Macrophage Accumulation Research Articles

Bisphenol S exposure induces intestinal inflammation via altering gut microbiome

Bisphenol S (BPS), a substitute for bisphenol A, is widely used in the manufacture of food packaging materials, raising concern over its toxicity. However, evidence is still lacking on whether gut microbiota involved in BPS induced intestinal inflammation in mammals, as well as its underlying mechanism. Using mouse BPS exposure model, we found intestinal inflammation characterized by shortened colon length, crypt distortion, macrophage accumulation and increased apoptosis. As for gut microbiota, 16s rRNA gene amplicon sequencing showed BPS exposure induced gut dysbiosis, including increased pro-inflammatory microbes such as Ileibacterium, and decreased anti-inflammatory genera such as Lactobacillus, Blautia and Romboutsia. Besides, LC-MS/MS-based untargeted metabolomic analysis indicated BPS impaired both bacteria and host metabolism. Additionally, transcriptome analysis of the intestine revealed abnormal gene expression in intestinal mucosal barrier and inflammation. More importantly, treating mice with antibiotics significantly attenuated BPS-induced gut inflammation via the regulation of both bacterial and host metabolites, indicating the role of gut microbiota. Collectively, BPS exposure induces intestinal inflammation via altering gut microbiota in mouse. This study provides the possibility of madecassic acid, an anti-inflammatory metabolite, to prevent BPS-induced intestinal inflammation and also new insights in understanding host-microbiota interaction in BPS toxicity.

Is PAS Stain Necessary to Exclude Whipple Disease in Duodenal Biopsies?

Objective. Whipple disease, caused by Tropheryma whipplei, is a rare infectious condition primarily presenting with malabsorptive diarrhea. Small bowel biopsies typically reveal foamy macrophages containing periodic acid-Schiff-positive/diastase (PAS/D) resistant T. whipplei bacilli, and PAS(D) staining is occasionally requested by clinicians in duodenal biopsies, which are often histologically unremarkable. The yield of PAS(D) staining in such biopsies has never been reported to our knowledge. Methods. The anatomic pathology database was searched for all specimens of duodenal biopsies stained with PAS(D) from 1993 to 2021. Specimens were categorized by the following histomorphologic features: unremarkable, nonspecific changes, or expansion of the lamina propria by aggregates of foamy histiocytes. Follow-up information was collected, including microbiologic confirmatory testing. Results. There was a total of 193 specimens of duodenal biopsies stained with PAS(D). Biopsies lacking foamy histiocytes on H&E (n = 158) were never PAS-positive. Thirteen biopsies contained PAS-positive histiocytes; 9 out of the 13 PAS-positive specimens were subsequently confirmed to be T. whipplei. Of the 193 specimens, 124 specimens had a clinical request for PAS(D) staining. Only 3 of the 124 (2.4%) specimens showed foamy histiocytes containing PAS-positive granules, all of which were confirmed positive for T. whipplei. Conclusion. PAS(D) staining is unnecessary to exclude Whipple disease in duodenal biopsies without foamy macrophage aggregates, regardless of clinical suspicion. Clinical suspicion-driven biopsies often yield negative results for Whipple disease.

Gut Dysbiosis Drives Inflammatory Bowel Disease Through the CCL4L2-VSIR Axis in Glycogen Storage Disease.

Patients with glycogen storage disease type Ib (GSD-Ib) frequently have inflammatory bowel disease (IBD). however, the underlying etiology remains unclear. Herein, this study finds that digestive symptoms are commonly observed in patients with GSD-Ib, presenting as single or multiple scattered deep round ulcers, inflammatory pseudo-polyps, obstructions, and strictures, which differ substantially from those in typical IBD. Distinct microbiota profiling and single-cell clustering of colonic mucosae in patients with GSD are conducted. Heterogeneous oral pathogenic enteric outgrowth induced by GSD is a potent inducer of gut microbiota immaturity and colonic macrophage accumulation. Specifically, a unique population of macrophages with high CCL4L2 expression is identified in response to pathogenic bacteria in the intestine. Hyper-activation of the CCL4L2-VSIR axis leads to increased expression of AGR2 and ZG16 in epithelial cells, which mediates the unique progression of IBD in GSD-Ib. Collectively, the microbiota-driven pathomechanism of IBD is demonstrated in GSD-Ib and revealed the active role of the CCL4L2-VSIR axis in the interaction between the microbiota and colonic mucosal immunity. Thus, targeting gut dysbiosis and/or the CCL4L2-VISR axis may represent a potential therapy for GSD-associated IBD.

