thiosulfate showed efficacy in terms of hearing protection. The SIOPEL 6 trial consisted solely of patients with localised hepatoblastoma and no effects on survival were shown. In the ACCL0431 trial, which included heterogeneous patients, a post-hoc analysis showed significantly worse overall survival among patients who had disseminated disease receiving sodium thiosulfate than among controls, but not among those with localised disease. Intratympanically administered drugs have mainly been assessed in adults and include N-acetylcysteine and dexamethasone. Inconsistent effects of these drugs were identified but these studies were limited by design, small sample size, and statistical approach. Future studies of systemic drugs will need to consider the measurement of disease outcomes through study design and sample size, and ototoxicity endpoints should be harmonised to enhance comparability between trials.
Topics: Acetylcysteine; Adolescent; Amifostine; Anti-Inflammatory Agents; Antineoplastic Agents; Chelating Agents; Child; Cisplatin; Cytoprotection; Dexamethasone; Disulfiram; Ditiocarb; Humans; Neoplasms; Ototoxicity; Thiosulfates
PubMed: 31160205
DOI: 10.1016/S2352-4642(19)30115-4 -
Journal of Clinical Toxicology Jun 2017Accidental or intentional cyanide ingestion is an-ever present danger. Rapidly acting, safe, inexpensive oral cyanide antidotes are needed that can neutralize large...
OBJECTIVE
Accidental or intentional cyanide ingestion is an-ever present danger. Rapidly acting, safe, inexpensive oral cyanide antidotes are needed that can neutralize large gastrointestinal cyanide reservoirs. Since humans cannot be exposed to cyanide experimentally, we studied oral cyanide poisoning in rabbits, testing oral sodium thiosulfate with and without gastric alkalization.
SETTING
University research laboratory.
SUBJECTS
New Zealand white rabbits.
INTERVENTIONS
Seven animal groups studied; Groups 1-5 received high dose oral NaCN (50 mg, >LD100) and were treated immediately with oral ( nasogastric tube): 1) saline, 2) glycine, 3) sodium thiosulfate or 4) sodium thiosulfate and glycine, or 5) after 2 min with intramuscular injection of sodium nitrite and sodium thiosulfate plus oral sodium thiosulfate and glycine. Groups 6-7 received moderate dose oral NaCN (25 mg, LD70) and delayed intramuscular 6) saline or 7) sodium nitrite-sodium thiosulfate.
MEASUREMENTS AND MAIN RESULTS
All animals in the high dose NaCN group receiving oral saline or glycine died very rapidly, with a trend towards delayed death in glycine-treated animals; saline glycine-treated animals died at 10.3+3.9 and 14.6+5.9 min, respectively (p=0.13). In contrast, all sodium thiosulfate-treated high dose cyanide animals survived (p<0.01), with more rapid recovery in animals receiving both thiosulfate and glycine, compared to thiosulfate alone (p<0.03). Delayed intramuscular treatment alone in the moderate cyanide dose animals increased survival over control animals from 30% to 71%. Delayed treatment in high dose cyanide animals was not as effective as immediate treatment, but did increase survival time and rescued 29% of animals (p<0.01 cyanide alone).
CONCLUSIONS
Oral sodium thiosulfate with gastric alkalization rescued animals from lethal doses of ingested cyanide. The combination of oral glycine and sodium thiosulfate may have potential for treating high dose acute cyanide ingestion and merits further investigation. The combination of systemic and oral therapy may provide further options.
PubMed: 28868209
DOI: 10.4172/2167-7972.1000355 -
Iranian Endodontic Journal 2021Our study evaluated the impact of sodium thiosulfate (ST) irrigation, subsequent to sodium hypochlorite (NaOCl) and just before root canal filling, on the filling...
INTRODUCTION
Our study evaluated the impact of sodium thiosulfate (ST) irrigation, subsequent to sodium hypochlorite (NaOCl) and just before root canal filling, on the filling quality (interfacial adaptation and penetration segment) of an epoxy resin-based root canal sealer.
