Downregulation Of Proinflammatory Cytokines Research Articles

Histological In Vivo Evaluation of Intense Pulsed Light Technology: Assessing the Safety on Oral Soft and Hard Tissues

Intense pulsed light (IPL) is used for aesthetic and therapeutic purposes. According to recent literature, utilizing IPL may boost upregulation of anti-inflammatory cytokines, and downregulation of pro-inflammatory cytokines. Concerns have been raised about potential thermal damage to the soft and hard tissues in the oral cavity. Therefore, the aim of this study was to determine the safety of using IPL of various intensities in the tissues of the oral cavity. Methods: Three adult pigs were included in the trial. The oral cavity was divided into four quadrants and projected with a wide range of IPL settings. Alveolar bone, buccal mucosa, and gingival tissue samples were taken immediately and after 24 h. In each animal, one quadrant of the jaw was left untreated and served as a control. All samples were processed and stained with H&E. Results: Clinical examination showed no evidence of changes in the integrity of the examined tissues. Histological examination of the different tissues did not demonstrate significant thermal damage or changes in the characterization of the cells compared to the control tissues. Conclusions: The use of IPL in the oral cavity is safe and does not negatively affect the tissues.

Blockage of mechanosensitive Piezo1 channel alleviates the severity of experimental malaria-associated acute lung injury

BackgroundMalaria-associated acute lung injury (MA-ALI) is a well-recognized clinical complication of severe, complicated malaria that is partly driven by sequestrations of infected red blood cells (iRBCs) on lung postcapillary induced impaired blood flow. In earlier studies the mechanosensitive Piezo1 channel emerged as a regulator of mechanical stimuli, but the function and underlying mechanism of Piezo1 impacting MA-ALI severity via sensing the impaired pulmonary blood flow are still not fully elucidated. Thus, the present study aimed to explore the role of Piezo1 in the severity of murine MA-ALI.MethodsHere, we utilized a widely accepted murine model of MA-ALI using C57BL/6 mice with Plasmodium berghei ANKA infection and then added a Piezo1 inhibitor (GsMTx4) to the model. The iRBC-stimulated Raw264.7 macrophages in vitro were also targeted with GsMTx4 to further explore the potential mechanism.ResultsOur data showed an elevation in the expression of Piezo1 and number of Piezo1+-CD68+ macrophages in lung tissues of the experimental MA-ALI mice. Compared to the infected control mice, the blockage of Piezo1 with GsMTx4 dramatically improved the survival rate but decreased body weight loss, peripheral blood parasitemia/lung parasite burden, experimental cerebral malaria incidence, total protein concentrations in bronchoalveolar lavage fluid, lung wet/dry weight ratio, vascular leakage, pathological damage, apoptosis and number of CD68+ and CD86+ macrophages in lung tissues. This was accompanied by a dramatic increase in the number of CD206+ macrophages (M2-like subtype), upregulation of anti-inflammatory cytokines (e.g. IL-4 and IL-10) and downregulation of pro-inflammatory cytokines (e.g. TNF-α and IL-1β). In addition, GsMTx4 treatment remarkably decreased pulmonary intracellular iron accumulation, protein level of 4-HNE (an activator of ferroptosis) and the number of CD68+-Piezo1+ and CD68+-4-HNE+ macrophages but significantly increased protein levels of GPX4 (an inhibitor of ferroptosis) in experimental MA-ALI mice. Similarly, in vitro study showed that the administration of GsMTx4 led to a remarkable elevation in the mRNA levels of CD206, IL-4, IL-10 and GPX-4 but to a substantial decline in CD86, TNF-α, IL-1β and 4-HNE in the iRBC-stimulated Raw264.7 cells.ConclusionsOur findings indicated that blockage of Piezo1 with GsMTx4 alleviated the severity of experimental MA-ALI in mice partly by triggering pulmonary macrophage M2 polarization and subsequent anti-inflammatory responses but inhibited apoptosis and ferroptosis in lung tissue. Our data suggested that targeting Piezo1 in macrophages could be a promising therapeutic strategy for treating MA-ALI.Graphical

P128 Salt-Inducible Kinase 2 is a promising therapeutic target in patients with ulcerative colitis