Endocannabinoid Receptor 2 Function is Associated with Tumor-Associated Macrophage Accumulation and Increases in T Cell Number to Initiate a Potent Antitumor Response in a Syngeneic Murine Model of Glioblastoma.

Introduction: Glioblastoma patients have a highly immunosuppressive tumor microenvironment and systemic immunosuppression that comprise a major barrier to immune checkpoint therapy. Based on the production of endocannabinoids by glioblastomas, we explored involvement of endocannabinoid receptor 2 (CB2R), encoded by the CNR2 gene, which is predominantly expressed by immune cells, in glioblastoma-related immunosuppression. Materials & Methods: Bioinformatics of human glioblastoma databases was used to correlate enzymes involved in the synthesis and degradation of endocannabinoids, as well as CB2Rs, with patient overall survival. Intrastriatal administration of luciferase-expressing, murine GL261 glioblastoma cells was used to establish in in vivo glioblastoma model for characterization of tumor growth and intratumoral immune cell infiltration, as well as provide immune cells for in vitro co-culture experiments. Involvement of CB2Rs was determined by treatment with CB2R agonist (GW405833) or CB2R antagonist (AM630). ELISA, FACS, and immunocytochemistry were used to determine perforin, granzyme B, and surface marker levels. Results: Bioinformatics of human glioblastoma databases showed high expression of CB2R and elevated endocannabinoid production correlated with poorer prognosis, and involved immune-associated pathways. AM630treatment of GL261 glioblastoma-bearing mice induced a potent antitumor response, with survival plateauing at 50% on Day 40, when all control mice (median survival 28 days) and mice treated with GW405833 (median survival 21 days) had died. Luciferase tumor imaging revealed accelerated tumor growth by GW405833 treatment, but stable or regressing tumors in AM630-treated mice. Notably, in spleens, AM630 treatment caused an 83% decrease in monocytes/macrophages, and 1.8- and 1.6-fold increases in CD8+ and CD4+ cells, respectively. Within tumors, there was a corresponding decrease in tumor-associated macrophages (TAMs) and increase in CD8+ T cells. In vitro, lymphocytes from AM630-treated mice showed greater cytotoxic function (increased percentage of perforin- and granzyme B-positive CD8+ T cells). Discussion: These results suggest that inhibition of CB2R enhances both immunosuppressive TAM infiltration and systemic T-cell suppression through CB2R activation, and that inhibition of CB2Rs can potently counter both the immunosuppressive tumor microenvironment, as well as systemic immunosuppression in glioblastoma.

Protein-energy restriction-induced lipid metabolism disruption causes stable-to-progressive disease shift in Mycobacterium avium-infected female mice

