Inflammatory Macrophage Interleukin-1ß Mediates High-Fat Diet-Induced Heart Failure With Preserved Ejection Fraction.

Diabetes mellitus (DM) is a main risk factor for diastolic dysfunction (DD) and heart failure with preserved ejection fraction. High-fat diet (HFD) mice presented with diabetes mellitus, DD, higher cardiac interleukin (IL)-1ß levels, and proinflammatory cardiac macrophage accumulation. DD was significantly ameliorated by suppressing IL-1ß signaling or depleting macrophages. Mice with macrophages unable to adopt a proinflammatory phenotype were low in cardiac IL-1ß levels and were resistant to HFD-induced DD. IL-1ß enhanced mitochondrial reactive oxygen species (mitoROS) in cardiomyocytes, and scavenging mitoROS improved HFD-induced DD. In conclusion, macrophage-mediated inflammation contributed to HFD-associated DD through IL-1ß and mitoROS production.

Liraglutide Lowers Endothelial Vascular Cell Adhesion Molecule-1 in Murine Atherosclerosis Independent of Glucose Levels.

The authors determined the effect of the GLP-1 receptor agonist liraglutide on endothelial surface expression of vascular cell adhesion molecule (VCAM)-1 in murine apolipoprotein E knockout atherosclerosis. Contrast-enhanced ultrasound molecular imaging using microbubbles targeted to VCAM-1 and control microbubbles showed a 3-fold increase in endothelial surface VCAM-1 signal in vehicle-treated animals, whereas in the liraglutide-treated animals the signal ratio remained around 1 throughout the study. Liraglutide had no influence on low-density lipoprotein cholesterol or glycated hemoglobin, but reduced TNF-α, IL-1ß, MCP-1, and OPN. Aortic plaque lesion area and luminal VCAM-1 expression on immunohistology were reduced under liraglutide treatment.

Effect of fermented red ginseng on gut microbiota dysbiosis- or immobilization stress-induced anxiety, depression, and colitis in mice.

Background: Red ginseng (RG) alleviates psychiatric disorders. Fermented red ginseng (fRG) alleviates stress-induced gut inflammation. Gut dysbiosis causes psychiatric disorders with gut inflammation. To understand the gut microbiota-mediated action mechanism of RG and fRG against anxiety/depression (AD), we investigated the effects of RG, fRG, ginsenoside Rd, and 20(S)-ß-D-glucopyranosyl protopanaxadiol (CK) on gut microbiota dysbiosis-induced AD and colitis in mice. Methods: Mice with AD and colitis were prepared by exposing to immobilization stress (IS) or transplanting the feces of patients with ulcerative colitis and depression (UCDF). AD-like behaviors were measured in the elevated plus maze, light/dark transition, forced swimming, and tail suspension tests. Results: Oral gavage of UCDF increased AD-like behaviors and induced neuroinflammation, gastrointestinal inflammation, and gut microbiota fluctuation in mice. Oral administration of fRG or RG treatment reduced UCDF-induced AD-like behaviors, hippocampal and hypothalamic IL-6 expression, and blood corticosterone level, whereas UCDF-suppressed hippocampal BDNF+NeuN+ cell population and dopamine and hypothalamic serotonin levels increased. Furthermore, their treatments suppressed UCDF-induced colonic inflammation and partially restored UCDF-induced gut microbiota fluctuation. Oral administration of fRG, RG, Rd, or CK also decreased IS-induced AD-like behaviors, blood IL-6 and corticosterone and colonic IL-6 and TNF-α levels, and gut dysbiosis, while IS-suppressed hypothalamic dopamine and serotonin levels increased. Conclusion: Oral gavage of UCDF caused AD, neuroinflammation, and gastrointestinal inflammation in mice. fRG mitigated AD and colitis in UCDF-exposed mice by the regulation of the microbiota-gut-brain axis and IS-exposed mice by the regulation of the hypothalamic-pituitary-adrenal axis.

Bisphenols, but not phthalate esters, modulate gene expression in activated human MAIT cells in vitro.

