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Frontiers in Immunology 2019Inflammasomes play a crucial role in innate immunity by serving as signaling platforms which deal with a plethora of pathogenic products and cellular products associated... (Review)
Review
Inflammasomes play a crucial role in innate immunity by serving as signaling platforms which deal with a plethora of pathogenic products and cellular products associated with stress and damage. By far, the best studied and most characterized inflammasome is NLRP3 inflammasome, which consists of NLRP3 (nucleotide-binding domain leucine-rich repeat (NLR) and pyrin domain containing receptor 3), ASC (apoptosis-associated speck-like protein containing a caspase recruitment domain), and procaspase-1. Activation of NLRP3 inflammasome is mediated by highly diverse stimuli. Upon activation, NLRP3 protein recruits the adapter ASC protein, which recruits the procaspase-1 resulting in its cleavage and activation, inducing the maturation, and secretion of inflammatory cytokines and pyroptosis. However, aberrant activation of the NLRP3 inflammasome is implicated in various diseases including diabetes, atherosclerosis, metabolic syndrome, cardiovascular, and neurodegenerative diseases; raising a tremendous clinical interest in exploring the potential inhibitors of NLRP3 inflammasome. Recent investigations have disclosed various inhibitors of the NLRP3 inflammasome pathway which were validated through studies and experiments in animal models of NLRP3-associated disorders. Some of these inhibitors directly target the NLRP3 protein whereas some are aimed at other components and products of the inflammasome. Direct targeting of NLRP3 protein can be a better choice because it can prevent off target immunosuppressive effects, thus restrain tissue destruction. This paper will review the various pharmacological inhibitors of the NLRP3 inflammasome and will also discuss their mechanism of action.
Topics: Animals; Dipeptides; Glyburide; Humans; Inflammasomes; NLR Family, Pyrin Domain-Containing 3 Protein; Nitriles; Sulfones; ortho-Aminobenzoates; para-Aminobenzoates
PubMed: 31749805
DOI: 10.3389/fimmu.2019.02538 -
Journal of Neuroinflammation Aug 2021Chronic cerebral hypoperfusion (CCH) causes white matter damage and cognitive impairment, in which astrogliosis is the major pathology. However, underlying cellular...
BACKGROUND
Chronic cerebral hypoperfusion (CCH) causes white matter damage and cognitive impairment, in which astrogliosis is the major pathology. However, underlying cellular mechanisms are not well defined. Activation of Na/H exchanger-1 (NHE1) in reactive astrocytes causes astrocytic hypertrophy and swelling. In this study, we examined the role of NHE1 protein in astrogliosis, white matter demyelination, and cognitive function in a murine CCH model with bilateral carotid artery stenosis (BCAS).
METHODS
Sham, BCAS, or BCAS mice receiving vehicle or a selective NHE1 inhibitor HOE642 were monitored for changes of the regional cerebral blood flow and behavioral performance for 28 days. Ex vivo MRI-DTI was subsequently conducted to detect brain injury and demyelination. Astrogliosis and demyelination were further examined by immunofluorescence staining. Astrocytic transcriptional profiles were analyzed with bulk RNA-sequencing and RT-qPCR.
RESULTS
Chronic cerebral blood flow reduction and spatial working memory deficits were detected in the BCAS mice, along with significantly reduced mean fractional anisotropy (FA) values in the corpus callosum, external capsule, and hippocampus in MRI DTI analysis. Compared with the sham control mice, the BCAS mice displayed demyelination and axonal damage and increased GFAP astrocytes and Iba1 microglia. Pharmacological inhibition of NHE1 protein with its inhibitor HOE642 prevented the BCAS-induced gliosis, damage of white matter tracts and hippocampus, and significantly improved cognitive performance. Transcriptome and immunostaining analysis further revealed that NHE1 inhibition specifically attenuated pro-inflammatory pathways and NADPH oxidase activation.
CONCLUSION
Our study demonstrates that NHE1 protein is involved in astrogliosis with pro-inflammatory transformation induced by CCH, and its blockade has potentials for reducing astrogliosis, demyelination, and cognitive impairment.
Topics: Animals; Astrocytes; Carotid Stenosis; Cerebrovascular Circulation; Cognition; Cognitive Dysfunction; Gliosis; Guanidines; Inflammation; Mice; Microglia; Sodium-Hydrogen Exchanger 1; Sulfones; White Matter
PubMed: 34454529
DOI: 10.1186/s12974-021-02234-8 -
Journal of Neuroinflammation Jun 2021Chronic neuropathic pain is a frequent sequel to peripheral nerve injury and maladaptive nervous system function. Divanillyl sulfone (DS), a novel structural derivative...