Disease susceptibility and progression of Mycobacterium avium complex pulmonary disease (MAC-PD) is associated with multiple factors, including low body mass index (BMI). However, the specific impact of low BMI on MAC-PD progression remains poorly understood. This study aims to examine the progression of MAC-PD in the context of low BMI, utilising a disease-resistant mouse model. We employed a MAC infection-resistant female A/J mouse model to compare the progression of MAC-PD under two dietary conditions: one group was fed a standard protein diet, representing protein-energy unrestricted conditions, and the other was fed a low protein diet (LPD), representing protein-energy restriction. Our results reveal that protein-energy restriction significantly exacerbates MAC-PD progression by disrupting lipid metabolism. Mice fed an LPD showed elevated fatty acid levels and related gene expressions in lung tissues, similar to findings of increased fatty acids in the serum of patients who exhibited the MAC-PD progression. These mice also exhibited increased CD36 expression and lipid accumulation in macrophages upon MAC infection. Invitro experiments emphasised the crucial role of CD36-mediated palmitic acid uptake in bacterial proliferation. Importantly, invivo studies demonstrated that administering anti-CD36 antibody to LPD-fed A/J mice reduced macrophage lipid accumulation and impeded bacterial growth, resulting in remarkable slowing disease progression. Our findings indicate that the metabolic status of host immune cells critically influences MAC-PD progression. This study highlights the potential of adequate nutrient intake in preventing MAC-PD progression, suggesting that targeting CD36-mediated pathways might be a host-directed therapeutic strategy to managing MAC infection. This research was funded by the National Research Foundation of Korea, the Korea Research Institute of Bioscience and Biotechnology, and the Korea National Institute of Health.

Trans, trans-2,4-decadienal, a lipid peroxidation product, aggravates insulin resistance in obese mice by promoting adipose inflammation.

Peroxidation of polyunsaturated fatty acids results in the creation of numerous α, β-unsaturated aldehydes, many of which are complicated by the development of diabetes. Trans, trans-2,4-decadienal (DDE) is a dietary α, β-unsaturated aldehyde that is commonly found in food and the environment. However, it is unknown whether DDE exposure has some negative effects on glucose homeostasis and insulin sensitivity. This study investigated the biological effects of long-term DDE exposure in normal chow diet (NCD)-fed non-obese mice and high-fat diet (HFD)-fed obese mice. Results showed that oral administration of DDE for 14 weeks did not cause severe toxicity in NCD-fed non-obese mice but had significant adverse effects in HFD-fed obese mice. It was found that DDE exposure caused significant increases in LDL and ALT levels and aggravated glucose intolerance and insulin resistance in obese mice. Moreover, DDE robustly accumulated in adipose tissue and promoted the impairment of the insulin signaling pathway in the adipose tissue of obese mice while not affecting the skeletal muscle or liver. Mechanistically, DDE aggravated adipose tissue inflammation by promoting M1 macrophage accumulation and increasing proinflammatory cytokines in the adipocytes of obese mice, thus leading to impaired systemic insulin resistance. These findings provide crucial insights into the potential health impacts of long-term DDE exposure.

Overview of histiocytic and dendritic disorders by the 5th version of WHO Classifi cation of Hematolymphoid Tumours from 2022.

Histiocytoses are rare disorders characterized by the accumulation of macrophages, dendritic cells, or monocyte-derived cells in various tissues and organs of children and adults, with a wide range of clinical manifestations, presentations, and histology. The histiocytoses are classified according to the WHO Classification, the last version of which was published in 2022, or according to the Histiocyte Society Classification, with the last version published in 2016. This text provides an overview of histiocytoses as described in the WHO Classification 2022.

Effect of repeated sciatic nerve crush on the conditioning lesion response: Generating an experimental animal model to prolong the denervation period while maintaining peripheral nerve continuity

Peripheral nerves exhibit long-term residual motor dysfunction following injury. The length of the denervation period before nerve and muscle reconnection is an important factor in motor function recovery. We aimed to investigate whether repeated nerve crush injuries to the same site every 7 days would preserve the conditioning lesion (CL) response and to determine the number of nerve crush injuries required to create an experimental animal model that would prolong the denervation period while maintaining peripheral nerve continuity. Rats were grouped according to the number of sciatic nerve crushes. A significant decrease in the soleus muscle fiber cross-sectional area was observed with increased crushes. After a single crush, macrophage accumulation and macrophage chemotaxis factor CCL2 expression in dorsal root ganglia were markedly increased, which aligned with the gene expression of Ccl2 and its receptor Ccr2. Macrophage numbers, histological CCL2 expression, and Ccl2 and Ccr2 gene expression levels decreased, depending on the number of repeated crushes. Histological analysis and gene expression analysis in the group with four repeated crushes did not differ significantly when compared with uninjured animals. Our findings indicated that repeated nerve crushes at the same site every 7 days sustained innervation loss and caused a loss of the CL response. The experimental model did not require nerve stump suturing and is useful for exploring factors causing prolonged denervation-induced motor dysfunction. Significance StatementThis study elucidates the effects of repeated nerve crush injury to the same site on innervation and conditioning lesion responses and demonstrates the utility of an experimental animal model that recapitulates the persistent residual motor deficits owing to prolonged denervation without requiring nerve transection and transection suturing.