METHODS AND MATERIALS
Twenty single-rooted human teeth were prepared with the ProTaper system. The specimens were then divided into the following groups: 5.25% NaOCl irrigation (NaOCl group) and 5.25% NaOCl irrigation+0.5% sodium thiosulfate (NaOCl+ST group). The root canals were filled using single-cone technique with ProTaper F3 cones and AH-Plus sealer, labeled with rhodamine B dye to allow analysis under a confocal laser scanning microscopy (CLSM). All samples were sectioned at 2, 4, and 6 mm from the apex and prepared for CLSM analysis. The percentage of voids, gaps and dentinal sealer penetration segment of the canal were calculated at the apical, middle and coronal thirds. The non-parametric Mann-Whitney statistical test was used at 5% significance level.
RESULTS
Higher percentage of gaps and voids were observed at all root thirds of the NaOCl group when compared to the NaOCl+ST group (<0.05). There was a significant increase in the penetration segment of NaOCl+ST group at the coronal and middle root third when compared to the NaOCl group (<0.05).
CONCLUSION
Our results showed that the use of ST as an antioxidant agent after NaOCl irrigation promoted a better interfacial adaptation and penetration of epoxy resin-based root canal fillings.
PubMed: 36704417
DOI: 10.22037/iej.v16i1.27566 -
Journal of Clinical Medicine Dec 2023(1) Background: Calcinosis of the skin mainly appears in connective tissue disorders (dystrophic subtype). It may cause inflammation, ulceration, pain, and restricted...
(1) Background: Calcinosis of the skin mainly appears in connective tissue disorders (dystrophic subtype). It may cause inflammation, ulceration, pain, and restricted joint mobility. Management is difficult; sodium thiosulfate is one potential therapeutic agent with promising data on intralesional and topical formulation for smaller calcified lesions. There are very limited data on systemic administration. (2) Methods: A retrospective study was conducted at our department to assess the efficacy of oral and intravenous sodium thiosulfate in dystrophic calcinosis between 2003 and 2023. (3) Results: Seven patients were identified, who received systemic sodium thiosulfate (intravenous or oral). The mean duration of calcinosis at the time of administration was 3.8 ± 4 years (range 0-11). Intravenous sodium thiosulfate was administered in doses of 12.5-25 g two or three times during one week of the month for 4.5 ± 3.9 months on average. Orally, 1-8 g was administered daily for 29.1 ± 40.9 months on average. Four of seven patients had a partial response (57.1%). Despite no complete response, pain, ulceration and inflammation frequency decreased, and sodium thiosulfate prevented further progression in responsive patients. (4) Conclusions: Based on our experience and literature data, systemic sodium thiosulfate may be a potential adjunct therapy in calcinosis, especially if inflamed or ulcerating.
PubMed: 38137810
DOI: 10.3390/jcm12247741 -
Current Opinion in Obstetrics &... Feb 2023Our objective is to provide a history, rationale, and review of the use of hyperthermic intraperitoneal chemotherapy (HIPEC) in the treatment of ovarian cancer. (Review)
Review
PURPOSE OF REVIEW
Our objective is to provide a history, rationale, and review of the use of hyperthermic intraperitoneal chemotherapy (HIPEC) in the treatment of ovarian cancer.
RECENT FINDINGS
In the last decade, there has been an increase in the literature regarding HIPEC in the treatment of ovarian cancer. The rationale for HIPEC extends from earlier trials demonstrating improved survival using intraperitoneal chemotherapy. HIPEC provides a one-time opportunity for intraperitoneal chemotherapy at the time of cytoreduction and with the addition of hyperthermia. Cisplatin HIPEC has been demonstrated to have a survival benefit when used in the interval cytoreductive setting. In terms of safety, nephroprotection remains a key concern when administering HIPEC. Sodium thiosulfate provides nephroprotection and should be considered when performing HIPEC. Various institutions have created multidisciplinary protocols for administering HIPEC, which include operating room staff, nursing, anesthesia, pharmacy, and surgical teams.
