Mild Inflammation Research Articles

Th17/Treg balance is regulated by myeloid-derived suppressor cells in experimental autoimmune myocarditis.

Autoimmune myocarditis is caused by both innate and adaptive immune responses. Many studies have found that myeloid-derived suppressor cells (MDSCs) suppress T-cell responses and reduce immune tolerance, while MDSCs may serve as a key player in inflammatory responses and pathogenesis in variety of autoimmune diseases. However, research into the role of MDSCs in experimental autoimmune myocarditis (EAM) remains lacking. We discovered that the expansion of MDSCs in EAM was closely related to the severity of myocardial inflammation. At an early stage of EAM, both adoptive transfer (AT) and selective depletion of MDSCs could inhibit the expression of IL-17 in CD4+ cells and downregulate the Th17/Treg ratio, alleviating excessive inflammation of EAM myocarditis. In another experiment, in addition, MDSCs transferred after selective depletion could increase IL-17 and Foxp3 expressions in CD4+ cells, as well as the Th17/Treg ratio, contributing to the aggravation of myocardial inflammation. MDSCs promoted the Th17 cell induction under Th17-polarizing conditions in vitro but suppressed Treg expansion. These findings suggest that MDSCs play a plastic role in sustaining mild inflammation in EAM by shifting Th17/Treg balance.

Natural deletion of mouse carboxylesterases Ces1c/d/e impacts drug metabolism and metabolic syndrome development

Mammalian carboxylesterase 1 enzymes can hydrolyze many xenobiotic chemicals and endogenous lipids. We here identified and characterized a mouse strain (FVB/NKI) in which three of the eight Ces1 genes were spontaneously deleted, removing Ces1c and Ces1e partly, and Ces1d entirely. We studied the impact of this Ces1c/d/e deficiency on drug and lipid metabolism and homeostasis. Ces1c/d/e-/- mice showed strongly impaired conversion of the anticancer prodrug irinotecan to its active metabolite SN-38 in plasma, spleen and lung. Plasma hydrolysis of the oral anticancer prodrug capecitabine to 5-DFCR was also profoundly reduced in Ces1c/d/e-/- mice. Our findings resolved previously unexplained FVB/NKI pharmacokinetic anomalies. On a medium-fat diet, Ces1c/d/e-/- female mice exhibited moderately higher body weight, mild inflammation in gonadal white adipose tissue (gWAT), and increased lipid load in brown adipose tissue (BAT). Ces1c/d/e-/- males showed more pronounced inflammation in gWAT and an increased lipid load in BAT. On a 5-week high-fat diet exposure, Ces1c/d/e deficiency predisposed to developing obesity, enlarged and fatty liver, glucose intolerance and insulin resistance, with severe inflammation in gWAT and increased lipid load in BAT. Hepatic proteomics analysis revealed that the acute phase response, involved in the dynamic cycle of immunometabolism, was activated in these Ces1c/d/e-/- mice. This may contribute to the obesity-related chronic inflammation and adverse metabolic disease in this strain. While Ces1c/d/e deficiency clearly exacerbated metabolic syndrome development, long-term (18-week) high-fat diet exposure overwhelmed many, albeit not all, observed phenotypic differences.

DCDC2-Related Ciliopathy: Report of Six Polish Patients, Novel DCDC2 Variant, and Literature Review of Reported Cases.

The increasing usage of NGS technology has enabled the discovery of new causal genes in ciliopathies, including the DCDC2 gene. The aim of our study was to present the clinical, pathological and molecular report of six patients (from three unrelated families) with DCDC2 biallelic pathogenic variants. A detailed overview of the reported patients with DCDC2-related disease was provided. A retrospective chart review of the clinical, biochemical, pathological (liver histology) and molecular features of the study group was performed. The database PubMed (MEDLINE) was searched for relevant studies. All the patients presented with cholestatic jaundice and elevated GGT; the mean age was 2 months. The initial liver biopsy was performed in four children at a mean age of 3 months (age range: 2-5 months). In all of them, features of cholestasis, portal fibrosis and mild portal inflammation were observed; in three of them ductular proliferation was observed. One patient had undergone liver transplantation (LTx) at 8 years of age. At hepatectomy, a biliary-pattern cirrhosis was observed. Only one patient presented with features of renal disease. Whole exome sequencing was performed in all patients at the last follow-up visit (mean age 10 years). Three different variants (one novel) in the DCDC2 gene were identified in the study group. With our six patients, a total of 34 patients with DCDC2-related hepatic ciliopathy were identified. The main clinical presentation of DCDC2-related ciliopathy was liver disease in the form of neonatal sclerosing cholangitis. The predominance of early and severe liver disease associated with no or mildly expressed kidney involvement was observed. Our findings expand the molecular spectrum of pathogenic DCDC2 variants, provide a more accurate picture of the phenotypic expression associated with molecular changes in this gene and confirm a loss of functional behaviour as the mechanism of disease.

