Anti-inflammatory Protein Research Articles

Progressive genetic modifications of porcine cardiac xenografts extend survival to 9 months.

We report orthotopic (life-supporting) survival of genetically engineered porcine cardiac xenografts (with six gene modifications) for almost 9 months in baboon recipients. This work builds on our previously reported heterotopic cardiac xenograft (three gene modifications) survival up to 945 days with an anti-CD40 monoclonal antibody-based immunosuppression. In this current study, life-supporting xenografts containing multiple human complement regulatory, thromboregulatory, and anti-inflammatory proteins, in addition to growth hormone receptor knockout (KO) and carbohydrate antigen KOs, were transplanted in the baboons. Selective "multi-gene" xenografts demonstrate survival greater than 8 months without the requirement of adjunctive medications and without evidence of abnormal xenograft thickness or rejection. These data demonstrate that selective "multi-gene" modifications improve cardiac xenograft survival significantly and may be foundational for paving the way to bridge transplantation in humans.

Host Immune Responses to Salivary Components - A Critical Facet of Tick-Host Interactions.

Tick sialome is comprised of a rich cocktail of bioactive molecules that function as a tool to disarm host immunity, assist blood-feeding, and play a vibrant role in pathogen transmission. The adaptation of the tick’s blood-feeding behavior has lead to the evolution of bioactive molecules in its saliva to assist them to overwhelm hosts’ defense mechanisms. During a blood meal, a tick secretes different salivary molecules including vasodilators, platelet aggregation inhibitors, anticoagulants, anti-inflammatory proteins, and inhibitors of complement activation; the salivary repertoire changes to meet various needs such as tick attachment, feeding, and modulation or impairment of the local dynamic and vigorous host responses. For instance, the tick’s salivary immunomodulatory and cement proteins facilitate the tick’s attachment to the host to enhance prolonged blood-feeding and to modulate the host’s innate and adaptive immune responses. Recent advances implemented in the field of “omics” have substantially assisted our understanding of host immune modulation and immune inhibition against the molecular dynamics of tick salivary molecules in a crosstalk between the tick–host interface. A deep understanding of the tick salivary molecules, their substantial roles in multifactorial immunological cascades, variations in secretion, and host immune responses against these molecules is necessary to control these parasites. In this article, we reviewed updated knowledge about the molecular mechanisms underlying host responses to diverse elements in tick saliva throughout tick invasion, as well as host defense strategies. In conclusion, understanding the mechanisms involved in the complex interactions between the tick salivary components and host responses is essential to decipher the host defense mechanisms against the tick evasion strategies at tick-host interface which is promising in the development of effective anti-tick vaccines and drug therapeutics.

Reduced Plasma Extracellular Vesicle CD5L Content in Patients With Acute-On-Chronic Liver Failure: Interplay With Specialized Pro-Resolving Lipid Mediators.

Acute-on chronic liver failure (ACLF) is a syndrome that develops in patients with acutely decompensated cirrhosis (AD). It is characterized by a systemic hyperinflammatory state, leading to multiple organ failure. Our objective was to analyze macrophage anti-inflammatory protein CD5L in plasma extracellular vesicles (EVs) and assess its as yet unknown relationship with lipid mediators in ACLF. With this aim, EVs were purified by size exclusion chromatography from the plasma of healthy subjects (HS) (n=6) and patients with compensated cirrhosis (CC) (n=6), AD (n=11) and ACLF (n=11), which were defined as positive for CD9, CD5L and CD63 and their size, number, morphology and lipid mediator content were characterized by NTA, EM, and LC-MS/MS, respectively. Additionally, plasma CD5L was quantified by ELISA in 10 HS, 20 CC and 149 AD patients (69 ACLF). Moreover, macrophage CD5L expression and the biosynthesis of specialized lipid mediators (SPMs) were characterized in vitro in primary cells. Our results indicate that circulating EVs were significantly suppressed in cirrhosis, regardless of severity, and showed considerable alterations in CD5L and lipid mediator content as the disease progressed. In AD, levels of EV CD5L correlated best with those of the SPM RvE1. Analysis of total plasma supported these data and showed that, in ACLF, low CD5L levels were associated with circulatory (p<0.001), brain (p<0.008) and respiratory (p<0.05) failure (Mann-Whitney test). Functional studies in macrophages indicated a positive feedback loop between CD5L and RvE1 biosynthesis. In summary, we have determined a significant alteration of circulating EV contents in ACLF, with a loss of anti-inflammatory and pro-resolving molecules involved in the control of acute inflammation in this condition.