BACKGROUND
Chronic neuropathic pain is a frequent sequel to peripheral nerve injury and maladaptive nervous system function. Divanillyl sulfone (DS), a novel structural derivative of 4,4'-dihydroxydibenzyl sulfoxide from a traditional Chinese medicine Gastrodia elata with anti-nociceptive effects, significantly alleviated neuropathic pain following intrathecal injection. Here, we aimed to investigate the underlying mechanisms of DS against neuropathic pain.
METHODS
A chronic constrictive injury (CCI) mouse model of neuropathic pain induced by sciatic nerve ligation was performed to evaluate the effect of DS by measuring the limb withdrawal using Von Frey filament test. Immunofluorescence staining was used to assess the cell localizations and expressions of Iba-1, ASC, NLRP3, and ROS, the formation of autolysosome. The levels of NLRP3-related proteins (caspase-1, NLRP3, and IL-1β), mitophagy-related proteins (LC3, Beclin-1, and p62), and apoptosis-related proteins (Bcl-XL and Bax) were detected by Western blotting. The apoptosis of BV-2 cell and caspase activity were evaluated by flow cytometry.
RESULTS
DS significantly alleviated the neuropathic pain by increasing the mechanical withdrawal threshold and inhibiting the activation of NLRP3 in CCI-induced model mice. Our findings indicated that DS promoted the mitophagy by increasing the LC3II and Beclin 1 and decreasing the levels of p62 protein in BV-2 cell. This is accompanied by the inhibition of NLRP3 activation, which was shown as inhibited the expression of NLRP3 in lysates as well as the secretion of mature caspase-1 p10 and IL-1β p17 in supernatants in cultured BV-2 microglia. In addition, DS could promote mitophagy-induced improvement of dysfunctional mitochondria by clearing intracellular ROS and restoring mitochondrial membrane potential.
CONCLUSION
Together, our findings demonstrated that DS ameliorate chronic neuropathic pain in mice by suppressing NLRP3 inflammasome activation induced by mitophagy in microglia. DS may be a promising therapeutic agent for chronic neuropathic pain.
Topics: Animals; Apoptosis; Caspase 1; Cell Line; Disease Models, Animal; Inflammasomes; Male; Medicine, Chinese Traditional; Mice; Mice, Inbred C57BL; Microglia; Mitochondria; Mitophagy; NLR Family, Pyrin Domain-Containing 3 Protein; Neuralgia; Sciatic Nerve; Sulfones
PubMed: 34162415
DOI: 10.1186/s12974-021-02178-z -
International Journal For Vitamin and... Jul 2022: Methylsulfonylmethane (MSM) is an organosulfur compound with known benefits for joint health, sports nutrition, immune function, and anti-aging formulations and is...
: Methylsulfonylmethane (MSM) is an organosulfur compound with known benefits for joint health, sports nutrition, immune function, and anti-aging formulations and is gaining popularity as a nutritional supplement for the support of hair, skin and nails. : The study was conducted in two steps; in Part I (pilot study) a panel of 20 participants ingested either 3 g a day of MSM or placebo capsules for 16 weeks. Visual and subject self assessment of wrinkles and skin texture as the predominant sign of ageing was observed. In Part II (dose-response study), 63 participants ingested either 1 g or 3 g per day of MSM for 16 weeks. Expert clinical grading, instrumental measurements and consumer perception was used to evaluate skin conditions like lines and wrinkles. Additionally, instrumentational analysis was conducted using corneometer and cutometer for investigation of skin hydration, firmness and elasticity. : Part I of the study clearly indicates that oral ingestion of MSM (3 g/d) reduces signs of ageing like facial wrinkles ( < 0.05) and skin roughness ( < 0.05) as compared to placebo. Detailed analysis in Part II instrumentation assessments showed a significant ( < 0.05) improvement from baseline in the severity of facial wrinkles, as well as improved skin firmness, elasticity and hydration with MSM. Some of these parameters exhibited a good dose-response indicating that the higher (3 g/d) of the supplement was more effective than the lower dose of 1 g/d, but generally the lower dose of 1 g/d appeared to be sufficiently effective in reducing the facial signs of ageing. : This study indicated that MSM is effective in reducing visual signs of skin ageing even at a low dose of 1 g/d.