Research Highlights.

Research Highlights.

Variation of Proconvertase 1 and Resistin Gene as Risk Factor for Type II Diabetes Mellitus in Obesity Papua Population

Introduction: Risk factors for type 2 diabetes mellitus (T2DM) include obesity and some genetic factors. Obesity involves mild chronic inflammation that predisposes cells to insulin resistance. Two genes that influence obesity and insulin resistance are Proconvertase-1 (PC-1) and resistin (RETN). PC-1 affects the activation of hormones that regulate satiety and hunger. Resistin is one of the inflammatory factors that influence the occurrence of insulin resistance. This study aimed to determine the influence of polymorphism in the PC-1 gene rs1044498 (C>A) and resistin gene RETN + 299 G>A rs3745367 on the risk of diabetes in obese Papua population. Methods: This study involved 58 obese people with T2DM and 58 obese people without DM. We examined the characteristics of blood pressure, lipid profile and insulin resistance by HOMA-IR. The genes examined were PC-1 rs1044498 (C>A) and RETN+ 299 G>A rs3745367 by the PCR-RFLP method. The relationship of gene variations with biochemical parameters was determined with analysis of variance. The results were considered significantly different if P < 0.05. Results: In this study, parameters of diastolic blood pressure, triglycerides and insulin resistance were higher while high density lipoprotein (HDL) levels were lower and significantly different in the obese with T2DM group compared to the obese only group. The carrier of the A allele in the PC-1 gene rs1044498 was higher in the obese group than the obese with T2DM but not significantly different in biochemical parameters. Carrier of the AA genotype in the RETN gene + 299 G>A rs3745367 had higher triglycerides and HOMA-IR and lower HDL levels significantly different (P<0.05) than other genotypes in the obesity with T2DM group. Conclusion: PC-1 rs1044498 gene was a risk factor for obesity but not for T2DM, while RETN gene rs3745367 was a risk factor for dyslipidemia and diabetes in obese people in the Papua population.

Hypothalamic JNK1-hepatic fatty acid synthase axis mediates a metabolic rewiring that prevents hepatic steatosis in male mice treated with olanzapine via intraperitoneal: Additional effects of PTP1B inhibition

Olanzapine (OLA), a widely used second-generation antipsychotic (SGA), causes weight gain and metabolic alterations when administered orally to patients. Recently, we demonstrated that, contrarily to the oral treatment which induces weight gain, OLA administered via intraperitoneal (i.p.) in male mice resulted in body weight loss. This protection was due to an increase in energy expenditure (EE) through a mechanism involving the modulation of hypothalamic AMPK activation by higher OLA levels reaching this brain region compared to those of the oral treatment. Since clinical studies have shown hepatic steatosis upon chronic treatment with OLA, herein we further investigated the role of the hypothalamus-liver interactome upon OLA administration in wild-type (WT) and protein tyrosine phosphatase 1B knockout (PTP1B–KO) mice, a preclinical model protected against metabolic syndrome. WT and PTP1B–KO male mice were fed an OLA-supplemented diet or treated via i.p. Mechanistically, we found that OLA i.p. treatment induces mild oxidative stress and inflammation in the hypothalamus in a JNK1-independent and dependent manner, respectively, without features of cell dead. Hypothalamic JNK activation up-regulated lipogenic gene expression in the liver though the vagus nerve. This effect concurred with an unexpected metabolic rewiring in the liver in which ATP depletion resulted in increased AMPK/ACC phosphorylation. This starvation-like signature prevented steatosis. By contrast, intrahepatic lipid accumulation was observed in WT mice treated orally with OLA; this effect being absent in PTP1B–KO mice. We also demonstrated an additional benefit of PTP1B inhibition against hypothalamic JNK activation, oxidative stress and inflammation induced by chronic OLA i.p. treatment, thereby preventing hepatic lipogenesis. The protection conferred by PTP1B deficiency against hepatic steatosis in the oral OLA treatment or against oxidative stress and neuroinflammation in the i.p. treatment strongly suggests that targeting PTP1B might be also a therapeutic strategy to prevent metabolic comorbidities in patients under OLA treatment in a personalized manner.