Design and development of Branched Poly(ß-aminoester) nanoparticles for Interleukin-10 gene delivery in a mouse model of atherosclerosis

Atherosclerosis progression is a result of chronic and non-resolving inflammation, effective treatments for which still remain to be developed. We designed and developed branched poly(ß-amino ester) nanoparticles (NPs) containing plasmid DNA encoding IL-10, a potent anti-inflammatory cytokine to atherosclerosis. The NPs (NP-VHPK) are functionalized with a targeting peptide (VHPK) specific for VCAM-1, which is overexpressed by endothelial cells at sites of atherosclerotic plaque. The anionic coating affords NP-VHPK with significantly lower toxicity than uncoated NPs in both endothelial cells and red blood cells (RBCs). Following injection of NP-VHPK in ApoE−/− mice, Cy5-labelled IL-10 significantly accumulates in both whole aortas and aortic sinus sections containing plaque compared to injection with a non-targeted control. Furthermore, IL-10 gene delivery results in an attenuation of inflammation locally at the plaque site. NP-VHPK may thus have the potential to reduce the inflammatory component of atherosclerosis in a safe and effective manner. Statement of significanceAtherosclerosis is a chronic inflammatory disease that results in the formation of lipid-laden plaques within vascular walls. Although treatments using drugs and antibodies are now beginning to address the inflammation in atherosclerosis, neither is sufficient for long-term therapy. In this paper, we introduce a strategy to deliver genes encoding the anti-inflammatory protein interleukin-10 (IL-10) in vivo. We showed that Branched Poly(ß-aminoester) carrying the IL-10 gene are able to localize specifically at the plaque via surface-functionalized targeting moieties against inflamed VCAM-1 and/or ICAM-1 and to facilitate gene transcription by ECs to increase the local concentration of the IL-10 within the plaque. To date, there is no report involving non-viral nanotechnology to provide gene-based therapies for atherosclerosis.

Proteomic analysis of alcohol-associated hepatitis reveals glycoprotein NMB (GPNMB) as a novel hepatic and serum biomarker.

Alcohol consumption remains a leading cause of liver disease worldwide, resulting in a complex array of hepatic pathologies, including steatosis, steatohepatitis, and cirrhosis. Individuals who progress to a rarer form of alcohol-associated liver disease (ALD), alcohol-associated hepatitis (AH), require immediate life-saving intervention in the form of liver transplantation. Rapid onset of AH is poorly understood and the metabolic mechanisms contributing to the progression to liver failure remain undetermined. While multiple mechanisms have been identified that contribute to ALD, no cures exist and mortality from AH remains high. To identify novel pathways associated with AH, our group utilized proteomics to investigate AH-specific biomarkers in liver explant tissues. The goal of the present study was to determine changes in the proteome as well as epigenetic changes occurring in AH. Protein abundance and acetylomic analyses were performed utilizing nHPLC-MS/MS, revealing significant changes to proteins associated with metabolic and inflammatory fibrosis pathways. Here, we describe a novel hepatic and serum biomarker of AH, glycoprotein NMB (GPNMB). The anti-inflammatory protein GPNMB was significantly increased in AH explant liver and serum compared to healthy donors by 50-fold and 6.5-fold, respectively. Further, bioinformatics analyses identified an AH-dependent decrease in protein abundance across fatty acid degradation, biosynthesis of amino acids, and carbon metabolism. The greatest increases in protein abundance were observed in pathways for focal adhesion, lysosome, phagosome, and actin cytoskeleton. In contrast with the hyperacetylation observed in murine models of ALD, protein acetylation was decreased in AH compared to normal liver across fatty acid degradation, biosynthesis of amino acids, and carbon metabolism. Interestingly, immunoblot analysis found epigenetic marks were significantly increased in AH explants, including Histone H3K9 and H2BK5 acetylation. The increased acetylation of histones likely plays a role in the altered proteomic profile observed, including increases in GPNMB. Indeed, our results reveal that the AH proteome is dramatically impacted through unanticipated and unknown mechanisms. Understanding the origin and consequences of these changes will yield new mechanistic insight for ALD as well as identify novel hepatic and serum biomarkers, such as GPNMB.