Abstract Background Salt-Inducible Kinases (SIKs) are a family of 3 serine/threonine kinases which represent promising therapeutic targets in a number of inflammatory diseases including ulcerative colitis (UC). Their catalytic activity is highly phosphoregulated in response to changes in cellular homeostasis. Inactivation of SIKs results in proinflammatory cytokine downregulation and the concomitant upregulation of anti-inflammatory IL-10. Of the three isozymes, SIK2 is the most active in myeloid cells and is thought to be the key driver of IL-10 production. Selective pharmacological inhibition of SIKs has thus far proved challenging: a number of SIK inhibitors have previously been developed and whilst they have demonstrated biological activity in UC, dosing has been limited due to potential side effects underlining the need for improved selectivity. We hypothesized that more selective inhibition of SIK2 represents a promising approach in ulcerative colitis. Methods We sought to examine the effects of inhibiting SIK2 with a potent small molecule in both in vitro cell cultures and in ex vivo biopsies from UC patients. CD14+ monocytes were isolated from donor PBMCs and differentiated into hMDMs (monocyte-derived macrophages) and moDCs (monocyte-derived DCs). Cultures were treated with compound followed by LPS stimulation for 4 hours (hMDMs) or maturation for 48 hours (moDCs). To recapitulate the disease microenvironment ex vivo, a colonic explant culture model was used: colonic biopsies were collected from patients with active (Mayo 1 /2) and inactive UC and cultured in the presence of compound or control for 24-48h. Supernatants were assayed for cytokine and chemokine release. Cells or biopsies were lysed for qPCR. Surface markers were assessed by flow cytometry Results Using more SIK2-selective small molecules, we show that SIK inhibition modulates inflammatory and immunometabolic pathways in human myeloid cells. Furthermore, SIK2 inhibition drives a tolerogenic phenotype in dendritic cells, as demonstrated by suppression of proinflammatory cytokines and chemokines such as TNFα and the CC/CXC chemokine family as well as downregulation of activation markers such as CD80 and 83; functionally these modulated DCs can suppress Th1 CD4 T cell IFNγ production. Modulation of cytokine and chemokine production by SIK2 inhibition was also observed in colonic explant cultures from UC patients with a reduction in levels of TNFα and the CC chemokine family. Conclusion In both myeloid cellular cultures and UC biopsies, SIK2 inhibition modulates an inflammatory environment into a pro-resolution state supporting the therapeutic potential of SIK2 inhibition in UC.

Hypidone hydrochloride (YL-0919) protects mice from meningitis via Sigma1R-STAT1-NLRP3-GSDMD pathway

BackgroundA growing number of studies have found that antidepressants have anti-inflammatory effects while protecting nerves. Hypidone hydrochloride (YL-0919) is a novel highly selective 5-HT reuptake blocker. Our previous studies have demonstrated that YL-0919 exerts notable antidepressant- and anxiolytic-like as well as procognitive effects. However, whether YL-0919 can be used to treat inflammatory and infectious diseases remain unknown. In this study, we aimed to verify the anti-inflammatory effect of YL-0919 on bacterial meningitis and further explore the potential molecular mechanisms. MethodsWe performed the experiments on pneumococcal meningitis mice in vivo and S. pneumoniae infected macrophages/microglia in vitro, with or without YL-0919 treatment.Cognitive function was evaluated by open-field task, Morris water maze test, and novel object recognition test. Histopathological staining and immunofluorescence staining were used to detect the pathological damage of meningitis and NLRP3 inflammasome activation in microglia/macrophages. The expression of the STAT1/NLRP3/GSDMD signal pathway was measured by western blots. Proinflammatory cytokines associated with pyroptosis were detected by ELISA. ResultsYL-0919 protected mice from fatal pneumococcal meningitis, characterized by attenuated cytokine storms, decreased bacterial loads, improved neuroethology, and reduced mortality. NLRP3 plays a key role in the regulation of inflammation. When the underlying mechanisms were investigated, we found that YL-0919 inhibited the activation of NLRP3 via STAT1, and thus inhibited macrophages/microglia pyroptosis, resulting in downregulation of proinflammatory cytokines. In addition, Sigma1R was identified as a pivotal receptor that can be engaged by YL-0919 to inhibit NLRP3 activation and pyroptosis pathway in microglia/macrophages. ConclusionsThese results provide new insights into the mechanisms of inflammation regulation mediated by the antidepressant YL-0919. Moreover, targeting the STAT1/NLRP3 pyroptosis pathway is a promising strategy for the treatment of infectious diseases like bacterial meningitis.