Characteristics of Mycoplasma bovis, Mycoplasma arginini, and Mycoplasma californicum on immunological response of bovine synovial cells

Mycoplasma arthritis in calves caused by M. bovis exhibits joint swelling, lameness, and immobility. In contrast to M. bovis, M. arginini, and M. californicum which were similarly isolated from the affected joints, only induced mild inflammation. The changes in pathogenesis that depended on species, however, remained unknown. This investigation aims to examine the characteristics of immune responses to M. bovis, M. arginini, and M. californicum in synovial cells. Intracellular M. bovis was detected by gentamicin assay, but M. arginini and M. californicum were not detected. M. bovis-infected synovial cells were encouraged to proliferate and had their apoptosis suppressed. We suggest that M. bovis invaded and inhibited apoptosis of synovial to evade host immunity, which led to long term survival in joints. M. bovis infection significantly increased IL-6 mRNA expression compared to control, although M. arginini and M. californicum infection were comparable to control. We suggest that M. arginini and M. californicum have low abilities to induce inflammation in joints and therefore do not cause severe pathology. Our findings are the first to show the variations in synovial cell immune responses to M. bovis, M. arginini, and M. californicum, which are thought to be related to the pathogenicity of arthritis.

Self antigen-driven, undifferentiated memory-phenotype CD4 T lymphocytes can induce mild and systemic inflammation by differentiating into effector and regulatory T cells

Abstract In adaptive immune responses, naïve CD4 +T lymphocytes that have T cell receptors (TCRs) reactive to challenged foreign antigens are activated to differentiate into antigen-specific effector and memory cells. We have recently reported that in steady state, peripheral naïve precursors can also recognize self antigens to spontaneously acquire a memory phenotype (MP) and that such naturally arising “MP cells” can exert innate immune function in host defense. Given the self-reactivity of MP cells, it is likely that the same T lymphocyte population also has the capacity to induce autoimmune and/or inflammatory disease. Here we show that in lymphopenic environment, self antigen-driven MP cells can evoke mild and persistent inflammation in various organs including colon, lungs, kidneys, and liver. The MP cell-driven colitis is dependent on commensal microbiota as well as cytokines IFN-γ and IL-17A while inflammation in the other organs is independent of these factors. On the other hand, we demonstrate using combined single cell RNA sequencing, TCR sequencing, and flow cytometric approaches that MP as compared to naïve CD4 +T lymphocytes more efficiently differentiate into regulatory T (Treg) cells in a TGF-β-dependent fashion, thereby partially ameliorating inflammation. We further provide evidence arguing that these Th1, Th17, and Treg cells are generated from preexisting, undifferentiated T-bet −rather than T-bet +MP subset. Altogether, our results identify self-driven T-bet −MP cells as a multi-potent CD4 +T lymphocyte population that can induce systemic and mild inflammation by differentiating into Th1 and Th17 effector as well as Treg cells. This work was supported by the Japan Society for the Promotion of Science, Astellas Foundation for Research on Metabolic Disorders, Bristol-Myers Squibb, Cell Science Research Foundation, Chemo-Sero-Therapeutic Research Institute, Daiichi Sankyo Foundation of Life Science, GlaxoSmithKline, Gonryo Foundation for the Promotion of Medical Science, G-7 Scholarship Foundation, Harmonic Ito Foundation, Ichiro Kanehara Foundation for the Promotion of Medical Sciences and Medical Care, Inamori Foundation, Intelligent Cosmos Foundation, Japan Allergy Foundation, Japan Intractable Diseases Research Foundation, Kanae Foundation for the Promotion of Medical Science, Kobayashi Foundation, Life Science Foundation of Japan, Mitsubishi Foundation, Mochida Memorial Foundation for Medical and Pharmaceutical Research, MSD Life Science Foundation, Nakajima Foundation, Nakayama Foundation for Human Science, Ohyama Health Foundation, Okinaka Memorial Institute for Medical Research, Pharmacodynamics Research Foundation, Senri Life Science Foundation, Senshin Medical Research Foundation, Sumitomo Foundation, Takeda Science Foundation, Ube Industries Foundation, Uehara Memorial Foundation, and Waksman Foundation of Japan. Akihisa Kawajiri was supported by the PhD Scholarship (Kibou Project) from Japanese Society for Immunology.