CCL17 and CCL19 are markers of disease progression in alveolar echinococcosis

ObjectivesAlveolar echinococcosis (AE) represents one of the deadliest helminthic infections, characterized by an insidious onset and high lethality. MethodsThis study utilized the Gene Expression Omnibus (GEO) database, applied Weighted Correlation Network Analysis (WGCNA) and Differential Expression Analysis (DEA), and employed the Matthews Correlation Coefficient (MCC) to identify CCL17 and CCL19 as key genes in AE. Immunohistochemistry and immunofluorescence co-localization techniques were used to examine the expression of CCL17 and CCL19 in liver tissue lesions of AE patients. Additionally, a mouse model of multilocular echinococcus larvae infection was developed to study the temporal expression patterns of these genes, along with liver fibrosis and inflammatory responses. ResultsThe in vitro model simulating echinococcal larva infection mirrored the hepatic microenvironment post-infection with multilocular echinococcal tapeworms. Quantitative RT-PCR analysis showed that liver fibrosis occurred in AE patients, with proximal activation and increased expression of CCL17 and CCL19 over time post-infection. Notably, expression peaked during the late stages of infection. Similarly, F4/80, a macrophage marker, exhibited corresponding trends in expression. Upon stimulation of normal hepatocytes by vesicular larvae in cellular experiments, there was a significant increase in CCL17 and CCL19 expression at 12 h post-infection, mirroring the upregulation observed with F4/80. ConclusionCCL17 and CCL19 facilitate macrophage aggregation via the chemokine pathway and their increased expression correlates with the progression of infection, suggesting their potential as biomarkers for AE progression.

Acesulfame potassium triggers inflammatory bowel disease via the inhibition of focal adhesion pathway

Acesulfame potassium (ACK) was generally regarded as innocuous and extensively ingested. Nevertheless, ACK has recently gained attention as a burgeoning pollutant that has the potential to induce a range of health hazards, particularly to the digestive system. Herein, we uncover that ACK initiates inflammatory bowel disease (IBD) in mice and zebrafish, as indicated by the aggregation of macrophages in the intestine and the inhibition of intestinal mucus secretion. Transcriptome analysis of mice and zebrafish guts revealed that exposure to ACK typically impacts the cell cycle, focal adhesion, and PI3K-Akt signaling pathways. Using pharmacological approaches, we demonstrate that the PI3K-Akt signaling pathway and the generation of reactive oxygen species (ROS) triggered by cell division are not significant factors in the initiation of IBD caused by ACK. Remarkably, inhibition of the focal adhesion pathway is responsible for the IBD onset induced by ACK. Our results indicate the detrimental impacts and possible underlying mechanisms of ACK on the gastrointestinal system and provide insights for making informed choices about everyday dietary habits.

Myeloid cell-derived interleukin-6 induces vascular dysfunction and vascular and systemic inflammation.