Topical therapy of various dermatoses with ImpoyzTM (clobetasol propionate) cream 0.025%

The most widely prescribed drugs for the treatment of a variety of dermatoses are Topical corticosteroids (TC). These medications are approved for the treatment of inflammatory and pruritic manifestations of dermatologic disorders due to their powerful symptom-relieving impact. Clobetasol propionate (CP) is the most popular (TC) used to relieve itching, redness, and oedema caused by a variety of skin disorders. Anti-inflammatory, anti-pruritic, and vasoconstrictive characteristics are all present in it. CP works by binding to cytoplasmic glucocorticoid receptors and activating glucocorticoid receptor-mediated gene expression, resulting in the production of anti-inflammatory proteins while suppressing the production of inflammatory mediators. The formulation is free from known contact allergens, such as propylene glycol, short-chain alcohols, and sorbitol-based emulsifiers, and has demonstrated hypoallergenic effects. The efficacy, safety, and clinical experience of utilizing CP 0.025% cream for the treatment of various dermatologic disorders are discussed in this case series.

Effects of cottonseed protein concentrate on growth performance, hepatic function and intestinal health in juvenile largemouth bass, Micropterus salmoides

The study aimed to evaluate the effect of replacing fish meal (FM) by cottonseed protein concentrate (CPC) on growth, immune respone and health status of largemouth bass, Micropterus salmoides. Fish (initial body weight: 12.21 ± 0.15 g) were fed five isonitrogenous and isolipid diets (48% crude protein and 12% crude lipid) with CPC replacing 0 (control, CPC0), 15% (CPC15), 30% (CPC30), 45% (CPC45) or 60% (CPC60) of fishmeal for 8 weeks. The results showed that weight gain, specific growth rate and protein efficiency ratio were not appreciably reduced until more than 30% of the FM protein was replaced with CPC. Fish fed CPC60 diet had the lowest hepatic antioxidant enzymes (superoxide dismutase, SOD; catalase, CAT; glutathione peroxidase, GPX) activities and genes (SOD, CAT, GSH-Px) expression, but the highest malondialdehyde (MDA) level. Moreover, CPC60 diet significantly down-regulated the expression of anti-inflammatory genes (IL-10, TGF-β) and protein metabolism genes (P13K, AKT, m-TOR, S6K1), whereas up-regulated the expression of pro-inflammatory genes (IL-8, IL-1β, TNFα). Accordingly, the liver histological investigation showed that the histopathological alterations were dramatically increased in the CPC60 group compared to control and CPC30 group. In addition, the CPC60 group decreased the villi height and goblet cell number, and increased villi width and muscular thickness in midgut and hindgut compared with the other groups, respectively. Meanwhile, plasma diamine oxidase (DAO) activity, D-lactate and endotoxin contents increased markedly as the proportion of CPC increased. Notably, the increased dietary CPC levels down-regulated the expression of ZO-1, Claudin-1 and Occludin in intestine. The lower SOD, CAT activities and mRNA levels in intestine were also observed in CPC60 group. Broken-line model analysis based on WG against dietary CPC replacement level indicated that the optimum replacement level was 18.44% when supplemented with crystalline methionine and lysine. However, including too high proportion of CPC could suppress immune and antioxidant capacity, impair both the liver and intestinal health, and finally reduced growth of Micropterus salmoides.

Multi-Omic Profiling of Macrophages Treated with Phospholipids Containing Omega-3 and Omega-6 Fatty Acids Reveals Complex Immunomodulatory Adaptations at Protein, Lipid and Metabolic Levels.

In recent years, several studies have demonstrated that polyunsaturated fatty acids have strong immunomodulatory properties, altering several functions of macrophages. In the present work, we sought to provide a multi-omic approach combining the analysis of the lipidome, the proteome, and the metabolome of RAW 264.7 macrophages supplemented with phospholipids containing omega-3 (PC 18:0/22:6; ω3-PC) or omega-6 (PC 18:0/20:4; ω6-PC) fatty acids, alone and in the presence of lipopolysaccharide (LPS). Supplementation of macrophages with ω3 and ω6 phospholipids plus LPS produced a significant reprogramming of the proteome of macrophages and amplified the immune response; it also promoted the expression of anti-inflammatory proteins (e.g., pleckstrin). Supplementation with the ω3-PC and ω6-PC induced significant changes in the lipidome, with a marked increase in lipid species linked to the inflammatory response, attributed to several pro-inflammatory signalling pathways (e.g., LPCs) but also to the pro-resolving effect of inflammation (e.g., PIs). Finally, the metabolomic analysis demonstrated that supplementation with ω3-PC and ω6-PC induced the expression of several metabolites with a pronounced inflammatory and anti-inflammatory effect (e.g., succinate). Overall, our data show that supplementation of macrophages with ω3-PC and ω6-PC effectively modulates the lipidome, proteome, and metabolome of these immune cells, affecting several metabolic pathways involved in the immune response that are triggered by inflammation.

