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Disruption of circadian rhythm during pregnancy produces adverse health outcomes in offspring; however, the role of maternal circadian rhythms in the immune system of infants and their susceptibility to inflammation remains poorly understood. Here we show that disruption of circadian rhythms in pregnant mice profoundly aggravates the severity of neonatal inflammatory disorders in both male and female offspring, such as necrotizing enterocolitis and sepsis. The diminished maternal production of docosahexaenoic acid (DHA) and the impaired immunosuppressive function of neonatal myeloid-derived suppressor cells (MDSCs) contribute to this phenomenon. Mechanistically, DHA enhances the immunosuppressive function of MDSCs via PPARγ-mediated mitochondrial oxidative phosphorylation. Transfer of MDSCs or perinatal supplementation of DHA relieves neonatal inflammation induced by maternal rhythm disruption. These observations collectively demonstrate a previously unrecognized role of maternal circadian rhythms in the control of neonatal inflammation via metabolic reprograming of myeloid cells., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Alcoholic liver injury (ALI) is a major risk factor for alcoholic liver disease, characterized by excessive inflammatory response and abnormal liver dysfunction. Previous studies have indicated that O-alkyl and o-benzyl hesperetin derivative-1 L (HD-1 L) has anti-inflammatory and hepato-protective effects in CCl 4 -induced liver injury. However, its effect on ALI and underlying mechanism has not been elucidated. This study was designed to evaluate the protective effects of HD-1 L on alcoholic liver injury and reveal the underlying mechanisms. ALI model was established in male C57BL/6 J mice (aged 6-8 weeks) by Gao-Binge protocol. The mice were received different doses of HD-1 L (25 mg/kg, 50 mg/kg, 100 mg/kg) by daily intragastric administration, respectively. Liver function and inflammation were measured. Mechanism underlying the anti-inflammatory and hepato-protective effect of HD-1 L were studied in RAW264.7 cells. In alcoholic liver injury mice, HD-1 L effectively improved the liver pathology, and remarkably reduced the levels of alanine transaminase (ALT), aspartate transaminase (AST), triglyceride (TG) and total cholesterol (T-CHO) in serum. Moreover, HD-1 L markedly suppressed inflammation in vivo and inhibited the secretion of inflammatory factors in vitro. Our results showed that HD-1 L decreased the activity of Bromodomain-containing Protein 2 (BRD2) and inhibited expression of BRD2 in vivo and in vitro. Furthermore, HD-1 L further alleviated alcohol-induced inflammation after blocking BRD2 with inhibitor (JQ1) or BRD2 small interfering (si)-RNA in RAW264.7 cells. Besides, HD-1 L failed to effectively exert its anti-inflammatory effects after over expression of BRD2. In addition, HD-1 L significantly inhibited the phosphorylation and activation of NF-κB-P65 mediated by BRD2. In conclusion, HD-1 L alleviated liver injury and inflammation mainly by inhibiting BRD2-NF-κB signaling pathway, and HD-1 L may be a potential anti-inflammatory compound in treatment of alcoholic liver disease., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background: Neuroinflammation subsequent to traumatic brain injury (TBI) is important for the recovery of patients and is associated with neurodegenerative changes post-TBI. The tripartite motif containing 44 (TRIM44) protein is an E3 ligase involved in the regulation of immune function with no previously known link to TBI. This study explores the connection between TRIM44 and TBI., Methods: After induction of TBI in rats by control cortex injury, TRIM44 expressions were determined with quantitative real-time reverse transcription polymerase chain reaction and Western blot, and Toll-like receptor 4 (TLR4)-NF-κB signaling was examined by the expression of TLR4, p65 phosphorylation, and the specific NF-κB transcription activity. The effects of TRIM44 knockdown on inflammation, neurological function, and TLR4-NF-κB signaling in TBI rats were revealed by the detection of proinflammatory cytokines and TLR4-NF-κB signaling molecules, modified neurological severity score, brain water content, and Evans blue permeability., Results: We found that TRIM44 expression was significantly increased following TBI induction along with TLR4-NF-κB activation. Silencing of TRIM44 suppressed proinflammatory cytokine production, improved neurological outcomes, alleviated brain edema, and inhibited TLR4-NF-κB signaling in TBI rats., Conclusion: Our findings suggest that suppressing TRIM44 or modulation of relevant pathways may be a therapeutic strategy for TBI., (© 2022 S. Karger AG, Basel.)

Montelukast is a leukotriene receptor antagonist that is known to prevent allergic rhinitis and asthma. Blocking the Cysteinyl leukotriene receptor (CysLTR1), one of the primary receptors of leukotrienes, has been demonstrated to be efficacious in ameliorating experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS), through disrupting chemotaxis of infiltrating T cells. However, the role of CysLTR1 in the pathogenesis of MS is not well understood. Here, we show that MS patients had higher expression of CysLTR1 in the circulation and central nervous system (CNS). The majority of CD4 + T cells expressed CysLTR1 in MS lesions. Among T-cell subsets, Th17 cells had the highest expression of CysLTR1, and blocking CysLTR1 signalling abrogated their development in vitro. Inhibition of CysLTR1 by montelukast suppressed EAE development in both a prophylactic and therapeutic manner and inhibited myelin loss in EAE mice. Similarly, the in vivo results showed that montelukast inhibited Th17 response in EAE mice and that Th17 cells treated with montelukast had reduced encephalitogenic in adoptive EAE. Our findings strongly suggest that targeting Th17 response by inhibiting CysLTR1 signalling could be a promising therapeutic strategy for the treatment of MS and CNS inflammatory diseases., (© 2021 John Wiley & Sons Ltd.)