The cytokine interleukin-6 (IL-6) plays a central role in the inflammation cascade as well as cardiovascular disease progression. Since myeloid cells are a primary source of IL-6 formation, we aimed to generate a mouse model to study the role of myeloid cell-derived IL-6 in vascular disease. Interleukin-6-overexpressing (IL-6OE) mice were generated and crossed with LysM-Cre mice, to generate mice (LysM-IL-6OE mice) overexpressing the cytokine in myeloid cells. Eight- to 12-week-old LysM-IL-6OE mice spontaneously developed inflammatory colitis and significantly impaired endothelium-dependent aortic relaxation, increased aortic reactive oxygen species (ROS) formation, and vascular dysfunction in resistance vessels. The latter phenotype was associated with decreased survival. Vascular dysfunction was accompanied by a significant accumulation of neutrophils, monocytes, and macrophages in the aorta, increased myeloid cell reactivity (elevated ROS production), and vascular fibrosis associated with phenotypic changes in vascular smooth muscle cells. In addition to elevated Mcp1 and Cxcl1 mRNA levels, aortae from LysM-IL-6OE mice expressed higher levels of inducible NO synthase and endothelin-1, thus partially accounting for vascular dysfunction, whereas systemic blood pressure alterations were not observed. Bone marrow (BM) transplantation experiments revealed that vascular dysfunction and ROS formation were driven by BM cell-derived IL-6 in a dose-dependent manner. Mice with conditional overexpression of IL-6 in myeloid cells show systemic and vascular inflammation as well as endothelial dysfunction. A decrease in circulating IL-6 levels by replacing IL-6-producing myeloid cells in the BM improved vascular dysfunction in this model, underpinning the relevant role of IL-6 in vascular disease.

CD163+ Macrophages Induce Endothelial-to-Mesenchymal Transition in Atheroma.

Cell phenotype switching is increasingly being recognized in atherosclerosis. However, our understanding of the exact stimuli for such cellular transformations and their significance for human atherosclerosis is still evolving. Intraplaque hemorrhage is thought to be a major contributor to plaque progression in part by stimulating the influx of CD163+ macrophages. Here, we explored the hypothesis that CD163+ macrophages cause plaque progression through the induction of proapoptotic endothelial-to-mesenchymal transition (EndMT) within the fibrous cap. Human coronary artery sections from CVPath's autopsy registry were selected for pathological analysis. Athero-prone ApoE-/- and ApoE-/-/CD163-/- mice were used for in vivo studies. Human peripheral blood mononuclear cell-induced macrophages and human aortic endothelial cells were used for in vitro experiments. In 107 lesions with acute coronary plaque rupture, 55% had pathological evidence of intraplaque hemorrhage in nonculprit vessels/lesions. Thinner fibrous cap, greater CD163+ macrophage accumulation, and a larger number of CD31/FSP-1 (fibroblast specific protein-1) double-positive cells and TUNEL (terminal deoxynucleotidyl transferase-dUTP nick end labeling) positive cells in the fibrous cap were observed in nonculprit intraplaque hemorrhage lesions, as well as in culprit rupture sections versus nonculprit fibroatheroma sections. Human aortic endothelial cells cultured with supernatants from hemoglobin/haptoglobin-exposed macrophages showed that increased mesenchymal marker proteins (transgelin and FSP-1) while endothelial markers (VE-cadherin and CD31) were reduced, suggesting EndMT induction. Activation of NF-κB (nuclear factor kappa β) signaling by proinflammatory cytokines released from CD163+ macrophages directly regulated the expression of Snail, a critical transcription factor during EndMT induction. Western blot analysis for cleaved caspase-3 and microarray analysis of human aortic endothelial cells indicated that apoptosis was stimulated during CD163+ macrophage-induced EndMT. Additionally, CD163 deletion in athero-prone mice suggested that CD163 is required for EndMT and plaque progression. Using single-cell RNA sequencing from human carotid endarterectomy lesions, a population of EndMT was detected, which demonstrated significant upregulation of apoptosis-related genes. CD163+ macrophages provoke EndMT, which may promote plaque progression through fibrous cap thinning.