Wheat Bran Polyphenols Ameliorate DSS-Induced Ulcerative Colitis in Mice by Suppressing MAPK/NF-κB Inflammasome Pathways and Regulating Intestinal Microbiota.

Wheat bran (WB) is the primary by-product of wheat processing and contains a high concentration of bioactive substances such as polyphenols. This study analyzed the qualitative and quantitative components of polyphenols in wheat bran and their effects on ulcerative colitis (UC) using the dextran sulfate sodium (DSS)-induced colitis model in mice. The potential mechanism of wheat bran polyphenols (WBP) was also examined. Our findings indicate that the main polyphenol constituents of WBP were phenolic acids, including vanillic acid, ferulic acid, caffeic acid, gallic acid, and protocatechuic acid. Furthermore, WBP exerted remarkable protective effects against experimental colitis. This was achieved by reducing the severity of colitis and improving colon morphology. Additionally, WBP suppressed colonic inflammation via upregulation of the anti-inflammatory cytokine IL-10 and downregulation of pro-inflammatory cytokines (TNF-α, IL-6, IL-1β) in colon tissues. Mechanistically, WBP ameliorated DSS-induced colitis in mice by inhibiting activation of the MAPK/NF-κB pathway. In addition, microbiome analysis results suggested that WBP modulated the alteration of gut microbiota caused by DSS, with an enhancement in the ratio of Firmicutes/Bacteroidetes and adjustments in the number of Helicobacter, Escherichia-Shigella, Akkermansia, Lactobacillus, Lachnospiraceae_NK4A136_group at the genus level. To conclude, the findings showed that WBP has excellent prospects in reducing colonic inflammation in UC mice.

Modulatory effects of fermented Polygonatum cyrtonema Hua on immune homeostasis and gut integrity in a dextran-sulfate-sodium-induced colitis model.

The gut health-promoting properties of saponin-rich Polygonatum cyrtonema Hua (FP) fermented with Lactobacillus plantarum P9 were explored in a dextran sulfate sodium (DSS)-induced colitis mouse model. FP supplementation effectively inhibited DSS-induced physiological alteration and impaired immune responses by reducing the disease activity index (DAI) score and restoring the T helper (Th) 1/Th2 and regulatory T (Treg)/Th17 ratios. In addition, FP supplementation protected the gut barrier function against DSS-induced damage via upregulation of zonula occludens (ZO)-1 and occludin and downregulation of pro-inflammatory cytokines, including interleukin (IL)-1β, tumor necrosis factor-α (TNF-α), IL-18, and the granulocyte-macrophage colony-stimulating factor (GM-CSF). This study further elucidated the potential mechanisms underlying the FP-mediated suppression of the plasticity of type 3 innate lymphoid cells (ILC3) and subsequent macrophage polarization. Therefore, the FP supplementation effectively restored mucosal immune homeostasis and enhanced gut integrity. In addition, it suppressed the growth of Escherichia-Shigella and Enterococcus and promoted the enrichment of probiotics and short-chain fatty acid-producing microbes, such as Romboutsia, Faecalibaculum, and Blautia. In conclusion, P. cyrtonema Hua fermented with L. plantarum P9 might be a promising dietary intervention to improve gut health by sustaining overall gut homeostasis and related gut integrity.

Consumption of honey ameliorates lipopolysaccharide-induced intestinal barrier dysfunction via upregulation of tight junction proteins.

The leaky gut barrier is an important factor leading to various inflammatory gastrointestinal disorders. The nutritional value of honey and variety of its health benefits have long been recognized. This study was undertaken to assess the role of Indian mustard honey in preventing lipopolysaccharide (LPS)-induced intestinal barrier dysfunction using a combination of in vitro and in vivo experimental model systems. LPS was used to induce intestinal barrier damage in a trans-well model of Caco-2 cells (1µg/ml) and in Swiss albino mice (5mg/kg body weight). Gas chromatography-mass spectrometry (GC-MS) and liquid chromatography-mass spectrometry (LC-MS) were used to analyse sugar and phenolic components in honey samples. The Caco-2 cell monolayer integrity was evaluated by transepithelial electrical resistance (TEER) and paracellular permeability assays. The histopathology of intestinal tissue was analysed by haematoxylin and eosin dual staining. The quantitative reverse transcription-polymerase chain reaction (qRT-PCR) was used to quantify the transcription of genes. The protein expression was analysed by immunofluorescence, western blot and ELISA-based techniques. The in vitro data showed that honey prevented LPS-induced intestinal barrier dysfunction dose dependently as was measured by TEER and paracellular flux of FITC-dextran dye. Further, the in vivo data showed a prophylactic effect of orally administered honey as it prevented the loss of intestinal barrier integrity and villus structure. The cellular localization and expression of tight junction (TJ) proteins were upregulated along with downregulation of pro-inflammatory cytokines in response to the administration of honey with LPS. The findings of this study suggest a propitious role of honey in the maintenance of TJ protein integrity, thereby preventing LPS-induced intestinal barrier disintegration.