Spinal adenosine 2A receptor inhibition restores phrenic long-term facilitation during mild systemic inflammation

Inflammation undermines several forms of neuroplasticity, including phrenic long-term facilitation (pLTF), a form of respiratory motor plasticity elicited by moderate acute intermittent hypoxia (mAIH; 3, 5-min episodes, 5 min intervals; arterial PO2 ~ 40–50 mmHg). Mild inflammation elicited by a low dose of the TLR-4 receptor agonist lipopolysaccharide (LPS; 100 mg/kg, i.p.) abolishes mAIH-induced pLTF by a mechanism that requires spinal p38 MAP kinase and protein phosphatase activity. Neuroinflammation activates microglia and other cells in the CNS, elevating extracellular levels of adenosine—a purine nucleoside known to suppress mAIH-induced pLTF. We hypothesized basal adenosine levels in ventral spinal C 3 -C 5 segments are increased in adult male Sprague-Dawley rats 24 hours post-LPS administration, thereby undermining mAIH-induced pLTF via adenosine 2A receptor (A 2A ) activation. Thus, we predicted that cervical intrathecal administration of the A 2A receptor inhibitor MSX-3 (10 μM, 12 μL) would rescue mAIH-induced pLTF in rats pre-treated with LPS. As predicted, LPS significantly increased basal ventral C 3 -C 5 adenosine levels (p=0.010 vs controls; n=7 per group). In control rats (saline injection, i.p.), MSX-3 enhanced pLTF versus vehicle controls (LPS: 110 ± 16% baseline; controls: 53 ± 6%; p=0.002; each n=6). As expected, mAIH-induced pLTF was abolished in LPS-treated rats (4 ± 6% baseline; n=6). MSX-3 restored mAIH-induced pLTF to levels equivalent to MSX-3 treated control rats (120 ± 14%; p<0.001; n=6; versus LPS controls with MSX-3: p=0.539). Thus, mild LPS-induced inflammation abolishes mAIH-induced pLTF by a mechanism associated with increased spinal adenosine levels and A 2A receptor activation. As we move mAIH forward as a therapeutic modality to improve breathing and non-respiratory movements in people with spinal cord injury or ALS, pretreatment with A 2A receptor inhibitors may offset the undermining effects of systemic inflammation associated with these severe neuromuscular disorders. NIH HL147554, HL148030, T32HL134621 (ABM) and the UF McKnight Brain Institute This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

No Substantial Histopathologic Changes in Mops condylurus Bats Naturally Infected with Bombali Virus, Kenya

We found similar mild perivascular inflammation in lungs of Bombali virus-positive and -negative Mops condylurus bats in Kenya, indicating the virus is well-tolerated. Our findings indicate M. condylurus bats may be a reservoir host for Bombali virus. Increased surveillance of these bats will be important to reduce potential virus spread.