An injectable and antifouling hydrogel prevents the development of abdominal adhesions by inhibiting the CCL2/CCR2 interaction

Abdominal adhesion, a serious complication of abdominal surgery, often resists mitigation by current drug administration and physical barriers. To address this issue, we developed an injectable, antifouling hydrogel through the free-radical polymerization of methacrylate chondroitin sulfate (CS-GMA) and 2-methacryloyloxyethyl phosphorylcholine (MPC) monomers, dubbed the CGM hydrogel. We systematically analyzed its physicochemical properties, including rheological strength, biocompatibility, and antifouling capabilities. A rat abdominal cecum adhesion model was constructed to assess the effectiveness of CGM hydrogel in preventing postoperative adhesion and recurrent adhesion. In addition, multi-omics analyses identified the relationship between adhesion development and CCL2/CCR2 interaction. Notably, CGM hydrogel can thwart the recruitment and aggregation of fibroblasts and macrophages by inhibiting the CCL2/CCR2 interaction. Moreover, CGM hydrogel significantly dampens the activity of fibrosis-linked cytokines (TGF-βR1) and recalibrates extracellular matrix deposition-related cytokines (t-PA and PAI-1, Col Ⅰ and MMP-9). Cumulatively, the dual action of CGM hydrogel-as a physical barrier and cytokine regulator-highlights its promising potential in clinical application for abdominal adhesion prevention.

A Systematic Review and Meta-Analysis on the Role of Bempedoic Acid in Cardiovascular Outcomes for Patients With Statin Intolerance.

Atherosclerosis, a multifaceted pathogenic process affecting the arteries and aorta, poses a significant threat because of its potential to impede or entirely obstruct blood flow by narrowing blood vessels. This intricate progression involves various factors such as dyslipidemia, immunological responses, inflammation, and endothelial dysfunction. The initial phase manifests as the formation of fatty streaks, considered a pivotal hallmark in the inception of atherosclerotic plaques, a process that can commence as early as childhood. Over time, this process evolves, characterized by the thickening of the arterial inner layer (intima) and accumulation of lipid-laden macrophages, commonly known as foam cells, along with the buildup of the extracellular matrix. Subsequent stages witness the proliferation and aggregation of smooth muscle cells, culminating in the formation of atheroma plaques. As these lesions progress, apoptosis can occur in the deeper layers, further recruiting macrophages, which may undergo calcification and transform into atherosclerotic plaques. Notably, mechanisms such as arterial remodeling and intraplaque hemorrhage also contribute significantly to the progression of atherosclerotic cardiovascular disease, although these facets fall beyond the scope of this article. This study aimed to systematically review and conduct a meta-analysis of randomized controlled trials investigating the efficacy and safety of bempedoic acid in statin-intolerant patients with hyperlipidemia and to provide conclusions and recommendations accordingly. A systematic search of databases, such as PubMed, Web of Science, and Embase, will be performed. Only randomized trials will be included comparing bempedoic acid with placebo in statin-intolerant patients. This study aimed to provide a comprehensive understanding of the role of bempedoic acid in managing hyperlipidemia in statin-intolerant patients. In primary prevention, for patients unable to tolerate recommended statins, bempedoic acid was associated with a significant reduction in major adverse cardiovascular events (MACE) as the primary endpoint.

AN0025 in combination with definitive chemoradiotherapy (dCRT) in unresectable locally advanced or locally recurrent esophageal cancer (EC): A single-arm, open-label, multicenter, phase Ib study.