Obesity is a metabolic condition associated with multiple health problems such as endocrine and metabolic dysfunction and chronic inflammation in adipose tissues. In this study, the ADSCs could be stimulated to differentiate into brown adipocyte with rosiglitazone treatment based on the Oil-Red-O staining trial. Furthermore, the multilocular lipid droplets located in the center was increased in differentiated brown adipocytes, and brown fat-associated proteins, UCP1, PPAR- γ , and LPL were highly expressed in brown adipocytes differentiated from ADSCs. Additionally, the results of animal experiments showed that both weight and amount of VLDL and LDL were decreased in the serum of obese mice after transplantation of rosiglitazone-induced brown adipocytes, while the level of HDL increased. Moreover, the proteins associated with lipid metabolism, LPA and UCP1, were downregulated, and the inflammatory response was suppressed through inhibition of the ITGAM/NF- κ B-mediated proinflammatory responses and polarization of M2 macrophages. Similarly, the amounts of proinflammatory cytokines, TNF- α , IL-6, and IL-1 β were decreased after rosiglitazone-induced brown adipocyte transplantation. On the contrary, anti-inflammatory cytokine IL-10 was significantly increased in both groups of obese mice, with or without brown adipocyte transplantation. Therefore, the adipose-derived stromal cells with induced browning could promote lipid consumption and alternative polarization of M2 macrophages to attenuate adipose inflammation in obesity mouse models, which thus provides a potential therapy for obesity., Competing Interests: There is no conflict of interest., (Copyright © 2019 Wen-Chao Zhang et al.)

Neuropathic pain is a complicated clinical syndrome caused by heterogeneous etiology. Despite the fact that the underlying mechanisms remain elusive, it is well accepted that neuroinflammation plays a critical role in the development of neuropathic pain. Fascin-1, an actin-bundling protein, has been proved to be involved in the processing of diverse biological events including cellular development, immunity, and tumor invasion etc. Recent studies have shown that Fascin-1 participates in antigen presentation and the regulation of pro-inflammatory agents. However, whether Fascin-1 is involved in neuropathic pain has not been reported. In the present study we examined the potential role of Fascin-1 by using a rodent model of chronic constriction injury (CCI). Our results showed that Fascin-1 increased rapidly in dorsal root ganglions (DRG) and spinal cord (SC) after CCI. The increased Fascin-1 widely expressed in DRG, however, it localized predominantly in microglia, seldom in neuron, and hardly in astrocyte in the SC. Intrathecal injection of Fascin-1 siRNA not only suppressed the activation of microglia and the release of pro-inflammatory mediators, but also attenuated the mechanical allodynia and thermal hyperalgesia induced by CCI.

Neuro-axonal injury in the central nervous system (CNS) is one of the major pathological hallmarks of experimental autoimmune encephalomyelitis (EAE), an experimental model of multiple sclerosis (MS). Matrine (MAT), a quinolizidine alkaloid derived from the herb Radix Sophorae Flave, has recently been shown to effectively suppress EAE through an anti-inflammatory mechanism. However, whether MAT can also protect myelin/axons from damage is not known. In the present study we show that, while untreated rats developed severe clinical disease, CNS inflammatory demyelination, and axonal damage, these clinical and pathological signs were significantly reduced by MAT treatment. Consistently, MAT treatment reduced the concentration of myelin basic protein in serum and downregulated expression of β-amyloid (Aβ) and B-site APP cleaving enzyme 1 (BACE-1) in the CNS. Further, the CNS of MAT-treated rats exhibited increased expression of brain-derived neurotrophic factor (BDNF), an important factor for neuronal survival and axonal growth. Together, these results demonstrate that MAT effectively prevented neuro-axonal injury, which can likely be attributed to inhibiting risk factors such as BACE-1 and upregulating neuroprotective factors such as BDNF. We conclude that this novel natural reagent, MAT, which effectively protects neuro-axons from CNS inflammation-induced damage, could be a potential candidate for the treatment of neurodegenerative diseases such as MS., (Copyright © 2015 Elsevier Inc. All rights reserved.)

This study was designed to detect the modulation manner of melatonin on microglial activation and explore herein possible involvement of mammalian target of rapamycin (mTOR) pathway following traumatic brain injury (TBI). ICR mice were divided into four groups: sham group, TBI group, TBI+sal group and TBI+Melatonin group. A weight-drop model was employed to cause TBI. Neurological severity score (NSS) tests were performed to measure behavioral outcomes. Nissl staining was conducted to observe the neuronal degeneration and wet-to-dry weight ratio indicated brain water content. Immunofluorescence was designed to investigate microglial activation. Enzyme-linked immunosorbent assay (ELISA) was employed to evaluate proinflammatory cytokine levels (interleukin-beta (IL-1β), tumor necrosis factor-alpha (TNF-α)). Western blotting was engaged to analyze the protein content of mammalian target of rapamycin (mTOR), p70 ribosomal S6 kinase (p70S6K) and S6 ribosomal protein (S6RP). Melatonin administration was associated with markedly restrained microglial activation, decreased release of proinflammatory cytokines and increased the number of surviving neurons at the site of peri-contusion. Meanwhile, melatonin administration resulted in dephosphorylated mTOR pathway. In conclusion, this study presents a new insight into the mechanisms responsible for the anti-neuroinflammation of melatonin, with possible involvement of mTOR pathway., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

CtBP2 (C-terminal binding protein 2), which is widely expressed during developmental processes and differentiation, acts as a transcriptional repressor following recruitment to target promoters through repressors or other co-repressor proteins. In this study, we elucidated the dynamic expression changes and localization of CtBP2 in lipopolysaccharide (LPS)-induced neuroinflammatory processes in adult rats. CtBP2 expression was strongly induced in active glia cells (microglia and astrocytes) in inflamed spinal cord. In vitro studies indicated that the up-regulation of CtBP2 may be involved in the subsequent microglia activation following LPS exposure. And the knock-down of CtBP2 in microglia cell line HAPI by siRNA showed that CtBP2 increased the activation of microglia induced by LPS. Collectively, these results suggested CtBP2 may be important in host defense in microglia-mediated immune response. Understanding the cell signal pathway may provide a novel strategy against inflammatory and immune reaction in neuroinflammation in central nervous system.