Kolonun Divertiküler Hastalığında İnflamatuar Parametrelerin Tanısal ve Prognostik Önemi

Aim The aim of this study was to determine the presence of inflammation in asymptomatic diverticular disease using inflammatory parameters and to evaluate the relationship between inflammatory parameters and the degree of complication in symptomatic diverticular diseases. Material and Method Clinical and dermographic findings of patients with acute diverticulitis, patients with diverticulosis and healthy volunteers were compared. Results A healthy control group of 31 people, 40 patients with diverticulosis and 32 patients with acute diverticulitis were included in the study. Thirty-one (43.11%) patients were female and 41 (56.9%) male. RDW and MLR were significantly higher in patients with asymptomatic diverticulosis compared to the control group (p=0.02, p=0.00, respectively). NLR and SII were significantly different among Hinchey groups (p<0.01, p<0.01, respectively).Conclusion We concluded that there may be a mild inflammation in asymptomatic diverticulosis patients, and NLR and SII can provide information about the degree of acute diverticulitis. Keywords diverticulosis, inflammation, acute diverticulitis

A novel tetra-PEG based hydrogel for prevention of esophageal stricture after ESD in a porcine model

Endoscopic submucosal dissection (ESD) is an accepted treatment for early esophageal cancer and precancerous lesions, but resection of a large mucosal area often leads to postoperative esophageal stricture. Biomaterials provide a new option for the treatment of post-ESD ulcers. In this study, we developed a well-defined ammonolysis-based tetra-armed poly (ethylene glycol) (Tetra-PEG) hydrogel and investigated its efficacy and related mechanisms for preventing esophageal ESD-induced stricture in a porcine model. In terms of material properties, Tetra-PEG hydrogel present great biocompatibility，great capability to retain moisture, strong tissue adhesion and high mechanical strength. Then, six domestic female pigs were randomly divided into PEG (n = 3) and control groups (n = 3). A 3/4 of the esophageal circumference ESD was performed in all pigs. In PEG group, Tetra-PEG hydrogel was easily delivered via endoscopy and adhered to the ulcer bed tightly. Compared to control group, Tetra-PEG hydrogel accelerated esophageal ulcer healing at an early stage with enhanced epithelium regeneration, milder inflammation and lesser fibrosis by regulating TGF-β/Smad2 signaling. Taken together, our findings reveal Tetra-PEG hydrogel is a promising and attractive candidate for preventing the formation of fibrotic stricture in the process of esophageal ESD-induced ulcer repair.

Duodenal Eosinophilia in Functional Dyspepsia

Aim: to present observation of a patient diagnosed with functional dyspepsia based on current guidelines, and having increased eosinophil counts in the biopsy specimen of duodenal mucosa. To consider possible causes of duodenal eosinophilia in the light of present-day concepts.Highlights. Patient K., 40 years old, complained of dyspeptic phenomena, the first appearance of which she had noted at the age of 18. The patient noted poor tolerance to canned and fermented foods, which provoked an increase in dyspepsia and sometimes caused watery diarrhea. The examination excluded “symptoms of concern”. Successful antihelicobacter eradication therapy was carried out. Morphological examination of the stomach showed phenomena of mild chronic inflammation without intestinal metaplasia or glandular atrophy. A biopsy of the mucosa of the descending part of the duodenum showed a moderate increase in the levels of mononuclears and eosinophils in its lamina propria without penetration into the epithelium of the villi or formation of clusters. The patient suffers from pollinosis; sensitization to birch pollen was diagnosed by a skin prick test. However, she has no oral allergy symptoms, which does not allow linking duodenal eosinophilia to food allergy. Based on current guidelines, the patient was diagnosed with functional dyspepsia. In addition to dietary restrictions, treatment courses with a proton pump inhibitor, itopride, and S-methylmethionine sulfonium chloride, which has an antihistamine effect, were recommended for periods of worsening dyspepsia.Conclusion. The clinical significance of duodenal eosinophilia and local histamine production in patients with a clinical diagnosis of functional dyspepsia deserves special attention. Triggering factors provoking the worsening of symptoms should be analyzed; in particular, a food diary and exclusion of food allergies are recommended. Histamine-neutralizing drugs may play a role in the treatment of FD with duodenal eosinophilia in the future.