Jaceosidin protects L929 fibroblast cells by down-regulation of proinflammatory cytokines and attenuation of oxidative stress-induced impairment of cell proliferation and migration

Jaceosidin protects L929 fibroblast cells by down-regulation of proinflammatory cytokines and attenuation of oxidative stress-induced impairment of cell proliferation and migration

Integrating human iPSC-derived macrophage progenitors into retinal organoids to generate a mature retinal microglial niche.

In the retina, microglia are resident immune cells that are essential for development and function. Retinal microglia play a central role in mediating pathological degeneration in diseases such as glaucoma, retinitis pigmentosa, age-related neurodegeneration, ischemic retinopathy, and diabetic retinopathy. Current models of mature human retinal organoids (ROs) derived from iPS cell (hiPSC) do not contain resident microglia integrated into retinal layers. Increasing cellular diversity in ROs by including resident microglia would more accurately represent the native retina and better model diseases in which microglia play a key role. In this study, we develop a new 3D in vitro tissue model of microglia-containing retinal organoids by co-culturing ROs and hiPSC-derived macrophage precursor cells (MPCs). We optimized the parameters for successful integration of MPCs into retinal organoids. We show that while in the ROs, MPCs migrate to the equivalent of the outer plexiform layer where retinal microglia cells reside in healthy retinal tissue. While there, they develop a mature morphology characterized by small cell bodies and long branching processes which is only observed in vivo. During this maturation process these MPCs cycle through an activated phase followed by a stable mature microglial phase as seen by the down regulation of pro-inflammatory cytokines and upregulation of anti-inflammatory cytokines. Finally, we characterized mature ROs with integrated MPCs using RNAseq showing an enrichment of cell-type specific microglia markers. We propose that this co-culture system may be useful for understanding the pathogenesis of retinal diseases involving retinal microglia and for drug discovery directly in human tissue.

The angiotensin receptor neprilysin inhibitor LCZ696 attenuates renal fibrosis via ASK1/JNK/p38 MAPK-mediated apoptosis in unilateral ureteral obstruction.

The angiotensin receptor neprilysin inhibitor LCZ696 affords superior cardioprotection and renoprotection compared with renin-angiotensin blockade monotherapy, but the underlying mechanisms remain elusive. Herein, we evaluated whether LCZ696 attenuates renal fibrosis by inhibiting ASK1/JNK/p38 mitogen-activated protein kinase (MAPK)-mediated apoptosis in a rat model of unilateral ureteral obstruction (UUO) and in vitro. Rats with UUO were treated daily for 7 days with LCZ696, valsartan, or the selective ATP competitive inhibitor of apoptosis signal-regulating kinase 1 (ASK1), GS-444217. The effects of LCZ696 on renal injury were examined by assessing the histopathology, oxidative stress, intracellular organelles, apoptotic cell death, and MAPK pathways. H2O2-exposed human kidney 2 (HK-2) cells were also examined. LCZ696 and valsartan treatment significantly attenuated renal fibrosis caused by UUO, and this was paralleled by downregulation of proinflammatory cytokines and decreased inflammatory cell influx. Intriguingly, LCZ696 had stronger effects on renal fibrosis and inflammation than valsartan. UUO-induced oxidative stress triggered mitochondrial destruction and endoplasmic reticulum stress, which resulted in apoptotic cell death; these effects were reversed by LCZ696. Both GS-444217 and LCZ696 hampered the expression of death-associated ASK1/JNK/p38 MAPKs. In H2O2-treated HK-2 cells, LCZ696 and GS-444217 increased cell viability but decreased the production of intracellular reactive oxygen species and MitoSOX and apoptotic cell death. Both agents also deactivated H2O2-stimulated activation of ASK1/JNK/p38 MAPKs. These findings suggest that LCZ696 protects against UUO-induced renal fibrosis by inhibiting ASK1/JNK/p38 MAPK-mediated apoptosis.