SUMMARY
HIPEC has a role in the treatment paradigm of ovarian cancer. Currently, HIPEC is approved in the interval cytoreductive surgery setting. Further trials are needed to understand the appropriate timing, chemotherapeutic agents, and protocolization of HIPEC.
Topics: Humans; Female; Hyperthermic Intraperitoneal Chemotherapy; Hyperthermia, Induced; Ovarian Neoplasms; Combined Modality Therapy; Antineoplastic Combined Chemotherapy Protocols
PubMed: 36595646
DOI: 10.1097/GCO.0000000000000837 -
BioMed Research International 2017The high prevalence of arterial calcification in end-stage renal disease (ESRD) is far beyond the explanation by common cardiovascular risk factors such as aging,... (Review)
Review
The high prevalence of arterial calcification in end-stage renal disease (ESRD) is far beyond the explanation by common cardiovascular risk factors such as aging, diabetes, hypertension, and dyslipidemia. The finding relies on the fact that vascular and valvular calcifications are predictors of cardiovascular diseases and mortality in persons with chronic renal failure. In addition to traditional cardiovascular risk factors such as diabetes mellitus and blood pressure control, other ESRD-related risks such as phosphate retention, excess calcium, and prolonged dialysis time also contribute to the development of vascular calcification. The strategies are to reverse "calcium paradox" and lower vascular calcification by decreasing procalcific factors including minimization of inflammation (through adequate dialysis and by avoiding malnutrition, intravenous labile iron, and positive calcium and phosphate balance), correction of high and low bone turnover, and restoration of anticalcification factor balance such as correction of vitamin D and K deficiency; parathyroid intervention is reserved for severe hyperparathyroidism. The role of bone antiresorption therapy such as bisphosphonates and denosumab in vascular calcification in high-bone-turnover disease remains unclear. The limited data on sodium thiosulfate are promising. However, if calcification is to be targeted, ensure that bone health is not compromised by the treatments.
Topics: Humans; Kidney Failure, Chronic; Phosphates; Renal Dialysis; Risk Factors; Vascular Calcification; Vitamin D Deficiency; Vitamin K Deficiency
PubMed: 28286773
DOI: 10.1155/2017/9035193 -
Advances in Pharmacological and... 2022The airway epithelial glycocalyx plays an important role in preventing severe acute respiratory syndrome coronavirus 2 entry into the epithelial cells, while the... (Review)
Review
The airway epithelial glycocalyx plays an important role in preventing severe acute respiratory syndrome coronavirus 2 entry into the epithelial cells, while the endothelial glycocalyx contributes to vascular permeability and tone, as well as modulating immune, inflammatory, and coagulation responses. With ample evidence in the scientific literature that coronavirus disease 2019 (COVID-19) is related to epithelial and endothelial dysfunction, preserving the glycocalyx should be the main focus of any COVID-19 treatment protocol. The most studied functional unit of the glycocalyx is the glycosaminoglycan heparan sulfate, where the degree and position of the sulfate groups determine the biological activity. N-acetylcysteine (NAC) and other sulfur donors contribute to the inorganic sulfate pool, the rate-limiting molecule in sulfation. NAC is not only a precursor to glutathione but also converts to hydrogen sulfide, inorganic sulfate, taurine, Coenzyme A, and albumin. By optimising inorganic sulfate availability, and therefore sulfation, it is proposed that COVID-19 can be prevented or at least most of the symptoms attenuated. A comprehensive COVID-19 treatment protocol is needed to preserve the glycocalyx in both the prevention and treatment of COVID-19. The use of NAC at a dosage of 600 mg bid for the prevention of COVID-19 is proposed, but a higher dosage of NAC (1200 mg bid) should be administered upon the first onset of symptoms. In the severe to critically ill, it is advised that IV NAC should be administered immediately upon hospital admission, and in the late stage of the disease, IV sodium thiosulfate should be considered. Doxycycline as a protease inhibitor will prevent shedding and further degradation of the glycocalyx.
PubMed: 35992575
DOI: 10.1155/2022/4555490