Ketamine Induced RCVS (P3-12.008)

<h3>Objective:</h3> To present a case of RCVS induced by ketamine infusions compounded with triptan and NSAID usage. <h3>Background:</h3> A 47 yo female with a history of depression and migraines presented with a persistent headache for 3 days. On the day of presentation, the patient reported the “worst headache of her life”. The headache was “sharp and squeezing”, frontal and retro-orbital in location, radiating to the back of her head, and exasperated by laying flat. The patient reported taking multiple high-dose NSAIDs along with sumatriptan. She had completed a 3-week course of ketamine infusions (75 mg twice weekly for depression) with last infusion 2 days prior to presentation. She was also on a chronic SSRI for depression. Patient denied any alcohol or current recreational drug use, but did report a history of opioid dependency. Initial CT head demonstrated a moderate-sized right frontal lobe subarachnoid and a small subarachnoid in the right posterior parietal lobe. CTA of head and neck demonstrated vasospasm of the left supraclinoid ICA, left M1 segment, and basilar artery. The location, radiographic appearance, and temporal course was consistent with RCVS. CT Angiogram was negative for any luminal irregularity, focal stenosis, or narrowing. MRI brain with contrast redemonstrated the subarachnoid hemorrhage without evidence of a vasculitic process. Lab work-up was negative for ANA, C4, C3, Sjogren’s Antibodies, RF, Anti-DNAs Ab. CRP and ESR were mildly elevated suggesting mild inflammation. <h3>Design/Methods:</h3> N/A <h3>Results:</h3> The etiology of the headache and subarachnoid hemorrhage was suspected to be medication induced RCVS in the setting of concomitant use of sumatriptan, SSRI, and high doses of ketamine. <h3>Conclusions:</h3> Although a rare phenomena, RCVS is a concerning cause of thunderclap headache that should be recognized. RCVS is not a common occurrence with ketamine usage but clinicians should be aware is this possible adverse effect. <b>Disclosure:</b> Dr. Mufti has nothing to disclose. Dr. Canlas has nothing to disclose. Dr. Ritenuti has nothing to disclose.

Renal pathology in wild European rabbits.

There is a relative paucity of data examining the prevalence of renal pathology in wild rabbits. Sixty-two wild rabbits that had been shot for population control in Cambridgeshire, UK, underwent postmortem examination, including macroscopic and microscopic renal assessment. The majority (82%) of the animals had macroscopically and microscopically normal kidneys. One animal (1.6%) had severe perirenal abscessation. Pasteurella spp. was isolated from this lesion. Ten rabbits (16%) had microscopic renal pathology comprising minimal to mild renal inflammation or fibrosis. No Encephalitozoon cuniculi organisms were detected histologically. The sample population was composed of shot rabbits, so the probability of detecting moribund individuals was reduced. Extrapolation of these data to the wider UK wild rabbit population may be limited as rabbits were shot at two sites within a 3km radius of each other. Renal pathology is rare in the population examined.

Imine Derivatives of Benzoxazole Attenuate High-Fat Diet-Induced Hyperlipidemia by Modulation of Lipid-Regulating Genes.

Purpose: Hyperlipidemia being the prominent risk factor of cardiovascular diseases and side effects associated with the current lipid-lowering drugs have attracted the interest of scientists in the quest for new alternatives. In view of the diverse pharmacological potentials of benzoxazole (BZX) compounds, this study was designed to evaluate the antihyperlipidemic activity of imine derivatives of BZX in high-fat diet (HFD)-fed rats. Methods: Hyperlipidemia was induced in Sprague-Dawley rats by using HFD for 28 days. On the 28th day, blood samples were collected, and animals having serum triglycerides (TG) greater than 400 mg/dL and total cholesterol (TC) greater than 280 mg/dL were selected for further study. Hyperlipidemic rats were daily treated with either a vehicle or simvastatin (SIM; 20 mg/kg) or BZX compounds (10, 20, and 30 mg/kg), for 12 consecutive days. After the specified time duration, hyperlipidemic biomarkers were evaluated in the blood samples of sacrificed rats. Liver samples were collected for histopathological and mRNA analyses. Binding affinities of BZX derivatives with different targets were assessed by molecular docking. Results: The present study revealed that the BZX derivatives dose-dependently reduced the serum levels of TC, TG, low-density lipoprotein, and very low-density lipoprotein along with improvement in high-density lipoprotein levels. Similarly, all the compounds reduced HFD-induced alanine transaminase and aspartate aminotransferase levels except BZX-4. Histopathology of liver samples demonstrated mild to moderate fatty changes upon treatment with BZX-1, BZX-2, and BZX-4. The hepatic architecture of the BZX-3-treated samples was close to normal, and only mild inflammation was witnessed in these samples. Moreover, all the compounds significantly increased superoxide dismutase and glutathione levels, indicating their antioxidant potentials. Gene expression data showed that BZX-1 and BZX-3 reduced lipid levels by inhibiting HMGCR, APOB, PCSK9, SRB1, and VCAM1 and via improving PPAR-α and APOE mRNA levels. BZX-2 demonstrated its antihyperlipidemic effects mainly due to inhibition of APOB, while BZX-4-mediated effects appeared to be due to attenuation of APOB, PCSK9, and SRB1. BZX derivatives displayed strong binding affinities with HMGCR, APOB, and VCAM1, which suggested that some of the interactions might be required for inhibition of these target proteins. Conclusions: Based on the current findings, it can be concluded that BZX derivatives exert their antihyperlipidemic effects via modulation of multiple lipid-regulating genes.