Nuclear factor erythroid 2-related factor 2 (Nrf2)-antioxidant response element pathway has been proved to be the key regulator in reducing inflammatory damage, which is involved in subarachnoid hemorrhage (SAH). Here, in a traditional in vitro SAH model, we investigated the effect of Nrf2 depletion on pro-inflammatory cytokines production. Primary cultured astrocytes from Nrf2 wild type (WT) or knockout (KO) mouse were exposed or not exposed to oxyhemoglobin (OxyHb). Then the DNA-binding activity of transcription factor nuclear factor-κB (NF-κB) was detected by EMSA. The expression of TNF-α, IL-1β, IL-6 and MMP9 were evaluated. The activity of MMP9 was measured by Gelatin zymography. After exposure to OxyHb, NF-κB was activated and the expression of downstream pro-inflammatory cytokines was up-regulated in astrocytes. And such up-regulation was much higher in KO astrocytes than in WT astrocytes, which means more aggravated inflammation in Nrf2 deficient astrocytes. These results suggest that astrocytes participate in inflammatory process after SAH and the absence of Nrf2 may induce more aggressive inflammation through activation of NF-κB pathway.

Inflammatory response plays an important role in the pathogenesis of acute lung injury (ALI) after traumatic brain injury (TBI). Nuclear factor erythroid 2-related factor 2 (Nrf2) is a key transcription factor that plays a crucial role in cytoprotection against inflammation. The present study explored the influence of Nrf2 genotype on the production of cytokines and on activation of transcription factors in a murine TBI model. Wild-type Nrf2 (+/+) and Nrf2 (-/-) deficient mice were subjected to a moderately severe weight-drop impact-acceleration head injury. Lung wet/dry weight ratio, tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta), interleukin-6 (IL-6), intercellular adhesion molecule-1 (ICAM-1), and nuclear factor kapp-aB (NF-kappaB) were investigated at 24 hr after TBI. Nrf2 (-/-) mice were shown to have a greater increase in the lung wet/dry weight ratio compared to their wild-type Nrf2 (+/+) counterparts after TBI. This exacerbation of lung injury in Nrf2 (-/-) mice was associated with increased levels of TNF-alpha, IL-1beta, IL-6, ICAM-1, and their mediator, NF-kappaB. The results suggest that Nrf2 plays an important protective role in attenuating the pulmonary inflammatory response and NF-kappaB activation after TBI.

Vascular inflammation triggers the development of thoracic aortic dissection (TAD). Zinc deficiency could dampen tissue inflammation. However, the role of zinc as a nutritional intervention in the progression of TAD remains elusive. In this study, we employed a classical β-aminopropionitrile monofumarate (BAPN)-induced TAD model in mice treated with low zinc and observed that the TAD progression was greatly ameliorated under low zinc conditions. Our results showed that low zinc could significantly improve aortic dissection and rupture (BAPN + low zinc vs. BAPN, 36% vs. 100%) and reduce mortality (BAPN + low zinc vs. BAPN, 22% vs. 57%). Mechanically, low zinc attenuated the infiltration of macrophages and inhibited the expression of inflammatory cytokines, suppressed the phenotype switch of vascular smooth muscle cells from contractile to synthetic types, and eventually alleviated the development of TAD. In conclusion, this study suggested that low zinc may serve as a potential nutritional intervention approach for TAD prevention. [ABSTRACT FROM AUTHOR]

Skeletal muscle atrophy is an important characteristic of cachexia, which can be induced by chemotherapy and significantly contributes to functional muscle impairment. Inflammation and oxidative stress are believed to play important roles in the muscle atrophy observed in cachexia, but whether programmed cell death protein 1 (PD-1) is affected by this condition remains unclear. PD-1 is a membrane protein that is expressed on the surface of many immune cells and plays an important role in adaptive immune responses and autoimmunity. Thus, we investigated the role and underlying mechanism of PD-1 in cisplatin-induced muscle atrophy in mice. We found that PD-1 knockout dramatically contributed to skeletal muscle atrophy. Mechanistically, we found that E3 ubiquitin-protein ligases were significantly increased in PD-1 knockout mice after cisplatin treatment. In addition, we found that PD-1 knockout significantly exacerbated cisplatin-induced skeletal muscle inflammation and oxidative stress. Moreover, we found that there were significant increases in ferroptosis-related and autophagy-related genes in PD-1 knockout mice after cisplatin treatment. These data indicate that PD-1 plays an important role in cisplatin-induced skeletal muscle atrophy. [ABSTRACT FROM AUTHOR]

Several studies show that the immunosuppressive drugs targeting the interleukin-6 (IL-6) receptor, including tocilizumab, ameliorate lethal inflammatory responses in COVID-19 patients infected with SARS-CoV-2. Here, by employing single-cell analysis of the immune cell composition of two severe-stage COVID-19 patients prior to and following tocilizumab-induced remission, we identify a monocyte subpopulation that contributes to the inflammatory cytokine storms. Furthermore, although tocilizumab treatment attenuates the inflammation, immune cells, including plasma B cells and CD8+ T cells, still exhibit robust humoral and cellular antiviral immune responses. Thus, in addition to providing a high-dimensional dataset on the immune cell distribution at multiple stages of the COVID-19, our work also provides insights into the therapeutic effects of tocilizumab, and identifies potential target cell populations for treating COVID-19-related cytokine storms. Tocilizumab has been used to treat the excessive inflammatory responses in COVID-19 patients. Here, the authors use single-cell RNA sequencing results from two severe COIVD-19 patients to provide high-dimensional immune profiling data, and to implicate potential cellular and molecular insights for the therapeutic effects of tocilizumab. [ABSTRACT FROM AUTHOR]