Plasma Concentration of Tumor Necrosis Factor-Stimulated Gene-6 as a Novel Diagnostic and 3-Month Prognostic Indicator in Non-Cardioembolic Acute Ischemic Stroke.

BackgroundTumor necrosis factor-stimulated gene-6 (TSG-6) is a multifunctional, anti-inflammatory, and protective protein, while the association between TSG-6 and acute ischemic stroke (AIS) remains unclear in humans. This study aims to investigate the potential diagnostic and short-term prognosis predictive values of TSG-6 in non-cardioembolic AIS.MethodsA total of 134 non-cardioembolic AIS patients within 24 h after AIS onset and 40 control subjects were recruited. Using an AIS dataset from the Gene Expression Omnibus database and setting the median expression level of TNFAIP6 as the cutoff point, data were divided into TNFAIP6-high and TNFAIP6-low expression groups. Differently expressed genes (DEGs) were extracted to perform gene enrichment analysis and protein–protein interaction (PPI) network. Baseline data were analyzed in a four-group comparison plotted as plasma TSG-6 concentration median and 25th/75th percentiles. The correlative factors of 3-month outcome were evaluated by logistic regression. TSG-6 concentrations and TSG-6-to-interleukin-8 ratios were compared in a block design. A receiver-operating characteristic curve was used to analyze the detective value of TSG-6 and 3-month prognosis predictive values of TSG-6 and TSG-6-to-interleukin-8 ratio.ResultsNon-cardioembolic AIS patients had significantly higher plasma TSG-6 levels than control subjects (P < 0.0001). The large-artery atherosclerosis group had significantly higher TSG-6 levels than the small-artery occlusion group (P = 0.0184). Seven hundred and eighty-two DEGs might be both AIS-related and TNFAIP6-correlated genes, and 17 targets were deemed AIS-related being closely relevant to TNFAIP6. Interleukin-8 was selected for further study. The National Institutes of Health Stroke Scale and the Acute Stroke Registry and Analysis of Lausanne scores at admission, lesion volume, neutrophil count, neutrophil-to-lymphocyte ratio, and interleukin-8 level were positively correlated with TSG-6 level, respectively (P < 0.0001). The unfavorable outcome group had meaningfully higher TSG-6 levels (P < 0.0001) and lower TSG-6-to-interleukin-8 ratios (P < 0.0001) than the favorable outcome group. After adjusting for confounding variables, elevated TSG-6 levels remained independently associated with 3-month poor prognosis of non-cardioembolic AIS (P = 0.017). In non-cardioembolic AIS, the cutoff values of TSG-6 concentration for detection and 3-month prognosis prediction and the TSG-6-to-interleukin-8 ratio for the 3-month prognosis prediction were 8.13 ng/ml [AUC, 0.774 (0.686–0.861); P < 0.0001], 10.21 ng/ml [AUC, 0.795 (0.702–0.887); P < 0.0001], and 1.505 [AUC, 0.873 (0.795–0.951); P < 0.0001].ConclusionsPlasma TSG-6 concentration was a novel indicator for non-cardioembolic AIS diagnosis and 3-month prognosis. Elevated TSG-6-to-interleukin-8 ratio might suggest a 3-month favorable outcome.

Anti-inflammatory role demonstrated both in vitro and in vivo models using nonsteroidal tetranortriterpenoid, Nimbin (N1) and its analogs (N2 and N3) that alleviate the domestication of alternative medicine.