One route of human exposure to environmental chemicals is oral uptake. This is primarily true for chemicals that may leach from food packaging materials, such as bisphenols and phthalate esters. Upon ingestion, these compounds are transported along the intestinal tract, from where they can be taken up into the blood stream or distributed to mucosal sites. At mucosal sites, mucosal immune cells and in the blood stream peripheral immune cells may be exposed to these chemicals potentially modulating immune cell functions. In the present study, we investigated the impact of three common bisphenols and two phthalate esters on mucosal-associated invariant T (MAIT) cells in vitro, a frequent immune cell type in the intestinal mucosae and peripheral blood of humans. All compounds were non-cytotoxic at the chosen concentrations. MAIT cell activation was only slightly affected as seen by flow cytometric analysis. Phthalate esters did not affect MAIT cell gene expression, while bisphenol-exposure induced significant changes. Transcriptional changes occurred in ∼ 25 % of genes for BPA, ∼ 22 % for BPF and ∼ 8 % for BPS. All bisphenols down-modulated expression of CCND2, CCL20, GZMB and IRF4, indicating an effect on MAIT cell effector function. Further, BPA and BPF showed a high overlap in modulated genes involved in cellular stress response, activation signaling and effector function suggesting that BPF may not be safe substitute for BPA.

Obesity hormones and itaconate mediating inflammation in human colon cancer cells - Another lead to early-onset colon cancer?

Background: Chronic inflammation is a key feature of obesity and a hallmark of colon cancer (CC). The obesity-related hormones leptin and adiponectin alter inflammatory gene profiles in cancer, but their specific role in CC is unclear. We have previously studied the effects of leptin and the macrophage-specific mediator itaconate on M2-like macrophages. This current study evaluates their effects on CC cells. Methods: HT-29 CC cells (derived from a young patient, stage III CC) were treated with either leptin, adiponectin, 4-octyl itaconate (OI) or dimethyl itaconate (DI). Gene expression after treatment was analyzed at four time points (3, 6, 18, and 24 h). Results: CCL22 was upregulated after treatment with adiponectin (at 18 h [FC 16.3, p < 0.001]). IL-8 expression increased following both adiponectin (at 3 h [FC 68.1, p < 0.001]) and leptin treatments (at 6 h [FC 7.3, p < 0.001]), while OI induced downregulation of IL-8 (at 24 h [FC -5.0, p < 0.001]). CXCL10 was upregulated after adiponectin treatment (at 6 h [FC 3.0, p = 0.025]) and downregulated by both OI and DI at 24 h, respectively (OI [FC -10.0, p < 0.001]; DI [FC -10.0, p < 0.001]). IL-1ß was upregulated after adiponectin treatment (at 3 h [FC 10.6, p < 0.001]) and downregulated by DI (at 24 h [FC -5.0, p < 0.001]). TNF-α expression was induced following adiponectin (at 6 h [FC 110.7, p < 0.001]), leptin (at 18 h [FC 5.8, p = 0.027]) and OI (at 3 h [FC 91.1, p = 0.001]). PPARγ was affected by both OI (at 3 h [FC 10.1, p = 0.031], at 24 h [FC -10.0, p = 0.031]) and DI (at 18 h [FC -1.7, p = 0.033]). Conclusions: Obesity hormones directly affect inflammatory gene expression in HT29 CC cells, potentially enhancing cancer progression. Itaconate affects the prognostic marker PPARγ in HT29 CC cells. Leptin, adiponectin and itaconate may represent a link between obesity and CC.

Clinical efficacy of combination therapy of FuXi-Tiandi-Wuxing Decoction and anti-viral drugs in the treatment of novel coronavirus pneumonia: A prospective interventional study.