Mechanism of regulatory T cells in heat stroke-induced acute kidney injury

To investigate the mechanism of regulatory T cells (Treg) in heat stroke (HS)-induced acute kidney injury (AKI). Male SPF Balb/c mice were randomly divided into control group, HS group (HS+Rat IgG), HS+PC61 group, and HS+Treg group (n = 6). The HS mice model was established by making the body temperature of the mice reach 42.7 centigrade at room temperature 39.5 centigrade with relative humidity 60% for 1 hour. In HS+PC61 group, 100 μg PC61 antibody (anti-CD25) was injected through the tail vein in consecutive 2 days before the model was established to eliminate Tregs. Mice in HS+Treg group was injected with 1×106 Treg via tail vein immediately after successful modeling. The proportion of Treg infiltrated in the kidney, serum creatinine (SCr) and histopathology, levels of interferon-γ (IFN-γ) and tumor necrosis factor-α (TNF-α) both in the serum and kidney tissue, as well as proportion of neutrophils and macrophages located in the kidney were observed at 24 hours after HS. HS dampened renal function and exaggerated kidney injury, up-regulated levels of inflammatory cytokines both in local kidney and circulation, and increased infiltration of neutrophils and macrophages to the injured kidneys. The proportion of Treg (Treg/CD4+) infiltrated in kidney was significantly decreased in HS group, compared with control group [(3.40±0.46)% vs. (7.67±0.82)%, P < 0.01]. Compared with HS group, local Tregs in kidney were almost completely depleted via PC61 antibody [(0.77±0.12)% vs. (3.40±0.46)%, P < 0.01]. Depletion of Tregs could exacerbate HS-AKI, indicating by increased serum creatinine [SCr (mmol/L): 348.22±35.36 vs. 254.42±27.40, P < 0.01] and pathological injury (Paller score: 4.70±0.20 vs. 3.60±0.20, P < 0.01), incremental levels of IFN-γand TNF-α both in injured kidney and serum [serum IFN-γ (ng/L): 747.70±64.52 vs. 508.46±44.79, serum TNF-α (ng/L): 647.41±26.62 vs. 464.53±41.80, both P < 0.01], and more infiltrated neutrophils and macrophages in the injured kidney [neutrophil proportion: (6.63±0.67)% vs. (4.37±0.43)%, macrophage proportion: (38.70±1.66)% vs. (33.19±1.55)%, both P < 0.01]. On the contrast, adoptive transfer of Tregs could reverse the aforementioned effects of Treg depletion, indicating by incremental proportion of Tregs in the injured kidney [(10.58±1.19)% vs. (3.40±0.46)%, P < 0.01], decreased serum creatinine [SCr (mmol/L): 168.24±40.56 vs. 254.42±27.40, P < 0.01] and pathological injury (Paller score: 2.73±0.11 vs. 3.60±0.20, P < 0.01), reduced levels of IFN-γ and TNF-α both in injured kidney and serum [serum IFN-γ (ng/L): 262.62±22.68 vs. 508.46±44.79, serum TNF-α (ng/L): 206.41±22.58 vs. 464.53±41.80, both P < 0.01], and less infiltrated neutrophils and macrophages in the injured kidney [neutrophil proportion: (3.04±0.33)% vs. (4.37±0.43)%, macrophage proportion: (25.68±1.93)% vs. (33.19±1.55)%, both P < 0.01]. Treg might be involved in HS-AKI, possibly via down-regulation of pro-inflammatory cytokines and infiltration of inflammatory cells.

Nonreleasing AgNP Colloids Composite Hydrogel with Potent Hemostatic, Photodynamic Bactericidal and Wound Healing-Promoting Properties.