Background: We previously showed that mice lacking MΦLRP1-/- (low-density lipoprotein receptor-related protein 1 in macrophages) undergo accelerated atherosclerotic plaque formation due to changes in macrophages including increased apoptosis, decreased efferocytosis, and exaggerated transition to the inflammatory M1 phenotype. Here we sought to explore the role of macrophage low-density lipoprotein receptor-related protein 1 during regression of atherosclerosis since regressing plaques are characterized by transitioning of macrophages to M2 status as inflammation resolves.Methods: Apolipoprotein E-/- mice on a high-fat diet for 12 weeks were reconstituted with bone marrow from apolipoprotein E-producing wild-type or MΦLRP1-/- mice, and then placed on a chow diet for 10 weeks (n=9 to 11 mice/group). A cohort of apolipoprotein E-/- mice reconstituted with apolipoprotein E-/- bone marrow served as baseline controls (n=9).Results: Plaques of both wild-type and MΦLRP1-/- bone marrow recipients regressed compared with controls (11% and 22%, respectively; P<0.05), and plaques of MΦLRP1-/- recipients were 13% smaller than those of wild-type recipients ( P<0.05). Recipients of MΦLRP1-/- marrow had 36% fewer M1 macrophages ( P<0.01) and 2.5-fold more CCR7 (C-C chemokine receptor type 7)-positive macrophages in the plaque relative to wild-type mice ( P<0.01). Additionally, in vivo studies of cellular egress showed a 4.6-fold increase in 5-ethynyl-2´-deoxyuridine-labeled CCR7+ macrophages in mediastinal lymph nodes. Finally, in vivo studies of reverse cholesterol transport showed a 1.4-fold higher reverse cholesterol transport in MΦLRP1-/- recipient mice ( P<0.01).Conclusions: Absence of macrophage low-density lipoprotein receptor-related protein 1 unexpectedly accelerates atherosclerosis regression, enhances reverse cholesterol transport, and increases expression of the motility receptor CCR7, which drives macrophage egress from lesions. [ABSTRACT FROM AUTHOR]

Background and aims Gut microbiota plays a major role in metabolic disorders. Berberine is used to treat obesity, diabetes and atherosclerosis. The mechanism underlying the role of berberine in modulating metabolic disorders is not fully clear because berberine has poor oral bioavailability. Thus, we evaluated whether the antiatherosclerotic effect of berberine is related to alterations in gut microbial structure and if so, whether specific bacterial taxa contribute to the beneficial effects of berberine. Methods Apoe −/− mice were fed either a normal-chow diet or a high-fat diet (HFD). Berberine was administered to mice in drinking water (0.5 g/L) for 14 weeks. Gut microbiota profiles were established by high throughput sequencing of the V3–V4 region of the bacterial 16S ribosomal RNA gene. The effects of berberine on metabolic endotoxemia, tissue inflammation and gut barrier integrity were also investigated. Results Berberine treatment significantly reduced atherosclerosis in HFD-fed mice. Akkermansia spp. abundance was markedly increased in HFD-fed mice treated with berberine. Moreover, berberine decreased HFD-induced metabolic endotoxemia and lowered arterial and intestinal expression of proinflammatory cytokines and chemokines. Berberine treatment increased intestinal expression of tight junction proteins and the thickness of the colonic mucus layer, which are related to restoration of gut barrier integrity in HFD-fed mice. Conclusions Modulation of gut microbiota, specifically an increase in the abundance of Akkermansia , may contribute to the antiatherosclerotic and metabolic protective effects of berberine, which is poorly absorbed orally. Our findings therefore support the therapeutic value of gut microbiota manipulation in treating atherosclerosis. [ABSTRACT FROM AUTHOR]

Background: This study aimed to investigate whether exogenous hydrogen sulfide (H2S) can protect the RAW264.7 macrophages against the inflammation induced by free fatty acids (FFA) by blunting NLRP3 inflammasome activation via a specific TLR4/NF-κB pathway. Methods: RAW264.7 macrophages were exposed to increasing concentrations of FFA for up to 3 days to induce FFA-induced inflammation. The cells were pretreated with NaHS (a donor of H2S) before exposure to FFA. Cell viability, cell apoptosis, TLR4, NF-κB, NLRP3 inflammasome, IL- 1β, IL-18 and cleaved caspase-3 expression were measured by a combination of MTT assay, ELISA, and immunoblotting. Results: H2S attenuated FFA-induced cell apoptosis, and reduced the expression of NLRP3, ASC, pro-caspase-1, caspase-1, IL- 1β, IL-18 and caspase-3. In addition, H2S inhibited the FFA-induced activation of TLR4 and NF-κB. Furthermore, NLRP3 inflammasome activation was regulated by the TLR4 and NF-κB pathway. Conclusion: The present study demonstrated for the first time that H2S appears to suppress FFA-induced macrophage inflammation and apoptosis by inhibiting the TLR4/ NF-κB pathway and its downstream NLRP3 inflammasome activation. Thus H2S might possess potential in the treatment of diseases resulting from FFA overload like insulin resistance and type diabetes. [ABSTRACT FROM AUTHOR]