Ellagic acid alleviates pulmonary inflammation and oxidative stress in mouse model of diisononyl phthalate-induced asthma

Polyvinyl chloride is plasticized using diisononyl phthalate (DiNP), and exposure to phthalates has been linked to the emergence of asthma and allergies. The adjuvant impact of DiNP exposure results in allergic airway inflammation. In the current study, we looked into how ellagic acid (ELA) impacted asthma brought on by DiNP. Male BALB/c mice (n=40, 20-30 g) were divided into 4 groups of 10 mice each, and the following treatments were given to each group: group 1 (control) received saline orally for 30 days; group 2 (ELA) received 10 mg/kg of ELA (oral) for 30 days; group 3 (DiNP &amp; ELA) received 10 mg/kg of ELA (oral) for 7 days prior to DiNP (50mg/kg) exposure (intraperitoneal and intranasal); group 4 (DiNP) received 50 mg/kg DiNP. After the last administration, mice were sacrificed, lungs were removed and their bronchoalveolar lavage fluid was collected which was used for biochemical and histopathological analysis. The mice given DiNP had changes in their histoarchitecture, inflammatory cells, antioxidant status, and inflammation markers. Malondialdehyde (MDA) and inflammatory biomarkers (NO, MPO) were considerably higher (p&lt; 0.05) in the lungs of DiNP-treated mice than in the control group. In the lungs, DiNP reduced the concentration of non-enzymatic antioxidants (GSH and AA), and the activity of enzymatic antioxidants (SOD, CAT, and GST). DiNP also altered inflammatory cells (eosinophils, neutrophils, lymphocytes, monocytes, leucocytes) in the BALF. ELA administration ameliorated these changes. Histopathological analysis revealed airway inflammation characterized by inflammatory cell infiltration, oedema, hemorrhage, and constricted alveoli space. Additionally, the mice co-treated with ELA and DiNP experienced mild inflammation of the alveoli and interstitial spaces as well as mild thickening of the alveolar septae. ELA offered a protective effect against DiNP-induced allergic asthma in mice.

Eating more sardines instead of fish oil supplementation: Beyond omega-3 polyunsaturated fatty acids, a matrix of nutrients with cardiovascular benefits.

Omega-3 polyunsaturated fatty acids (n-3 PUFA) play a significant role in the prevention and management of cardiometabolic diseases associated with a mild chronic pro-inflammatory background, including type 2 diabetes, hypertension, hypertriglyceridaemia, and fatty liver disease. The effects of n-3 PUFA supplements specifically, remain controversial regarding reducing risks of cardiovascular events. n-3 PUFA supplements come at a cost for the consumer and can result in polypharmacy for patients on pharmacotherapy. Sardines are a well-known, inexpensive source of n-3 PUFA and their consumption could reduce the need for n-3 PUFA supplementation. Moreover, sardines contain other cardioprotective nutrients, although further insights are crucial to translate a recommendation for sardine consumption into clinical practice. The present review discusses the matrix of nutrients contained in sardines which confer health benefits for cardiometabolism, beyond n-3 PUFA. Sardines contain calcium, potassium, magnesium, zinc, iron, taurine, arginine and other nutrients which together modulate mild inflammation and exacerbated oxidative stress observed in cardiovascular disease and in haemodynamic dysfunction. In a common serving of sardines, calcium, potassium, and magnesium are the minerals at higher amounts to elicit clinical benefits, whilst other nutrients are present in lower but valuable amounts. A pragmatic approach towards the consumption of such nutrients in the clinical scenario should be adopted to consider the dose-response relationship effects on physiological interactions. As most recommendations currently available are based on an indirect rationale of the physiological actions of the nutrients found in sardines, randomised clinical trials are warranted to expand the evidence on the benefits of sardine consumption.