Reactive oxygen species (ROS) produced by noble metallic nanoparticles under visible light is an effective way to combat drug-resistant bacteria colonized on the wound. However, the photocatalytic efficiency of noble metallic nanoparticles is limited by its self-aggregation in water media. Moreover, the fast release of noble metallic ions from nanoparticles might engender cellular toxicity and hazardous environmental issues. Herein, we chose AgNPs, the most common plasmonic noble metallic nanoparticles, as an example, modifying the surface of AgNPs with oleic acid and n-butylamine and imbedded them into calcium alginate (CA) hydrogel that holds tissue adhesion, rapid hemostatic, sunlight-sensitive antibacterial and anti-inflammatory abilities, and thus effectively promotes the healing of wounds. Unlike conventional AgNP-based materials, the constrain of colloids and hydrogel networks hinders the leach of Ag+. Nonetheless, the CA/Ag hydrogels exhibit on-demand photodynamic antibacterial efficacy due to the generation of ROS under visible light. In addition, the CA/Ag hydrogel can effectively stop the hemorrhage in a mouse liver bleeding model due to their skin-adaptive flexibility and tissue adhesiveness. The potent sunlight-responsive antibacterial activity of the CA/Ag hydrogel can effectively kill multidrug-resistant bacteria both in vitro (>99.999%) and in vivo (>99.9%), while the diminished Ag+ release guarantees its biocompatibility. The CA/Ag hydrogel significantly promotes the wound healing process by the downregulation of proinflammatory cytokines (TNF-α and IL-6) in a rodent full-thickness cutaneous wound model. Overall, the proposed multifunctional CA/Ag nanocomposite hydrogel has excellent prospects as an advanced wound dressing.

The protective effects of apple pectin and citrus pectins on post-cerebral I/R depression in mice: The role of NF-κB-p65 and pSTAT3 pathways

One of the serious consequences of brain stroke is depression, which affects a large number of patients. Finding new compounds that have antidepressant properties in these conditions can be very important. Therefore, in the present study, the antidepressant effects of apple pectin (AP) and citrus pectin (CP) in mice after induction of cerebral ischemia were studied. Seven days before transient middle cerebral artery occlusion (tMCAO) and three days thereafter, mice were given orally AP and CP by gavage (50 and 100 mg/kg). Forced swim test (FST), inclined beam-walking test and open field test were used to evaluate the behaviors of mice. Levels of IL-1β, INF-γ, TNF-α, IL-6 NF-κB-p65 and pSTAT3 were studied using enzyme-linked immunosorbent assay (ELISA) and the gene expressions of NF-κB-p65 and pSTAT3 were studied by qRT-PCR. Induction of cerebral I/R injury resulted in depressive-like behaviors in mice, which were confirmed by FST, inclined beam-walking test and OFT. However, beneficial effects of AP and CP were observed in reducing depressive-like behaviors in mice. The downregulation of proinflammatory cytokines and NF-κB-p65 and pSTAT3 proteins were observed as a result of oral AP and CP administration in cerebral I/R mice. AP and CP have antidepressant-like effects on cerebral I/R- induced depression due to reduced inflammation in the brain hippocampus.

Effects of fatty acid-ethanol amine (FA-EA) derivatives on lipid accumulation and inflammation.

This study aimed to investigate the effect of fatty acid-ethanol amine (FA-EA) derivatives (L1-L10) on the mitigation of intracellular lipid accumulation and downregulation of pro-inflammatory cytokines in vitro. First, the series of FA-EA derivatives were synthesized and characterized. Then, their cytotoxic, intracellular lipid accumulation and inhibition of pro-inflammatory cytokines were evaluated. The oil red O staining experiment showed that the tested compounds L4, L6, L8, L9, and L10 could reduce intracellular lipid accumulation induced by palmitic acid (PA). Moreover, ω-3/ω-6 PUFA-EA derivatives showed inhibitory effect on the production of pro-inflammatory cytokines in lipopolysaccharide (LPS) -stimulated RAW 264.7 cells. ω-3/ω-6 PUFA-EA derivatives at a concentrations of 10μM could significantly decrease mRNA levels of IL-6, IL-1β, and TNF-α, inhibit NO production, and alleviate the protein expression of IL-1β in lipopolysaccharide (LPS)-stimulated RAW 264.7 cells. These data suggest that ω-3 PUFA-EA derivatives can be beneficial for further pharmaceutical development to treat chronic low-grade inflammation diseases such as obesity.