Introduction: The National Administration of Traditional Chinese Medicine of the People's Republic of China (NATCM) and the State Administration of Traditional Chinese medicine (TCM) advocated a combination therapy of TCM and anti-viral drugs for novel coronavirus pneumonia (NCP) to improve the efficacy of clinical treatment. Methods: Forty-six patients diagnosed with NCP were sequentially divided into intent-to-treat population: the experimental group (combination of FuXi-Tiandi-Wuxing Decoction and anti-viral drugs; n = 23) and the control group (anti-viral drugs only) (n = 23). The two groups were compared in terms of duration of fever, cough symptom score, fatigue, appetite, dyspnea, out-of-bed activities, chest computer tomography (CT) recovery, virological clearance, average length of hospital stay, and clinical effective rate of drug. After 6 days of observation, patients from the control group were divided into as-treated population: experimental subgroup (n = 14) to obtain clinical benefit and control subgroup (n = 9). Results: There was a significant improvement in the duration of fever (1.087 ± 0.288 vs 4.304 ± 2.490), cough (0.437 ± 0.589 vs 2.435 ± 0.662; P < 0.05), chest CT evaluation (82.6% vs 43.4%; P < 0.05), and virological clearance (60.8% vs 8.7%; P < 0.05) in patients of the experimental group compared with patients in the control group. Further observation in as-treated population reported that cough (0.742 ± 0.463 vs 1.862 ± 0.347; P < 0.05) and fatigue (78.5% vs 33.3%; P < 0.05) were significantly relieved after adding FuXi-Tiandi-Wuxing Decoction to the existing treatment. Conclusion: An early treatment with combination therapy of FuXi-Tiandi-Wuxing Decoction and anti-viral drugs significantly relieves the clinical symptoms of NCP, shows improvement in chest CT scan, improves virological clearance, shortens average length of hospital stay, and reduces the risk of severe illness. The effect of FuXi-Tiandi-Wuxing Decoction in NCP may be clinically important and require further consideration.

Risk of SARS-CoV-2 infection in healthcare workers with inflammatory bowel disease: a case-control study.

Background: Whether healthcare workers with inflammatory bowel disease (IBD) are at increased risk of Novel coronavirus disease (COVID-19) due to occupational exposure is unknown. Aim: To assess the risk of COVID-19 in healthcare workers with IBD. Methods: A case control study enrolled 326 healthcare workers with IBD from 17 GETAID centres and matched non-healthcare workers with IBD controls (1:1) for gender, age, disease subtype and year of diagnosis. The study period was year 2020 during the COVID-19 outbreak. Results: In total, 59 COVID-19 were recorded among cases (n = 32) and controls (n = 27), including 2 severe COVID-19 (requiring hospitalization, mechanic ventilation) but no death. No difference was observed between healthcare workers and controls regarding the overall incidence rates of COVID-19 4.9 ± 2.2 vs. 3.8 ± 1.9 per 100 patient-semesters, P = 0.34) and the overall incidence rates of severe COVID-19 (0.6 ± 7.8 vs. 0.3 ± 5.5 per 100 patient-semesters, P = 0.42). In multivariate analysis in the entire study population, COVID-19 was associated with patients with body mass index > 30 kg/m2 (HR = 2.48, 95%CI [1.13-5.44], P = 0.02). Conclusion: Healthcare workers with IBD do not have an increased risk of COVID-19 compared with other patients with IBD.

Prediction of early-wheelchair dependence in multiple system atrophy based on machine learning algorithm: A prospective cohort study.

Objective: The predictive factors for wheelchair dependence in patients with multiple system atrophy (MSA) are unclear. We aimed to explore the predictive factors for early-wheelchair dependence in patients with MSA focusing on clinical features and blood biomarkers. Methods: This is a prospective cohort study. This study included patients diagnosed with MSA between January 2014 and December 2019. At the deadline of October 2021, patients met the diagnosis of probable MSA were included in the analysis. Random forest (RF) was used to establish a predictive model for early-wheelchair dependence. Accuracy, sensitivity, specificity, and area under the receiver operating characteristic curve (AUC) were used to evaluate the performance of the model. Results: Altogether, 100 patients with MSA including 49 with wheelchair dependence and 51 without wheelchair dependence were enrolled in the RF model. Baseline plasma neurofilament light chain (NFL) levels were higher in patients with wheelchair dependence than in those without (P = 0.037). According to the Gini index, the five major predictive factors were disease duration, age of onset, Unified MSA Rating Scale (UMSARS)-II score, NFL, and UMSARS-I score, followed by C-reactive protein (CRP) levels, neutrophil-to-lymphocyte ratio (NLR), UMSARS-IV score, symptom onset, orthostatic hypotension, sex, urinary incontinence, and diagnosis subtype. The sensitivity, specificity, accuracy, and AUC of the RF model were 70.82 %, 74.55 %, 72.29 %, and 0.72, respectively. Conclusion: Besides clinical features, baseline features including NFL, CRP, and NLR were potential predictive biomarkers of early-wheelchair dependence in MSA. These findings provide new insights into the trials regarding early intervention in MSA.