Human health may benefit from the study of natural compounds and phytoconstituents that can protect from inflammation. We investigated Nimbin (N1), a member of the ring C Seco-tetranortriterpenoids family, and its semi-natural analog deacetyl Nimbin namely N2 and N3 for their anti-inflammatory properties. As key findings, N1, N2, and N3 were able to improve wound healing by cell proliferation in a period of 24 h and were able to reduce the reactive oxygen species (ROS) production in Madin-Darby Canine Kidney cells which were screened using dichloro-dihydro fluorescein diacetate (DCF-DA) staining. When the zebrafish larvae were subjected to DCF-DA assay N1, N2, and N3 were able to substantially reduce the ROS levels in a dose-dependent manner. In zebrafish larvae, the cell death indicates the fluorescent intensity due to acridine orange staining that was found to be dramatically decreasing upon the treatment of N1, N2, and N3. The cell membrane lipid peroxidation levels were also reduced in a dose-dependent manner upon the treatment of Nimbin and its analogs indicating lesser blue fluorescent levels. Among the Nimbin and its analogs, N2 was subjected to have better activity. To confirm the activity of N1, N2, and N3, in silico characterization was performed using Density functional theory and molecular docking. As a result, N2 exhibited the lowest electronegative value and highest binding energy when docked with anti-inflammatory and antioxidant proteins CAT, COX, GP, IL-1, and MPO. Furthermore, the therapeutic potential of N2 must be explored at the molecular level as well as in clinical studies for the treatment of inflammation-associated diseases.

C1-Inhibitor: Structure, Functional Diversity and Therapeutic Development

Human C1-Inhibitor (C1INH), also known as C1-esterase inhibitor, is an important multifunctional plasma glycoprotein that is uniquely involved in a regulatory network of complement, contact, coagulation, and fibrinolytic systems. C1INH belongs to a superfamily of serine proteinase inhibitors (serpins) and exhibits its inhibitory activities towards several target proteases of plasmatic cascades, operating as a major antiinflammatory protein in the circulation. In addition to its inhibitory activities, C1INH is also involved in non-inhibitory interactions with some endogenous proteins, polyanions, cells and infectious agents. While C1INH is essential for multiple physiological processes, it is better known for its deficiency with regards to Hereditary Angioedema (HAE), a rare autosomal dominant disease clinically manifested by recurrent acute attacks of increased vascular permeability and edema. Since the link was first established between functional C1INH deficiency in plasma and HAE in the 1960s, tremendous progress has been made in the biochemical characterization of C1INH and its therapeutic development for replacement therapies in patients with C1INH-dependent HAE. Various C1INH biological activities, recent advances in the HAE-targeted therapies, and availability of C1INH commercial products have prompted intensive investigation of the C1INH potential for the treatment of clinical conditions other than HAE. This article provides an updated overview of the structural and biological activities of C1INH, its role in HAE pathogenesis, and recent advances in the research and therapeutic development of C1INH; it also considers some trends for using C1INH therapeutic preparations for applications other than angioedema, from sepsis and endotoxin shock to severe thrombotic complications in COVID-19 patients.

ISM1 protects lung homeostasis via cell-surface GRP78-mediated alveolar macrophage apoptosis

Alveolar macrophages (AMs) are critical for lung immune defense and homeostasis. They are orchestrators of chronic obstructive pulmonary disease (COPD), with their number significantly increased and functions altered in COPD. However, it is unclear how AM number and function are controlled in a healthy lung and if changes in AMs without environmental assault are sufficient to trigger lung inflammation and COPD. We report here that absence of isthmin 1 (ISM1) in mice (Ism1-/- ) leads to increase in both AM number and functional heterogeneity, with enduring lung inflammation, progressive emphysema, and significant lung function decline, phenotypes similar to human COPD. We reveal that ISM1 is a lung resident anti-inflammatory protein that selectively triggers the apoptosis of AMs that harbor high levels of its receptor cell-surface GRP78 (csGRP78). csGRP78 is present at a heterogeneous level in the AMs of a healthy lung, but csGRP78high AMs are expanded in Ism1-/- mice, cigarette smoke (CS)-induced COPD mice, and human COPD lung, making these cells the prime targets of ISM1-mediated apoptosis. We show that csGRP78high AMs mostly express MMP-12, hence proinflammatory. Intratracheal delivery of recombinant ISM1 (rISM1) depleted csGRP78high AMs in both Ism1-/- and CS-induced COPD mice, blocked emphysema development, and preserved lung function. Consistently, ISM1 expression in human lungs positively correlates with AM apoptosis, suggesting similar function of ISM1-csGRP78 in human lungs. Our findings reveal that AM apoptosis regulation is an important physiological mechanism for maintaining lung homeostasis and demonstrate the potential of pulmonary-delivered rISM1 to target csGRP78 as a therapeutic strategy for COPD.