In the article titled "Adipose-Derived Stromal Cells Attenuate Adipose Inflammation in Obesity through Adipocyte Browning and Polarization of M2 Macrophages" [[1]], the authors identified error in Figure 5(a) which was introduced during the preparation of the manuscript. REFERENCES 1 Zhang W.-C., Qin F., Wang X.-J., Liu Z.-F., Lin Z., Zeng A., Zhang M.-Z., Yu N.-Z., Long X. Adipose-Derived Stromal Cells Attenuate Adipose Inflammation in Obesity through Adipocyte Browning and Polarization of M2 Macrophages. [Extracted from the article]

Inflammation, demyelination, oligodendrocyte (OLG) death, and axonal degeneration are primary characteristics of multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE). OLGs generate myelin sheaths that surround axons, while damage to OLGs leads to demyelination and neurological functional deficit. Matrine (MAT), a quinolizidine alkaloid derived from the herb Radix Sophorae Flave, has been recently found to effectively ameliorate clinical signs in EAE. Its therapeutic mechanism has, however, not been completely elucidated. In the present study, we found that MAT retarded the disease process, attenuated the clinical severity of EAE rats, ameliorated inflammation and demyelination, and suppressed the apoptosis of OLGs in the central nervous system (CNS) of EAE rats. In addition, MAT markedly blocked increased expression of the proNGF-p75 NTR death signaling complex, which is known to mediate OLG death in EAE animals. At the same time, MAT also prevented a decrease in the levels of NGF and its receptor TrkA, which together mediate the cell survival pathway and differentiation of OLGs. ProNGF, NGF, and the downstream effector proteins play an important role in the growth, differentiation, and apoptosis of OLGs as well as the reparative response to neuronal damage. These findings thus indicate that MAT improves clinical severity of EAE in part by reducing OLG apoptosis via restoring the ratios of proNGF:NGF and the respective receptors p75 NTR :TrkA in vivo. Taken together, these results suggest that MAT may be a promising agent for MS treatment based on its protective effect on OLGs. [ABSTRACT FROM AUTHOR]

Background and Aim Oxidative stress and inflammation play important roles in the progression from simple fatty liver to non-alcoholic steatohepatitis ( NASH). The aim of this work was to investigate whether treatment with hydrogen sulfide ( H2S) prevented NASH in rats through abating oxidative stress and suppressing inflammation. Methods A methionine-choline-deficient ( MCD) diet rat model was prepared. Rats were divided into three experimental groups and fed for 8 weeks as follows: (i) control rats; (ii) MCD-diet-fed rats; (iii) MCD-diet-fed rats treated with NaHS (intraperitoneal injection of 0.1 mL/kg/day of 0.28 mol/L NaHS, a donor of H2S). Results MCD diet impaired hepatic H2S biosynthesis in rats. Treatment with H2S prevented MCD-diet-induced NASH, as evidenced by hematoxylin and eosin staining, reduced apoptosis and activities of alanine aminotransferase and aspartate aminotransferase, and attenuated hepatic fat accumulation in rats. Treatment with H2S abated MCD-diet-induced oxidative stress through reducing cytochrome p4502 E1 expression, enhancing heme oxygenase-1 expression, and suppressing mitochondrial reactive oxygen species formation, and suppressed MCD-diet-induced inflammation through suppressing activated nuclear factor κB signaling and reducing interleukin-6 and tumor necrosis factor α expressions. In addition, treatment of MCD-diet fed rats with H2S had a beneficial modulation on expression profiles of fatty acid metabolism genes in livers. Conclusions Treatment with H2S prevented NASH induced by MCD diet in rats possibly through abating oxidative stress and suppressing inflammation. [ABSTRACT FROM AUTHOR]

CLEC16A, C-type lectin domain family 16, member A was recently found to be associated with inflation process in the autoimmune diseases. In this study, we elucidated the dynamic expression changes and localization of CLEC16A in lipopolysaccharide (LPS)-induced neuroinflammatory processes in adult rats. CLEC16A expression was strongly induced in active astrocytes in inflamed cerebral cortex. In vitro studies indicated that the up-regulation of CLEC16A may be involved in the subsequent astrocyte activation following LPS challenge. And Knock-down of CLEC16A in cultured primary astrocytes by siRNA showed that CLEC16A was required for the activation of astrocytes induced by LPS. Collectively, these results suggested CLEC16A may be important in host defense in astrocyte-mediated immune response. Understanding the cell signal pathway may provide a novel strategy against inflammatory and immune reaction in neuroinflammtion in CNS. [ABSTRACT FROM AUTHOR]

The mortality risk of coronavirus disease 2019 (COVID-19) patients has been linked to the cytokine storm caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Understanding the inflammatory responses shared between COVID-19 and other infectious diseases that feature cytokine storms may therefore help in developing improved therapeutic strategies. Here, we use integrative analysis of single-cell transcriptomes to characterize the inflammatory signatures of peripheral blood mononuclear cells from patients with COVID-19, sepsis, and HIV infection. We identify ten hyperinflammatory cell subtypes in which monocytes are the main contributors to the transcriptional differences in these infections. Monocytes from COVID-19 patients share hyperinflammatory signatures with HIV infection and immunosuppressive signatures with sepsis. Finally, we construct a "three-stage" model of heterogeneity among COVID-19 patients, related to the hyperinflammatory and immunosuppressive signatures in monocytes. Our study thus reveals cellular and molecular insights about inflammatory responses to SARS-CoV-2 infection and provides therapeutic guidance to improve treatments for subsets of COVID-19 patients. [Display omitted] • Integrative analysis of single-cell transcriptomes from three infectious diseases • Hyperinflammatory signatures of monocytes differ in these infections • A "three-stage" model of COVID-19 patients is related to inflammatory signatures Liu et al. perform integrative analysis of single-cell transcriptomes to characterize the inflammatory signatures of peripheral blood mononuclear cells from patients with COVID-19, sepsis, and HIV infection. Analysis of heterogeneity among COVID-19 patients reveals a "three-stage" model, which is related to the hyperinflammatory and immunosuppressive signatures in monocytes. [ABSTRACT FROM AUTHOR]