Thymus vulgaris, a natural pharmacy against COVID-19: A molecular review.

Introduction: A worldwide pandemic infection by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the cause of a deadly disease called COVID-19. Interaction of the virus and the Angiotensin converting-enzyme 2 (ACE2) receptor leads to an inflammatory-induced tissue damage. Thymus vulgaris L. (TvL) is a plant with a long history in traditional medicine that has antimicrobial, antiseptic, and antiviral properties. Thymol and Carvacrol are two important biological components in Thyme that have anti-inflammatory, antioxidant, and immunomodulatory properties. This study is a molecular review on the potential effects of TvL and its active compounds on SARS-COV2 infection. Method: This is a narrative review in which using PubMed, Scopus, ISI, Cochrane, ScienceDirect, Google scholar, and Arxiv preprint databases, the molecular mechanisms of therapeutic and protective effects of TvL and its active compounds have been discussed regarding the molecular pathogenesis in COVID-19. Results: Thyme could suppress TNF-alpha, IL-6, and other inflammatory cytokines. It also enhances the anti-inflammatory cytokines like TGF-beta and IL-10. Thyme extract acts also as an inhibitor of cytokines IL-1-beta and IL-8, at both mRNA and protein levels. Thymol may also control the progression of neuro-inflammation toward neurological disease by reducing some factors. Thyme and its active ingredients, especially Thymol and Carvacrol, have also positive effects on the renin-angiotensin system (RAS) and intestinal microbiota. Conclusions: Accordingly, TvL and its bioactive components may prevent COVID-19 complications and has a potential protective role against the deleterious consequences of the disease.

Microbiome and the inflammatory pathway in peri-implant health and disease with an updated review on treatment strategies.

Crestal bone preservation around the dental implant for aesthetic and functional success is widely researched and documented over a decade. Several etiological factors were put forth for crestal bone loss; of which biofilm plays a major role. Biofilm is formed by the colonization of wide spectra of bacteria inhabited around dental implants. Bacterial adherence affects the regulators of bone growth and an early intervention preserves the peri-implant bone. Primary modes of therapy stated in early literature were either prevention or treatment of infection caused by biofilm. This narrative review overviews the microbiome during different stages of peri-implant health, the mechanism of bone destruction, and the expression of the biomarkers at each stage. Microbial contamination and the associated biomarkers varied depending on the stage of peri-implant infection. The comprehensive review helps in formulating a research plan, both in diagnostics and treatment aspects in improving peri-implant health.

Bellidifolin from Gentianella acuta (Michx.) Hulten protects H9c2 cells from hydrogen peroxide-induced injury via the PI3K-Akt signal pathway.

Cardiovascular disease is the most common disease in the world and the first among the causes of human death. Its morbidity and mortality increase annually, but no effective treatment is available. Therefore, new drugs should be developed to treat cardiovascular disease. Gentianella acuta (Michx.) Hulten (G. acuta) is an important Mongolian medicine in China and elicits protective effects on cardiovascular health. In this study, liquid chromatography-mass spectrometry (LC-MS) combined with network pharmacology was used to screen the main active ingredients and confirm that bellidifolin was one of the main components for the treatment of ischemic heart disease. Then, rat myocardial (H9c2) cells injury model induced by hydrogen peroxide (H2O2) in vitro was established to verify the effect of bellidifolin on oxidative stress stimulation, including determination of antioxidant enzyme activity and apoptosis. Transcriptome sequencing, qRT-PCR, and western blot were performed to further verify the antioxidant stress mechanism of bellidifolin. Results showed that bellidifolin pretreatment decreased the rate of apoptosis and the levels of lactate dehydrogenase (LDH), creatine kinase (CK), and alanine aminotransferase (ALT). Conversely, it increased the contents of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) in a dose-dependent manner, indicating that bellidifolin caused a protective effect on cardiomyocyte injury. Bellidifolin minimized the H2O2-induced cell injury by activating the PI3K-Akt signal pathway and downregulating glycogen synthase kinase-3ß (GSK-3ß) and p-Akt1/Akt1. Therefore, this work revealed that G. acuta has a good development prospect as an edible medicinal plant in cardiovascular disease. Its bellidifolin component is a potential therapeutic agent for cardiovascular disease induced by oxidative stress damage.