e16076 Background: AN0025 is a selective EP4 inhibitor that demonstrates antitumor activity by modulating the accumulation and function of macrophages and immunosuppressive myeloid cells in tumor microenvironment. The combination of AN0025 with CRT as neoadjuvant therapy has shown synergistic antitumor efficacy in locally advanced rectal cancer in a prior clinical trial (NCT03152370). Methods: This Phase Ib study includes a dose escalation phase followed by an expansion phase to evaluate the safety, tolerability, and feasibility of AN0025 plus dCRT for unresectable locally advanced or locally recurrent EC or esophagogastric junction cancer. Antitumor efficacy was assessed per RECIST v1.1. The eligible patients (pts) are candidates for dCRT, who received RT (2.0 Gy/fraction, totally 50-60 Gy) with concurrent weekly paclitaxel and carboplatin for 4 weeks, followed by two doses of consolidation chemotherapy on Week 8 and Week 12. AN0025 (250 mg or 500 mg QD) was administered orally for 15 weeks concurrently with dCRT. At the beginning of Week 17, pts would start AN0025 monotherapy in the maintenance phase. Results: As of Jan 12, 2024, 12 pts (11 males and 1 female, median age 62) with histologically confirmed esophageal squamous cell carcinoma (ESCC) were enrolled and received the study treatment, 5 at the 250 mg dose level and 7 at the 500 mg dose level. Among those 12 pts, 11 were locally advanced ESCCs and 1 was locally recurrent ESCC. The most common AN0025-related adverse events (AEs) were weight decreased (33%), anemia (33%), and white blood cell count decreased (25%). Two pts (17%) experienced Grade ≥3 AN0025-related AEs (one Grade 3 weight decreased and one Grade 3 esophageal fistula). No dose-limiting toxicity occurred at either dose level, and the maximum tolerated dose was not reached. The median follow-up was 14.2 months, with 8 pts remaining on study treatment and a maximum time on treatment of 2 years. The disease control rate (DCR) was 92% (11/12). The median progression-free survival (PFS) was not reached, with 6-month and 1-year PFS rates of 91% and 73%, respectively. The 1-year overall survival (OS) rate was 82%. Additionally, among the 8 pts with measurable lesion(s) at baseline, 1 (13%) achieved confirmed complete response (CR), and 6 achieved partial response (PR), including 5 confirmed PRs, giving an unconfirmed overall response rate (ORR) of 88% (7/8) and a confirmed ORR of 75% (6/8). AN0025 PK approached linearity at both 250 mg and 500 mg QD. AN0025 PK in combination with dCRT showed no interactions. Conclusions: This Phase Ib study suggests that AN0025 plus dCRT exhibits favorable safety and encouraging preliminary efficacy in unresectable locally advanced or locally recurrent EC, warranting further investigation. Clinical trial information: NCT05191667 .

Molecular mechanism of renal lipid accumulation in diabetic kidney disease.

Diabetic kidney disease (DKD) is a leading cause of end stage renal disease with unmet clinical demands for treatment. Lipids are essential for cell survival; however, renal cells have limited capability to metabolize overloaded lipids. Dyslipidaemia is common in DKD patients and renal ectopic lipid accumulation is associated with disease progression. Unveiling the molecular mechanism involved in renal lipid regulation is crucial for exploring potential therapeutic targets. In this review, we focused on the mechanism underlying cholesterol, oxysterol and fatty acid metabolism disorder in the context of DKD. Specific regulators of lipid accumulation in different kidney compartment and TREM2 macrophages, a lipid-related macrophages in DKD, were discussed. The role of sodium-glucose transporter 2 inhibitors in improving renal lipid accumulation was summarized.

Trem2 drives accumulation of pro-fibrotic monocyte-derived macrophages in the infarcted myocardium

Trem2 drives accumulation of pro-fibrotic monocyte-derived macrophages in the infarcted myocardium

LY86 facilitates ox-LDL-induced lipid accumulation in macrophages by upregulating SREBP2/HMGCR expression

LY86, also known as MD1, has been implicated in various pathophysiological processes including inflammation, obesity, insulin resistance, and immunoregulation. However, the role of LY86 in cholesterol metabolism remains incompletely understood. Several studies have reported significant up-regulation of LY86 mRNA in atherosclerosis; nevertheless, the regulatory mechanism by which LY86 is involved in this disease remains unclear. In this study, we aimed to investigate whether LY86 affects ox-LDL-induced lipid accumulation in macrophages. Firstly, we confirmed that LY86 is indeed involved in the process of atherosclerosis and found high expression levels of LY86 in human atherosclerotic plaque tissue. Furthermore, our findings suggest that LY86 may mediate intracellular lipid accumulation induced by ox-LDL through the SREBP2/HMGCR pathway. This mechanism could be associated with increased cholesterol synthesis resulting from enhanced endoplasmic reticulum stress response.