Marine toxin C17-SAMT causes major structural damage to vital organs in mice following subchronic toxicity trials

C17-sphinganine analog mycotoxin (C17-SAMT) has been characterized as the contaminant responsible for the atypical toxicity reported in mussels from the Bizerte lagoon (northern Tunisia) over the past decade. C17-SAMT exhibited common symptoms of toxicity in mice, including flaccid paralysis and severe respiratory distress, followed by rapid death. To determine the potential health risks of this neurotoxin, we assessed its subchronic toxicity according to the recommendations of OCDE n° 407. The body weight and the structural changes of vital organs were recorded. Biochemical and hematological parameters were also quantified. Macroscopic observations showed that mice treated with 0.9, 9, and 90 µg/kg C17-SAMT had significantly reduced stomach weights, swollen and fragile intestines, and signs of nephritis with renal abscesses. Transaminase assays pointed out that exposure to C17-SAMT can lead to transaminitis. Above-average lactate dehydrogenase values were recorded in both the treated and satellite groups. Hematology data showed a significant reduction in red blood cell counts in high-dose-treated group. Reductions in hemoglobin and hematocrit were also recorded. Mean leukocyte counts were significantly elevated in the high-, mid-dose treated and satellite groups. At the microscopic level, we noted myocardial atrophy and hyperemia. In the lungs, we noted necrosis associated with macrophages perivascular infiltration and congestion. The kidneys showed mild inflammation and glomerular atrophy. The stomach exhibited mucosal atrophy, while a thin colon and distended small intestine were observed in high-dose-treated group. The liver was affected by vascular congestion, inflammatory infiltration, and lobular necrosis that evolved into acute hepatitis. Lesions, such as inflammatory infiltration and mild necrosis of the liver, cortical abscess with central necrosis in the kidney, and mild congestion of cardiac tissue were recorded in the satellite group.

Indwelling stents cause severe inflammation and fibrosis of the ureter via urothelial–mesenchymal transition

To explore the pathways and mechanisms driving inflammation and fibrosis in stented ureters. In total, six healthy female pigs underwent cystoscopic unilateral ureteral stent insertion (6 Fr). After 14 days indwelling time, ureteral tissue was harvested in three pigs, while the remaining three pigs had their stents removed, and were recovered for 7 days. Three separate pigs served as controls. Tissue from stented and contralateral ureters was analysed histologically to evaluate tissue remodelling and classify the degree of inflammation and fibrosis, while genome, proteome and immunohistochemistry analysis was performed to assess changes at the transcriptional and translational levels. Finally, immunofluorescence was used to characterize the cell composition of the immune response and pathways involved in inflammation and fibrosis. Statistical analysis was performed using GraphPad Prism and RStudio for Welch ANOVA, Kruskal–Wallis and Dunnett’s T3 multiple comparison test. Stents cause significant inflammation and fibrosis of ureters. Gene set enrichment analysis confirmed fibrotic changes and tissue proliferation and suggests that epithelial–mesenchymal transition is a driver of fibrosis. Moreover, IL-6/JAK/STAT and TNFα via NF-κB signalling might contribute to chronic inflammation promoting a profibrotic environment. Immunostaining confirmed epithelial–mesenchymal transition in the urothelium and NF-κB expression in ureters stented for 14 days. Tissue alterations do not fully recover after 7 days. Histological evaluation showed that contralateral, unstented ureters are affected by mild inflammation. Our study showed that stenting has a significant impact on the ureter. Chronic inflammation and epithelial–mesenchymal transition are drivers of fibrosis, potentially impairing ureteral functionality in the long term. Furthermore, we observed mild inflammation in contralateral, unstented ureters.