TNFR1 Contributes to Activation-Induced Cell Death of Pathological CD4+ T Lymphocytes During Ischemic Heart Failure.

CD4+ T cells turn pathological during heart failure (HF). We show that the expression of tumor necrosis factor (TNF)-α and tumor necrosis factor receptor (TNFR1) increases in HF-activated CD4+ T cells. However, the role of the TNF-α/TNFR1 axis in T-cell activation/proliferation is unknown. We show that TNFR1 neutralization during T-cell activation (ex vivo) or the loss of TNFR1 in adoptively transferred HF-activated CD4+ T cells (in vivo) augments their prosurvival and proliferative signaling. Importantly, TNFR1 neutralization does not affect CD69 expression or the pathological activity of HF-activated TNFR1-/- CD4+ T cells. These results show that during HF TNFR1 plays an important role in quelling prosurvival and proliferative signals in CD4+ T cells without altering their pathological activity.

Regenerative medicine strategies for hair growth and regeneration: A narrative review of literature.

Hair loss, or alopecia, is associated with several psychosocial and medical comorbidities, and it remains an economic burden to individuals and the society. Alopecia is attributable to varied mechanisms and features a multifactorial predisposition, and the available conventional medical interventions have several limitations. Thus, several therapeutic strategies for alopecia in regenerative medicine are currently being explored, with increasing evidence suggesting that mesenchymal stem cell (MSC) implantation, MSC-derived secretome treatment, and blood-derived platelet-rich plasma therapies are potential treatment options. In this review, we searched the Cochrane Library, MEDLINE (PubMed), EMBASE, and Scopus using various combinations of terms, such as "stem cell," "alopecia," "hair loss," "Androgenetic alopecia," "male-pattern hair loss," "female-pattern hair loss," "regenerative hair growth," "cell therapy," "mesenchymal stem cells," "MSC-derived extracellular vesicles," "MSC-derived exosomes," and "platelet-rich plasma" and summarized the most promising regenerative treatments for alopecia. Moreover, further opportunities of improving efficacy and innovative strategies for promoting clinical application were discussed.

From structure to function - Ligand recognition by myeloid C-type lectin receptors.

The relevance of protein-glycan interactions in immunity has long been underestimated. Yet, the immune system possesses numerous classes of glycan-binding proteins, so-called lectins. Of specific interest is the group of myeloid C-type lectin receptors (CLRs) as they are mainly expressed by myeloid cells and play an important role in the initiation of an immune response. Myeloid CLRs represent a major group amongst pattern recognition receptors (PRRs), placing them at the center of the rapidly growing field of glycoimmunology. CLRs have evolved to encompass a wide range of structures and functions and to recognize a large number of glycans and many other ligands from different classes of biopolymers. This review aims at providing the reader with an overview of myeloid CLRs and selected ligands, while highlighting recent insights into CLR-ligand interactions. Subsequently, methodological approaches in CLR-ligand research will be presented. Finally, this review will discuss how CLR-ligand interactions culminate in immunological functions, how glycan mimicry favors immune escape by pathogens, and in which way immune responses can be affected by CLR-ligand interactions in the long term.

Pathogenesis of Alcohol-Associated Liver Disease.