Topics: Administration, Oral; Beauty; Dimethyl Sulfoxide; Humans; Pilot Projects; Skin Aging; Sulfones; Sulfur
PubMed: 32083522
DOI: 10.1024/0300-9831/a000643 -
Environmental Health Perspectives May 2023Per- and polyfluoroalkyl substances (PFAS) have been previously linked to polycystic ovarian syndrome (PCOS), but only a few legacy PFAS were examined.
Environmental Exposure to Emerging Alternatives of Per- and Polyfluoroalkyl Substances and Polycystic Ovarian Syndrome in Women Diagnosed with Infertility: A Mixture Analysis.
BACKGROUND
Per- and polyfluoroalkyl substances (PFAS) have been previously linked to polycystic ovarian syndrome (PCOS), but only a few legacy PFAS were examined.
OBJECTIVES
This study aimed to explore this association with a variety of PFAS, including legacy, branched-chain isomers, and emerging alternatives, as well as a PFAS mixture.
METHODS
From 2014 to 2016, we conducted a multicenter, hospital-based case-control study on environmental endocrine disruptors and infertility in China. Three hundred sixty-six women with PCOS-related infertility and 577 control participants without PCOS were included in the current analysis. Twenty-three PFAS, including 3 emerging PFAS alternatives, 6 linear and branched PFAS isomers, 6 short-chain PFAS, and 8 legacy PFAS, were quantified in the plasma. Logistic regression and two multipollutant models [quantile-based g-computation (QGC) and Bayesian kernel machine regression (BKMR) methods] were used to assess the association of individual PFAS and PFAS mixture with PCOS, as well as the potential interactions among the congeners.
RESULTS
After adjusting for potential confounders, Each 1-standard deviation higher difference in ln-transformed 6:2 chlorinated perfluoroalkyl ether sulfonic acid (6:2 Cl-PFESA) and hexafluoropropylene oxide dimer acid (HFPO-DA) level was significantly associated with a 29% (95% CI: 1.11, 1.52) and 39% (95% CI:1.16, 1.68) higher odds of PCOS, respectively. Meanwhile, branched isomers of perfluorooctane sulfonate (PFOS) and perfluorohexane sulfonate (PFHxS) (i.e., br-PFHxS, n-PFOS, , ), short-chain PFAS (i.e., PFPeS and PFHxA) and other legacy PFAS [i.e., total concentrations of PFOS (T-PFOS), and perfluorododecanoic acid (PFDoA)] were significantly associated with increased odds of PCOS. The PFAS mixture was positively related to PCOS in the BKMR model. A similar trend was observed in QGC model, a ln-unit increase in the PFAS mixture was associated with a 20% increased risk of PCOS [ (95% CI: 1.06, 1.37)]. After controlling for other PFAS homologs, 6:2 Cl-PFESA, HFPO-DA, , and PFDoA were the major contributors based on the QGC and BKMR models. The associations were more pronounced in overweight/obese women.
CONCLUSIONS
In this group of women, environmental exposure to a PFAS mixture was associated with an elevated odds of PCOS, with 6:2 Cl-PFESA, HFPO-DA, , and PFDoA being the major contributors, especially in overweight/obese women. https://doi.org/10.1289/EHP11814.
Topics: Humans; Female; Polycystic Ovary Syndrome; Case-Control Studies; Bayes Theorem; Overweight; Fluorocarbons; Environmental Exposure; Alkanesulfonic Acids; Infertility; Alkanesulfonates; Obesity; Environmental Pollutants
PubMed: 37134253
DOI: 10.1289/EHP11814 -
Clinical Journal of the American... Dec 2020Diabetic kidney disease is an important complication of type 2 diabetes. In a phase 2b study, adding esaxerenone to renin-angiotensin system inhibitors dose dependently... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND AND OBJECTIVES
Diabetic kidney disease is an important complication of type 2 diabetes. In a phase 2b study, adding esaxerenone to renin-angiotensin system inhibitors dose dependently reduced the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and microalbuminuria. This 52-week phase 3 study further investigated the effects of esaxerenone on the urinary albumin-to-creatinine ratio in this patient group.
DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS
In this multicenter, randomized, double-blind study, patients with type 2 diabetes and a urinary albumin-to-creatinine ratio of 45 to <300 mg/g creatinine treated with renin-angiotensin system inhibitors were randomized to esaxerenone or placebo for 52 weeks (=455). Esaxerenone was initiated at 1.25 mg/d and titrated to 2.5 mg/d on the basis of serum potassium monitoring. The primary endpoint was the proportion of patients achieving urinary albumin-to-creatinine ratio remission (<30 mg/g creatinine and ≥30% reduction from baseline on two consecutive occasions).