Ibudilast ameliorates experimentally induced colitis in rats via down-regulation of proinflammatory cytokines and myeloperoxidase enzyme activity

Objectives: This study was carried out to explore the possible anti-inflammatory effect of ibudilast on acetic acid-induced colitis in rats. Methods: Fifty adult Wistar rats were separated into 5 groups, including the control group, acetic acid group, acetic acid + vehicle, acetic acid + sulfasalazine (100 mg/kg/day)group, and acetic acid + ibudilast (30 mg/kg/day) group. Colitis was induced in rats by the inter-rectal installation of 2 ml of 4% (v/v) acetic acid. Sulfasalazine and ibudilast were administered orally for ten days after 2 hours of induction. Results: The treatment with ibudilast significantly reduced disease activity index (DAI), macroscopic colonic scores (MAC), and histopathological changes induced by acetic acid. Also, ibudilast markedly decreased the expression of proinflammatory markers (TNF-α and IL-1β) in colonic tissue. Moreover, ibudilast inhibited myeloperoxidase (MPO) enzyme activity that was increased by acetic acid. Conclusion: Therefore, ibudilast may have a therapeutic effect in the management of ulcerative colitis.

A critical review of belumosudil in adult and pediatric patients with chronic graft-versus-host disease

ABSTRACT Introduction Chronic graft-versus-host disease (cGVHD) is a complication of allogeneic hematopoietic cell transplantation (allo-HCT) and is the main cause of late non-relapse mortality (NRM). Three new agents are now approved to treat cGVHD, of which belumosudil has a unique and dual mechanism of action of i) targeting the Rho-GTPase-associated coiled-coil kinase 2 (ROCK2) in T helper follicular cells (TFH) and TH17 cells, this results in downregulation of proinflammatory cytokines (interleukin −21 and 17), the former in a STAT3-dependent mechanism, ii) inhibition of tissue fibrosis by targeting stress-induced polymerization of G-actin fibrils by inhibiting the Rho-ROCK-MRTF pathway. Areas covered In this review we describe the epidemiology of cGVHD, its cardinal symptoms, preventive and therapeutic options, including second-line approved therapies in the United States (US). Clinical trial data that led to approval of belumosudil is discussed, in addition to the clinical scenarios in which the approved drugs may be most applicable. Expert opinion Belumosudil is approved for treatment of adult and pediatric patients ≥ 12 years with cGVHD after failing two lines of therapy based on results of the ROCKstar study that showed high overall response rates (ORR), favorable adverse effect profiles, and low rates of severe infections. With the availability of three new agents for treatment of cGVHD, treating physicians have more therapeutic options for patients and have additional options of development new clinical trials using a combination of recently approved drugs.

β-Hydroxybutyrate alleviates pyroptosis in MPP+/MPTP-induced Parkinson's disease models via inhibiting STAT3/NLRP3/GSDMD pathway.

Parkinson's disease (PD) is a common neurodegenerative disease characterized by motor symptoms and non-motor symptoms, and affects millions of people worldwide. Growing evidence implies β-Hydroxybutyrate (BHB), one of the ketone bodies generated by ketogenesis, plays a neuroprotective role in neurodegenerative diseases. We aimed to verify the anti-inflammatory effect of BHB on PD and further explore potential molecular mechanisms. We performed the experiments on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced mice model in vivo and 1-methyl-4-phenylpyridinium (MPP+)-simulated BV2 cell model in vitro, with or without BHB pretreatment. Motor function was assessed by pole test, forced swimming test, traction test and open field test. Immunofluorescence was used to evaluate the loss of dopaminergic neurons and glial cell activation in MPTP-induced PD model mice. The expression of the STAT3/NLRP3/GSDMD signal pathway was measured by western blots. Proinflammatory cytokines was assessed by enzyme-linked immunosorbent assay (ELISA). BHB treatment reversed motor deficits, loss of dopaminergic neurons and glial cell activation in PD mice induced by MPTP. Moreover, BHB inhibited microglia pyroptosis by negatively regulating STAT3/NLRP3/GSDMD signal pathway, resulting in downregulation of proinflammatory cytokines (IL-1β and IL-18) in vivo and vitro. These data suggested BHB supplement inhibited pyroptosis by down-regulating STAT3-mediated NLRP3 inflammasome activation for PD models in vivo and in vitro. Our findings provided novel insights and available interventions for the prevention and treatment of PD, and highlighted pyroptosis as a potential therapeutic target for PD.