Excessive alcohol consumption is a global healthcare problem with enormous social, economic, and clinical consequences. While chronic, heavy alcohol consumption causes structural damage and/or disrupts normal organ function in virtually every tissue of the body, the liver sustains the greatest damage. This is primarily because the liver is the first to see alcohol absorbed from the gastrointestinal tract via the portal circulation and second, because the liver is the principal site of ethanol metabolism. Alcohol-induced damage remains one of the most prevalent disorders of the liver and a leading cause of death or transplantation from liver disease. Despite extensive research on the pathophysiology of this disease, there are still no targeted therapies available. Given the multifactorial mechanisms for alcohol-associated liver disease pathogenesis, it is conceivable that a multitherapeutic regimen is needed to treat different stages in the spectrum of this disease.

Macrophages in periodontitis: A dynamic shift between tissue destruction and repair.

Periodontitis is a chronic inflammatory disease associated with a dysbiotic bacterial biofilm in the subgingival environment that may disturb the balance between the oral microbiome and its host. The inability of the immune system to eliminate inflammation may result in the progressive destruction of tooth-support tissues. Macrophages are crucial cellular components of the innate immune system and play important roles in diverse physiological and pathological processes. In response to periodontitis-associated bacterial communities, macrophages contribute to inflammation and restoration of tissue homeostasis through pattern recognition receptor-induced signaling cascades; therefore, targeting macrophages can be a feasible strategy to treat patients with periodontitis. Although recent studies indicate that macrophages have a spectrum of activation states, ranging from pro-inflammatory to anti-inflammatory, the regulatory mechanism of the macrophage response to dysbiosis in a tissue-specific manner remains largely unclear. Herein, we attempt to summarize the potential role of macrophage activation in the progression of periodontitis, as well as its relevance to future approaches in the treatment of periodontitis.

Ischemic preconditioning upregulates Mitofusin2 and preserves muscle strength in tourniquet-induced ischemia/reperfusion.

Background: Tourniquet-induced ischemia and reperfusion (I/R) has been related to postoperative muscle atrophy through mechanisms involving protein synthesis/breakdown, cellular metabolism, mitochondrial dysfunction, and apoptosis. Ischemic preconditioning (IPC) could protect skeletal muscle against I/R injury. This study aims to determine the underlying mechanisms of IPC and its effect on muscle strength after total knee arthroplasty (TKA). Methods: Twenty-four TKA patients were randomized to receive either sham IPC or IPC (3 cycles of 5-min ischemia followed by 5-min reperfusion). Vastus medialis muscle biopsies were collected at 30 â€‹min after tourniquet (TQ) inflation and the onset of reperfusion. Western blot analysis was performed in muscle protein for 4-HNE, SOD2, TNF-ɑ, IL-6, p-Drp1ser616, Drp1, Mfn1, Mfn2, Opa1, PGC-1ɑ, ETC complex I-V, cytochrome c, cleaved caspase-3, and caspase-3. Clinical outcomes including isokinetic muscle strength and quality of life were evaluated pre- and postoperatively. Results: IPC significantly increased Mfn2 (2.0 â€‹± â€‹0.2 vs 1.2 â€‹± â€‹0.1, p â€‹= â€‹0.001) and Opa1 (2.9 â€‹± â€‹0.3 vs 1.9 â€‹± â€‹0.2, p â€‹= â€‹0.005) proteins expression at the onset of reperfusion, compared to the ischemic phase. There were no differences in 4-HNE, SOD2, TNF-ɑ, IL-6, p-Drp1ser616/Drp1, Mfn1, PGC-1ɑ, ETC complex I-V, cytochrome c, and cleaved caspase-3/caspase-3 expression between the ischemic and reperfusion periods, or between the groups. Clinically, postoperative peak torque for knee extension significantly reduced in the sham IPC group (-16.6 [-29.5, -3.6] N.m, p â€‹= â€‹0.020), while that in the IPC group was preserved (-4.7 [-25.3, 16.0] N.m, p â€‹= â€‹0.617). Conclusion: In TKA with TQ application, IPC preserved postoperative quadriceps strength and prevented TQ-induced I/R injury partly by enhancing mitochondrial fusion proteins in the skeletal muscle. The translational potential of this article: Mitochondrial fusion is a potential underlying mechanism of IPC in preventing skeletal muscle I/R injury. IPC applied before TQ-induced I/R preserved postoperative quadriceps muscle strength after TKA.