COVID-19 drugs in aquatic systems: a review

The outbreak of the human coronavirus disease 2019 (COVID-19) has induced an unprecedented increase in the use of several old and repurposed therapeutic drugs such as veterinary medicines, e.g. ivermectin, nonsteroidal anti-inflammatory drugs, protein and peptide therapeutics, disease-modifying anti-rheumatic drugs and antimalarial drugs, antiretrovirals, analgesics, and supporting agents, e.g. azithromycin and corticosteroids. Excretion of drugs and their metabolites in stools and urine release these drugs into wastewater, and ultimately into surface waters and groundwater systems. Here, we review the sources, behaviour, environmental fate, risks, and remediation of those drugs. We discuss drug transformation in aquatic environments and in wastewater treatment systems. Degradation mechanisms and metabolite toxicity are poorly known. Potential risks include endocrine disruption, acute and chronic toxicity, disruption of ecosystem functions and trophic interactions in aquatic organisms, and the emergence of antimicrobial resistance.

Activation of the MKK3-p38-MK2-ZFP36 Axis by Coronavirus Infection Restricts the Upregulation of AU-Rich Element-Containing Transcripts in Proinflammatory Responses.

Coronavirus infections induce the expression of multiple proinflammatory cytokines and chemokines. We have previously shown that in cells infected with gammacoronavirus infectious bronchitis virus (IBV), interleukin 6 (IL-6), and IL-8 were drastically upregulated, and the MAP kinase p38 and the integrated stress response pathways were implicated in this process. In this study, we report that coronavirus infection activates a negative regulatory loop that restricts the upregulation of a number of proinflammatory genes. As revealed by the initial transcriptomic and subsequent validation analyses, the anti-inflammatory adenine-uridine (AU)-rich element (ARE)-binding protein, zinc finger protein 36 (ZFP36), and its related family members were upregulated in cells infected with IBV and three other coronaviruses, alphacoronaviruses porcine epidemic diarrhea virus (PEDV), human coronavirus 229E (HCoV-229E), and betacoronavirus HCoV-OC43, respectively. Characterization of the functional roles of ZFP36 during IBV infection demonstrated that ZFP36 promoted the degradation of transcripts coding for IL-6, IL-8, dual-specificity phosphatase 1 (DUSP1), prostaglandin-endoperoxide synthase 2 (PTGS2) and TNF-α-induced protein 3 (TNFAIP3), through binding to AREs in these transcripts. Consistently, knockdown and inhibition of JNK and p38 kinase activities reduced the expression of ZFP36, as well as the expression of IL-6 and IL-8. On the contrary, overexpression of mitogen-activated protein kinase kinase 3 (MKK3) and MAPKAP kinase-2 (MK2), the upstream and downstream kinases of p38, respectively, increased the expression of ZFP36 and decreased the expression of IL-8. Taken together, this study reveals an important regulatory role of the MKK3-p38-MK2-ZFP36 axis in coronavirus infection-induced proinflammatory response. IMPORTANCE Excessive and uncontrolled induction and release of proinflammatory cytokines and chemokines, the so-called cytokine release syndrome (CRS), would cause life-threatening complications and multiple organ failure in severe coronavirus infections, including severe acute respiratory syndrome (SARS), Middle East respiratory syndrome (MERS) and COVID-19. This study reveals that coronavirus infection also induces the expression of ZFP36, an anti-inflammatory ARE-binding protein, promoting the degradation of ARE-containing transcripts coding for IL-6 and IL-8 as well as a number of other proteins related to inflammatory response. Furthermore, the p38 MAP kinase, its upstream kinase MKK3 and downstream kinase MK2 were shown to play a regulatory role in upregulation of ZFP36 during coronavirus infection cycles. This MKK3-p38-MK2-ZFP36 axis would constitute a potential therapeutic target for severe coronavirus infections.