RESULTS
Overall, 49 (22%) and nine (4%) patients in the esaxerenone and placebo groups, respectively, achieved urinary albumin-to-creatinine ratio remission (absolute difference 18%; 95% confidence interval, 12% to 25%; 0.001). The percent change in urinary albumin-to-creatinine ratio from baseline to end of treatment was significantly higher with esaxerenone versus placebo (-58% versus 8%; geometric least-squares mean ratio to placebo 0.38, 95% confidence interval, 0.33 to 0.44). There was a significant improvement with esaxerenone versus placebo in time to first remission (hazard ratio, 5.13; 95% confidence interval, 3.27 to 8.04) and time to first transition to urinary albumin-to-creatinine ratio ≥300 mg/g creatinine (hazard ratio, 0.23; 95% confidence interval, 0.11 to 0.48). More patients had a serum potassium level ≥6.0 or ≥5.5 mEq/L on two consecutive measurements in the esaxerenone group (20 [9%]) versus placebo (5 [2%]); these events were asymptomatic and resolved after dosage reduction or treatment discontinuation.
CONCLUSIONS
Adding esaxerenone to existing renin-angiotensin system inhibitor therapy in patients with type 2 diabetes and microalbuminuria increased the likelihood of albuminuria returning to normal levels, and reduced progression of albuminuria to higher levels.
Topics: Aged; Albuminuria; Biomarkers; Creatinine; Diabetes Mellitus, Type 2; Female; Humans; Japan; Kidney; Male; Middle Aged; Mineralocorticoid Receptor Antagonists; Pyrroles; Remission Induction; Risk Factors; Sulfones; Time Factors; Treatment Outcome
PubMed: 33239409
DOI: 10.2215/CJN.06870520 -
Hypertension (Dallas, Tex. : 1979) Jan 2020Mineralocorticoid receptors (MRs) are implicated in the pathology of hypertension. MR blockers are recommended for the treatment of salt-sensitive or resistant... (Comparative Study)
Comparative Study Randomized Controlled Trial
Mineralocorticoid receptors (MRs) are implicated in the pathology of hypertension. MR blockers are recommended for the treatment of salt-sensitive or resistant hypertension. However, use of currently available MR blockers is limited by adverse events. This phase 3 multicenter, randomized, double-blind study compared the efficacy and safety of esaxerenone, a new selective nonsteroidal MR blocker, at 2.5 and 5 mg/day and eplerenone 50 mg/day in Japanese patients with essential hypertension. After a 4-week washout period, 1001 eligible adults with hypertension were randomized evenly to esaxerenone 2.5 or 5 mg/day or eplerenone 50 mg/day treatments, taken orally once daily for 12 weeks. Primary end points were changes in sitting systolic or diastolic blood pressure (BP) from baseline at the end of treatment. Esaxerenone 2.5 mg/day was noninferior to eplerenone for reductions in sitting and 24-hour BP. Reductions in BP with esaxerenone 5 mg/day were significantly greater than those with esaxerenone 2.5 mg/day. Changes in diurnal BP showed persistent 24-hour antihypertensive effects in all treatment groups. The proportions of patients achieving target sitting BP (<140/90 mm Hg) were 31.5%, 41.2%, and 27.5% with esaxerenone 2.5 and 5 mg/day and eplerenone 50 mg/day, respectively. Incidences of adverse events (all mild or moderate) were similar across treatment groups. These results indicate that esaxerenone is an effective and well-tolerated MR blocker in Japanese patients with essential hypertension, with BP-lowering activity at least equivalent to eplerenone. Clinical Trial Registration- URL: http://www.clinicaltrials.gov. Unique identifier: NCT02890173.