Vaginal microbiome-host interactions modeled in a human vagina-on-a-chip

BackgroundA dominance of non-iners Lactobacillus species in the vaginal microbiome is optimal and strongly associated with gynecological and obstetric health, while the presence of diverse obligate or facultative anaerobic bacteria and a paucity in Lactobacillus species, similar to communities found in bacterial vaginosis (BV), is considered non-optimal and associated with adverse health outcomes. Various therapeutic strategies are being explored to modulate the composition of the vaginal microbiome; however, there is no human model that faithfully reproduces the vaginal epithelial microenvironment for preclinical validation of potential therapeutics or testing hypotheses about vaginal epithelium-microbiome interactions.ResultsHere, we describe an organ-on-a-chip (organ chip) microfluidic culture model of the human vaginal mucosa (vagina chip) that is lined by hormone-sensitive, primary vaginal epithelium interfaced with underlying stromal fibroblasts, which sustains a low physiological oxygen concentration in the epithelial lumen. We show that the Vagina Chip can be used to assess colonization by optimal L. crispatus consortia as well as non-optimal Gardnerella vaginalis-containing consortia, and to measure associated host innate immune responses. Co-culture and growth of the L. crispatus consortia on-chip was accompanied by maintenance of epithelial cell viability, accumulation of D- and L-lactic acid, maintenance of a physiologically relevant low pH, and down regulation of proinflammatory cytokines. In contrast, co-culture of G. vaginalis-containing consortia in the vagina chip resulted in epithelial cell injury, a rise in pH, and upregulation of proinflammatory cytokines.ConclusionThis study demonstrates the potential of applying human organ chip technology to create a preclinical model of the human vaginal mucosa that can be used to better understand interactions between the vaginal microbiome and host tissues, as well as to evaluate the safety and efficacy of live biotherapeutics products.AsSRkJhp7GmswS9e3XcXgrVideo

Inhibition Effects of Nippostrongylus brasiliensis and Its Derivatives against Atherosclerosis in ApoE-/- Mice through Anti-Inflammatory Response.

Atherosclerosis (AS) is a dominant and growing cause of death and disability worldwide that involves inflammation from its inception to the emergence of complications. Studies have demonstrated that intervention with helminth infections or derived products could modulate the host immune response and effectively prevent or mitigate the onset and progression of inflammation-related diseases. Therefore, to understand the molecular mechanisms underlying the development of atherosclerosis, we intervened in ApoE-/- mice maintained on a high-fat diet with Nippostrongylus brasiliensis (N. brasiliensis) infection and immunized with its derived products. We found that N. brasiliensis infection and its derived proteins had suitable protective effects both in the initial and progressive stages of atherosclerosis, effectively reducing aortic arch plaque areas and liver lipid contents and downregulating serum LDL levels, which may be associated with the significant upregulation of serum anti-inflammatory cytokines (IL-10 and IL-4) and the down-regulation of proinflammatory cytokines (TNF-α and IFN-γ) in the serum. In conclusion, these data highlighted the effective regulatory role of N. brasiliensis and its derived proteins in the development and progression of atherosclerosis. This could provide a promising new avenue for the prevention and treatment of atherosclerosis.

IRF7 expression correlates with HIV latency reversal upon specific blockade of immune activation.

The persistence of latent HIV reservoirs allows for viral rebound upon antiretroviral therapy interruption, hindering effective HIV-1 cure. Emerging evidence suggests that modulation of innate immune stimulation could impact viral latency and contribute to the clearing of HIV reservoir. Here, the latency reactivation capacity of a subclass of selective JAK2 inhibitors was characterized as a potential novel therapeutic strategy for HIV-1 cure. Notably, JAK2 inhibitors reversed HIV-1 latency in non-clonal lymphoid and myeloid in vitro models of HIV-1 latency and also ex vivo in CD4+ T cells from ART+ PWH, albeit its function was not dependent on JAK2 expression. Immunophenotypic characterization and whole transcriptomic profiling supported reactivation data, showing common gene expression signatures between latency reactivating agents (LRA; JAK2i fedratinib and PMA) in contrast to other JAK inhibitors, but with significantly fewer affected gene sets in the pathway analysis. In depth evaluation of differentially expressed genes, identified a significant upregulation of IRF7 expression despite the blockade of the JAK-STAT pathway and downregulation of proinflammatory cytokines and chemokines. Moreover, IRF7 expression levels positively correlated with HIV latency reactivation capacity of JAK2 inhibitors and also other common LRAs. Collectively, these results represent a promising step towards HIV eradication by demonstrating the potential of innate immune modulation for reducing the viral reservoir through a novel pathway driven by IRF7.