Background: Gastrointestinal dysfunction could be frequently observed in the patients suffering from SAH. This study test the hypothesis that experimental SAH could induce histopathological changes and inflammatory response associating with NF-κB activation pathway in the gut. Materials and methods: A total of 17 rabbits were randomly divided into two groups: control group (n = 8) and SAH group (n = 9). In the SAH group, the animals were subjected to experimental SAH according to the “two-hemorrhage” method. The histopathological study was performed to detect the intestinal mucosal morphological changes and immunohistochemical study was used to detect the TNF-α and ICAM-1 expressions. NF-κB binding activity was measured using the electrophoretic mobility shift assay. Results: It was demonstrated that some damage changes and leukocytes infiltration occurred in the intestinal mucosa after SAH. More positive cells for TNF-α and ICAM-1 were observed in the SAH group. The NF-κB binding activity in the intestines was significantly increased in the SAH group (P < 0.01). Conclusions: The results of the present study suggest that SAH in the rabbits could induce NF-κB and proinflammatory cytokines activation in the intestine, which is associated with morphological changes. [Copyright &y& Elsevier]

Effective therapies for stroke are still limited due to its complex pathological manifestations. QiShenYiQi (QSYQ), a component-based Chinese medicine capable of reducing organ injury caused by ischemia/reperfusion, may offer an alternative option for stroke treatment and post-stroke recovery. Recently, we reported a beneficial effect of QSYQ for acute stroke via modulation of the neuroinflammatory response. However, if QSYQ plays a role in subacute stroke remains unknown. The pharmacological action of QSYQ was investigated in experimental stroke rats which underwent 90 min ischemia and 8 days reperfusion in this study. Neurological and locomotive deficits, cerebral infarction, brain edema, and BBB integrity were assessed. TMT-based quantitative proteomics were performed to identify differentially expressed proteins following QSYQ treatment. Immunohistochemistry, western blot analysis, RT-qPCR, and ELISA were used to validate the proteomics data and to reveal the action mechanisms. Therapeutically, treatment with QSYQ (600 mg/kg) for 7 days significantly improved neurological recovery, attenuated infarct volume and brain edema, and alleviated BBB breakdown in the stroke rats. Bioinformatics analysis indicated that protein galectin-3 and its mediated inflammatory response was closely related to the beneficial effect of QSYQ. Specially, QSYQ (600 mg/kg) markedly downregulated the mRNA and protein expression levels of galectin-3, TNF-α, and IL-6 in CI/RI brain as well as serum levels of TNF-α and IL-6. Overall, our findings showed that the effective action of QSYQ against the subacute phase of CI/RI occurs partly via regulating galectin-3 mediated inflammatory reaction. [ABSTRACT FROM AUTHOR]

• COS promoted the blood perfusion and neovascularization in hindlimb ischemia of mice. • COS suppressed inflammation and oxidative stress in ischemic hindlimb. • COS improved disbalance of gut microbiota community induced by ischemia. • COS affected the metabolomics in plasma of mice with hindlimb ischemia. This study was designed to explore the effect of Chitosan oligosaccharides (COS) on mouse hindlimb ischemia by femoral artery ligation. Here, we demonstrated that COS treatment statistically promoted the blood perfusion and neovascularization in ischemic hindlimb of mice, accompanied by the suppression of inflammation and oxidative stress. By 16S rDNA gene sequencing, the disbalanced gut microbiota was observed in ischemic mice, while COS treatment, at least in part, restored the abundance changes of some intestinal bacteria at either phylum or genus levels. Based on metabolomics analysis on mouse plasma by UPLC-QTOF-MS, we screened 20 metabolites with the largest responses to ischemia, several of which were markedly reversed by COS. By Spearman's correlation analysis, the changed metabolites might act as a bridge between improved intestinal bacterial structure and alleviated hindlimb ischemia of mice treated by COS. Our studies point towards a potential role of COS in treatment of peripheral ischemia diseases. [ABSTRACT FROM AUTHOR]

Background: This study aimed to investigate whether exogenous hydrogen sulfide (H2S) can protect the RAW264.7 macrophages against the inflammation induced by free fatty acids (FFA) by blunting NLRP3 inflammasome activation via a specific TLR4/NF-κB pathway. Methods: RAW264.7 macrophages were exposed to increasing concentrations of FFA for up to 3 days to induce FFA-induced inflammation. The cells were pretreated with NaHS (a donor of H2S) before exposure to FFA. Cell viability, cell apoptosis, TLR4, NF-κB, NLRP3 inflammasome, IL-1β, IL-18 and cleaved caspase-3 expression were measured by a combination of MTT assay, ELISA, and immunoblotting. Results: H2S attenuated FFA-induced cell apoptosis, and reduced the expression of NLRP3, ASC, pro-caspase-1, caspase-1, IL- 1β, IL-18 and caspase-3. In addition, H2S inhibited the FFA-induced activation of TLR4 and NF-κB. Furthermore, NLRP3 inflammasome activation was regulated by the TLR4 and NF-κB pathway. Conclusion: The present study demonstrated for the first time that H2S appears to suppress FFA-induced macrophage inflammation and apoptosis by inhibiting the TLR4/ NF-κB pathway and its downstream NLRP3 inflammasome activation. Thus H2S might possess potential in the treatment of diseases resulting from FFA overload like insulin resistance and type diabetes.