Topics: Aged; Antihypertensive Agents; Blood Pressure; Double-Blind Method; Eplerenone; Essential Hypertension; Female; Humans; Male; Middle Aged; Pyrroles; Sulfones; Treatment Outcome
PubMed: 31786983
DOI: 10.1161/HYPERTENSIONAHA.119.13569 -
Bioscience Reports Oct 2022Sulfoquinovose (SQ, 6-deoxy-6-sulfo-D-glucose) is a sulfo-sugar with a ubiquitous distribution in the environment due to its production by plants and other... (Review)
Review
Sulfoquinovose (SQ, 6-deoxy-6-sulfo-D-glucose) is a sulfo-sugar with a ubiquitous distribution in the environment due to its production by plants and other photosynthetic organisms. Bacteria play an important role in degradation of SQ and recycling of its constituent sulfur and carbon. Since its discovery in 1963, SQ was noted to have a structural resemblance to glucose-6-phosphate and proposed to be degraded through a pathway analogous to glycolysis, termed sulfoglycolysis. Studies in recent years have uncovered an unexpectedly diverse array of sulfoglycolytic pathways in different bacteria, including one analogous to the Embden-Meyerhof-Parnas pathway (sulfo-EMP), one analogous to the Entner-Doudoroff pathway (sulfo-ED), and two involving sulfo-sugar cleavage by a transaldolase (sulfo-TAL) and transketolase (sulfo-TK), respectively, analogous to reactions in the pentose phosphate (PP) pathway. In addition, a non-sulfoglycolytic SQ degradation pathway was also reported, involving oxygenolytic C-S cleavage catalyzed by a homolog of alkanesulfonate monooxygenase (sulfo-ASMO). Here, we review the discovery of these new mechanisms of SQ degradation and lessons learnt in the study of new catabolic enzymes and pathways in bacteria.
Topics: Transaldolase; Glucose-6-Phosphate; Transketolase; Bacteria; Glycolysis; Sulfur; Glucose; Carbon; Alkanesulfonates; Mixed Function Oxygenases; Phosphates; Pentoses
PubMed: 36196895
DOI: 10.1042/BSR20220314 -
Cancer Letters Nov 2023Rigosertib (RGS) is a benzyl styryl sulfone which exhibits impressive cytotoxicity in cancer cells. However, its modulating effect on tumor immune microenvironment...
Rigosertib (RGS) is a benzyl styryl sulfone which exhibits impressive cytotoxicity in cancer cells. However, its modulating effect on tumor immune microenvironment remains elusive. In our experiments, compared with immunodeficient mouse model, increased tumor growth arrest and robust anti-tumor immunity were observed in RGS-treated colorectal cancer (CRC) isograft tumors in immunocompetent mice. Intriguingly, RGS markedly down-regulated programmed cell death ligand 1 (PD-L1) expression in both vivo and in vitro. Meanwhile, RGS increased autophagic vacuole number in CRC cells as seen by transmission electron microscopy and immunofluorescence. Moreover, increased LC3-II level and tandem-mRFP- GFP- LC3 labeled vacuole accumulation demonstrated RGS-induced autophagic flux. Mechanistically, it is the activation of AMP-activated protein kinase-UNC-51-like kinase 1 (AMPK-ULK1) axis, rather than the canonical mTOR signaling pathway, that plays a pivotal role in RGS-induced autophagy. AMPK-ULK1 dependent autophagy inhibition, by either short interfering RNA or chemical inhibitors, blocked RGS-induced PD-L1 degradation. Finally, RGS exhibited synergistic anti-tumor activity with cytotoxic T-lymphocyte-associated protein 4 monoclonal antibody in the CRC isograft model. Furthermore, apart from the immunomodulatory effect, we also confirmed the direct cytotoxicity of RGS in inducing mitochondria-related apoptosis. Altogether, considering its PD-L1 inhibitory and cytotoxic effects, RGS could be a promising drug for CRC therapy.
Topics: Animals; Mice; AMP-Activated Protein Kinases; Autophagy; B7-H1 Antigen; Colorectal Neoplasms; Sulfones; Tumor Microenvironment
PubMed: 37805162
DOI: 10.1016/j.canlet.2023.216422 -
Chemistry, An Asian Journal Dec 2022Fluorescent indicators that respond to changes in biological membrane potentials provide a powerful complement to existing methods for monitoring neuronal activity....
Fluorescent indicators that respond to changes in biological membrane potentials provide a powerful complement to existing methods for monitoring neuronal activity. Indicators that absorb and emit in the near infrared window are especially attractive, since lower energy wavelengths excite fewer biological molecules and can penetrate more deeply into biological tissues. In this work, we incorporate sulfone rhodamine chromophores into a voltage-sensitive scaffold in order to generate voltage sensitive fluorophores which absorb and emit above 700 nm. These Sulfone Rhodamine Voltage Reporters (SuRhoVRs) partition into cell membranes and display good sensitivity to membrane potential changes. The most sensitive SuRhoVR derivative also displays excellent photostability and can track membrane potential changes in dissociated rat hippocampal neurons.
Topics: Rats; Animals; Rhodamines; Fluorescent Dyes; Diagnostic Imaging; Sulfones
PubMed: 36356288
DOI: 10.1002/asia.202200906