Definitive chemoradiotherapy induces T-cell-inflamed tumor microenvironment in unresectable locally advanced esophageal squamous cell carcinoma.

Chemoradiotherapy (CRT) modulates the tumor immune microenvironment of multiple cancer types, including esophageal cancer, which potentially induces both immunogenicity and immunosuppression by upregulating the presentation of tumor-specific antigens and immune checkpoint molecules in tumors, respectively. The prognostic effects of immune modification by CRT in esophageal squamous cell carcinoma (ESCC) remain controversial because of the lack of detailed immunological analyses using paired clinical specimens before and after CRT. We aimed to clarify the immunological changes in the tumor microenvironment caused by CRT and elucidate the predictive importance of clinical response and prognosis and the rationale for the necessity of subsequent programmed cell death protein 1 (PD-1) inhibitor treatment. In this study, we performed a comprehensive immunological analysis of paired biopsy specimens using multiplex immunohistochemistry before and after CRT in patients with unresectable locally advanced ESCC. CRT significantly increased the intra-tumoral infiltration and PD-1 expression of CD8+ T cells and conventional CD4+ T cells but decreased those of regulatory T cells and the accumulation of tumor-associated macrophages. Multivariate analysis of tumor-infiltrating T-cell phenotypes revealed that the density of PD-1+CD8+ T cells in the tumor after CRT could predict a confirmed complete response and favorable survival. This study showed that CRT improved the immunological characteristics of unresectable locally advanced ESCC and identified the density of PD-1+CD8+ T cells as a predictive factor for prognosis. This finding supports the rationale for the necessity of subsequent PD-1 inhibitor treatment.

Pathological Effects of Aflatoxin on Hepatic Tissue of Rats, Experimental Study

The objective of studying this research is to discuss the pathological influence of aflatoxin on hepatic tissue. Aflatoxin was produced in this work using Aspergillus flavus. The samples were mixed with Potato Dextrose Agar (PDA) and left to incubate at a temperature of 28 ± 2°C for three to five days. We employed the fungal species for further usage once they were incubated. The AF was made via a fermentation process with Aspergillus parasitcus and rice, After the rice had fermented properly, it was steams to destroy the fungus, dried, and pulverised into a powder. The AF concentration in rice residue was determined using a TLC fluorometric densitometer on TLC spots. Ten rats from each of the two experimental groups—"G1 Control" (fed a baseline diet without AF) and "AF" (fed a different diet)—were randomly assigned to participate in the study. Group 2 rats were given 25 μg of AF daily. This study's duration was ninety days. Then, blood specimens were drawn by heart puncture using a syringe to determine serum enzyme levels. The animals were sacrificed in order to get tissue samples as well enzyme levels were assessed in serum specimens that had been centrifuged at 4000 × g for 15 minutes at 4 °C. The levels of AST, ALT, and GGT were determined using a spectrophotometer and a kit that was received from Biolabo. Liver samples were collected from rats after scarification, embedded in paraffin wax, and fixed with 10% neutralised formaldehyde. Hematoxylin and eosin were used for staining. The AF-treated group had substantially high levels of those enzymes compare to the control group (p < 0.05). G2 demonstrated that macrophage aggregations in the liver parenchyma constitute granulomatous lesions. Another portion showed hepatocyte apoptosis, which is defined by dense nuclei in the hepatocyte's irregular esonophilic cytoplasm, and a necrotic region with pyknosis or no nuclei at all. A portion of the liver of rats that were treated with aflatoxin showed proliferation of kupffer cells together with a few clusters of mononuclear cells around the major vein. In conclusion, Aflatoxin can affect of liver tissue histology as well as liver enzymes such as ALT, AST as well as GGT.