• 7-O-(2-(Propylamino)-2-oxoethyl) hesperetin (HD-4d), a new synthesized compound in our laboratory. • HD-4d has obvious anti-inflammatory effect in vivo and in vitro. • HD-4d promoted NLRP12 expression in EtOH and lipopolysaccharide (LPS)-induced RAW264.7 cells and alcohol-induced mouse liver. • HD-4d can suppress p -P65 expression through activating NLRP12 expression. Alcoholic liver disease (ALD) is a liver disease caused by long-term heavy drinking. Alcoholic liver injury is a part of alcoholic liver disease. A large number of studies have shown that alcohol metabolism and endotoxin / lipopolysaccharide (LPS) and cycles can cause massive activation of macrophages, leading alcoholic liver injury. Hesperetin is a dihydro-flavonoid extracted from the fruits of Citrus in Rutaceae. It has a variety of pharmacological activities, including antibacterial, anti-inflammatory, antioxidant and so on, but recent studies have shown that hesperetin derivatives have stronger anti-inflammatory effects than hesperetin. In order to improve the anti-inflammatory activity of hesperetin, our group used ethyl-bromoacetate to replace the hydroxyl group at the 7 position of hesperetin to obtain the hesperetin derivative 7-O-(2-(Propylamino)-2-oxoethyl) hesperetin (HD-4d). In this study, we found that HD-4d had hepatoprotective and anti-inflammatory effects on alcoholic liver injury in C57BL/6J mice, and it also had noticeable anti-inflammatory effects in EtOH and LPS-induced RAW264.7 cells. Besides, we found that HD-4d can reduce the expression of inflammatory factors by up-regulating NLRP12 in vivo and in vitro. We found that the expression of NLRP12 was significantly increased in EtOH and LPS-induced RAW264.7 cells compared with the control group. Moreover, the inhibitory effect of HD-4d on inflammation weakened considerably after silencing NLRP12 in RAW264.7 cells. However, when NLRP12 was overexpressed with plasmid pEX-3-NLRP12, the effect of HD-4d on alcohol and LPS induced inflammation was remarkably increased. In addition, further studies indicated that HD-4d inhibited the activation and phosphorylation of the p65 protein by up-regulating NLRP12. In conclusion, HD-4d activated NLRP12 to reduce liver injury and inflammatory response through the NF-кB pathway. [ABSTRACT FROM AUTHOR]

Liver fibrosis, a chronic inflammatory healing reaction, progresses to hepatocirrhosis without effective intervention. Hesperetin derivative (HD-16), a monomer compound derived from hesperitin, exerts anti-inflammatory and hepatoprotective effects against a spectrum of liver diseases. However, the anti-fibrotic potential of HD-16 in liver fibrosis and its underlying mechanism have not yet been elucidated. In this study, we investigated the anti-fibrotic effect of HD-16 on mouse liver fibrosis induced by CCl 4 and on LX-2 cells (human immortalized HSCs) stimulated by TGF-β1, in vivo and in vitro. HD-16 exerted an anti-fibrotic effect via regulation of the AMPK/SIRT3 pathway. Pharmacodynamic results showed that HD-16 alleviated the degree of injury and inflammation in CCl 4 -induced mouse liver fibrosis. Consistently, HD-16 also effectively inhibited the expression of α-SMA, Col1α1, Col3α1, and TIMP-1 in TGF-β1-activated LX-2 cells. Mechanistically, HD-16 promoted SIRT3 expression and activity in fibrotic liver and activated LX-2 cells. Furthermore, SIRT3 depletion attenuated the anti-fibrotic effects of HD-16. Intriguingly, HD-16 increased AMPK phosphorylation, whereas inhibition of SIRT3 expression did not affect AMPK phosphorylation. In contrast, AMPK silencing suppressed SIRT3 expression, suggesting that SIRT3 is a downstream target of AMPK in liver fibrosis. Overall, HD-16 attenuated CCl 4 -induced liver inflammation and fibrosis by activating the AMPK/SIRT3 pathway, and HD-16 may be a potential anti-fibrotic compound in the treatment of liver fibrosis. A schematic model of hesperetin derivative-16 attenuates CCl 4 -induced inflammation and liver fibrosis by activating the AMPK/SIRT3 pathway. Hesperetin derivative-16 alleviates liver injury, inflammation, and fibrogenesis in CCl 4 -induced mouse liver fibrosis and in LX-2 cells (human immortalized HSCs) stimulated by TGF-β1. HD-16 activates the AMPK/SIRT3 pathway in liver fibrosis, and activation of the AMPK/SIRT3 pathway facilitates the anti-fibrotic effect of HD-16. [Display omitted] [ABSTRACT FROM AUTHOR]

Abstract: Background: Inflammatory response has been proven to play a crucial role in the pathophysilogical process after traumatic brain injury (TBI). Myeloid differentiation primary response protein 88 (Myd88) is considered as a vital factor for inflammation and immunity. Therefore, it is essential to know the detailed expression of Myd88 after TBI. However, the expression patterns of Myd88 in patients with TBI remain obscure. Hence, the aim of present study was to investigate the cortical expression of Myd88 in human contused brain. Methods: Nineteen contused brain tissue biopsies were obtained from 19 patients undergoing surgery for brain contusions 3 h–17 d after trauma, and samples of control group were from three patients in the pathway during surgical removal of deep benign tumors. The expression of Myd88 was assessed by quantitative real-time polymerase chain reaction, Western blotting, immunohistochemistry and double immunofluorescent staining, and the messenger RNA (mRNA) levels of tumor necrosis factor-alpha (TNF-α) and interleukin 1beta (IL-1β) were measured by quantitative real-time polymerase chain reaction. Results: The progressively elevated mRNA and protein levels of Myd88 were detected after trauma, with the maximum after 72 h post-injury, and the distribution of Myd88 was found in neurons, astrocytes, and microglia. TNF-α and IL-1β mRNA levels ascended significantly within 12 h, and then descended gradually until after 72 h post-injury. Interestingly, there was a positive relationship between the expression of Myd88 and the proinflammatory cytokine TNF-α. Conclusions: These findings indicated that Myd88 might play an important role in the inflammatory response after human TBI. [Copyright &y& Elsevier]

Abstract: Objective: Atherosclerosis (AS) is widely accepted as an inflammatory disease and monocytes are particularly important in inflammatory immune responses. As an important biomarker of monocytes activation, Siglec-1 is highly expressed on circulating monocytes and atherosclerotic plaques of coronary artery disease (CAD) patients, but the exact role of Siglec-1 has not been elucidated. Methods: M-CSF, INF-α, IFN-γ, TNF-α and ox-LDL alone or in combination were used to stimulate Siglec-1 expression on monocytes, whereas small interfering RNA (si-RNA) or blocking antibody was used to down-regulate Siglec-1. Meanwhile, the role of Siglec-1 in chemokines secretion was determined. Then monocytes from CAD patients or healthy controls were cocultured with CD4+ or CD8+ T cells from a third healthy individual, and lymphocyte proliferation and activation were determined. Results: All the stimuluses could enhance Siglec-1 expression on monocytes in a dose-dependent manner, and M-CSF could synergistically stimulate Siglec-1 expression with ox-LDL. Moreover, the secretion of MCP-1, MIP-1α and MIP-2 were enhanced when Siglec-1 was up-regulated and down to normal level when Siglec-1 was blocked. More importantly, increased Siglec-1 expression on monocytes was related to the increased T cell proliferation and pro-inflammatory cytokines secretion in CAD patients. However, down-regulation of Siglec-1 could attenuate proliferation and activation of cocultured CD4+ and CD8+ T cells. Conclusion: Siglec-1 can promote chemokines and pro-inflammatory cytokines secretion and influence the inflammatory process of AS. [Copyright &y& Elsevier]

• 3-B-RUT ameliorated ALI by attenuating inflammation and oxidative stress in vivo. • 3-B-RUT has high anti-inflammatory activity and low cytotoxicity in vitro. • 3-B-RUT is a better option for employ in pharmaceutical field than RUT. • 3-B-RUT may serve as a possible clinical candidate for ALI treatment. Alcoholic liver disease (ALD) is the most common chronic liver disease worldwide. Currently, there is no definitive treatment for alcohol-induced liver injury (ALI). Inflammatory response and oxidative stress play a crucial role in ALI. Cyclooxygenase 2 (COX-2) can be induced by inflammation and it has been reported that the enhanced expression of COX-2 in alcoholic liver injury. Rutaecarpine (RUT) was extracted from evodia rutaecarpa. RUT has a wide range of pharmacological activities. In order to increase its anti-inflammatory activity, our group introduced sulfonyl group to synthesized the 3-[2-(trifluoromethoxy)benzenesulfonamide]-rutaecarpine (3-B-RUT). In this study, we explored the protective effect of 3-B-RUT on alcoholic liver injury in vivo and in vitro and preliminarily explore its mechanism. Mice ALI model was established according to the chronic-plus-binge ethanol model. Results showed that 3-B-RUT (20 μg/kg) attenuated alcohol-induced liver injury and suppressed liver inflammation and oxidative stress, and the effect was comparable to RUT (20 mg/kg). In vitro results are consistent with in vivo results. Mechanistically, the 3-B-RUT might suppress inflammatory response and oxidative stress by regulating activation of NF-κB/COX-2 pathway. In summary, 3-B-RUT, a derivative of RUT, may be a promising clinical candidate for ALI treatment. [ABSTRACT FROM AUTHOR]

The inflammatory mediator high-mobility group box 1 (HMGB1)-induced signaling pathway has been shown to play an important role in the pathogenesis of multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE). Matrine (MAT), a quinolizidine alkaloid component derived from the root of Sophorae flavescens , has the capacity to effectively suppress EAE. However, the impact of MAT treatment on HMGB1-induced signaling is not known. In the present study, we show that MAT treatment alleviated disease severity of ongoing EAE, reduced inflammatory infiltration and demyelination, and reduced the production of inflammatory factors including TNF-α, IL-6, and IL-1β in the CNS. Moreover, MAT administration significantly reduced the protein and RNA expression of HMGB1 and TLR4 in the spinal cord, particularly in astrocytes and microglia/infiltrating macrophages. The expression of MyD88 and TRAF6, and the phosphorylation of NF-κB p65, was also down-regulated after MAT treatment. In contrast, the level of IκB-α, an inhibitory molecule for NF-κB activation, was significantly increased. Furthermore, the direct inhibitory effect of MAT on HMGB1/TLR4/NF-κB signaling in macrophages was further confirmed in vitro. Taken together, these findings demonstrate that MAT treatment alleviated CNS inflammatory demyelination and activation of astrocytes and microglia/macrophages in EAE rats, and that the mechanism underlying these effects may be closely related to modulation of HMGB1/TLR4/NF-κB signaling pathway. Unlabelled Image • Matrine suppressed inflammation, demyelination and inflammatory cytokines in the CNS of EAE. • Matrine inhibited HMGB1, TLR4 expression in both astrocytes and microglia. • Matrine also inhibited MyD88, TRAF6 expression and NF-κB activation, with upregulated expression of IκB-α, an inhibitory molecule for NF-κB activation in the CNS. [ABSTRACT FROM AUTHOR]