An atlas of the germ ball-cercaria-schistosomulum transition in Schistosoma mansoni, using confocal microscopy and in situ hybridisation

Schistosomes are complex platyhelminth parasites with a genome comprising ∼12,000 protein-coding genes, three distinct generations, and at least seven distinct phenotypes. We chart here cellular and gene expression changes associated with development of the cercaria, in the intramolluscan daughter sporocyst, and its transformation into the skin stage schistosomulum upon infection of the mammalian host. We describe the morphology of the early daughter sporocyst and the increasing complexity of cellular organisation in germ balls as they rapidly develop into cercariae. We show how individual myocytes differentiate and combine to create the complex musculature of the head capsule and body wall. In situ hybridisation reveals that some transcripts encoding the secretory proteins, released during skin penetration, are expressed in gland-cell precursors very early in germ ball development. However, those for the projected anti-inflammatory protein Sm16-stathmin are widely expressed in germ ball tissues, suggesting the protein has intracellular functions. Transcripts for smkk7 are expressed in six cells of the larval body, while the KK7 protein is present throughout the peripheral nerve net, including sensory nerve bulbs, providing a marker for the nerve net in adult worms. We also note that the cercaria-schistosomulum transformation is accompanied by tissue remodelling without growth.

A genomic approach identifies sRAGE as a putatively causal protein for asthma

Asthma is a complex respiratory condition caused by environmental and genetic factors. Although lower concentrations of the anti-inflammatory protein soluble receptor for advanced glycation end products (sRAGE) have been associated with asthma in humans and mouse models, it is uncertain whether sRAGE plays a causal role in asthma. We designed a 2-stage study of sRAGE in relation to asthma with association analysis in FHS participants as well as causal inference testing using Mendelian randomization (MR). We measured plasma levels of sRAGE and performed cross-sectional analysis to examine the association between plasma sRAGE concentration and asthma status in 6546 FHS participants. We then used sRAGE protein advanced glycation end products (pQTLs) derived from a genome-wide association study of plasma sRAGE levels in ∼7000 FHS participants with UK Biobank asthma genome-wide association study in MR to consider sRAGE as a putatively causal protein for asthma. We also performed replication MR using an externally derived sRAGE pQTL from the INTERVAL study. Last, we conducted colocalization using cis-pQTL variants at the advanced glycosylation end-product specific receptor (AGER) locus with variants from the UK Biobank asthma genome-wide association study. Association analysis revealed that each 1 SD increment in sRAGE concentration was associated with a 14% lower odds of asthma in FHS participants (95% CI 0.76-0.96). MR identified sRAGE as putatively causal for and protective against asthma on the basis of self-reported (odds ratio [per 1 SE increment in inverse-rank-normalized sRAGE]= 0.97, 95% CI 0.95-0.99; P= .005) and doctor-diagnosed asthma (odds ratio= 0.97, 95% CI 0.95-0.99; P= .011). Through this genomic approach, we identified sRAGE as a putatively causal, biologically important, and protective protein in relation to asthma. Functional studies incell/animal models are needed to confirm our findings.

Shenkang Injection and Its Three Anthraquinones Ameliorates Renal Fibrosis by Simultaneous Targeting IƙB/NF-ƙB and Keap1/Nrf2 Signaling Pathways.

Oxidative stress and inflammation are important and critical mediators in the development and progression of chronic kidney disease (CKD) and its complications. Shenkang injection (SKI) has been widely used to treat patients with CKD. Although the anti-oxidative and anti-inflammatory activity was involved in SKI against CKD, its bioactive components and underlying mechanism remain enigmatic. A rat model of adenine-induced chronic renal failure (CRF) is associated with, and largely driven by, oxidative stress and inflammation. Hence, we identified the anti-oxidative and anti-inflammatory components of SKI and further revealed their underlying mechanism in the adenine-induced CRF rats. Compared with control rats, the levels of creatinine, urea, uric acid, total cholesterol, triglyceride, and low-density lipoprotein cholesterol in serum were significantly increased in the adenine-induced CRF rats. However, treatment with SKI and its three anthraquinones including chrysophanol, emodin, and rhein could reverse these aberrant changes. They could significantly inhibit pro-fibrotic protein expressions including collagen I, α-SMA, fibronectin, and vimentin in the kidney tissues of the adenine-induced CRF rats. Of note, SKI and rhein showed the stronger inhibitory effect on these pro-fibrotic protein expressions than chrysophanol and emodin. Furthermore, they could improve dysregulation of IƙB/NF-ƙB and Keap1/Nrf2 signaling pathways. Chrysophanol and emodin showed the stronger inhibitory effect on the NF-κB p65 protein expression than SKI and rhein. Rhein showed the strongest inhibitory effect on p65 downstream target gene products including NAD(P)H oxidase subunits (p47phox, p67phox, and gp91phox) and COX-2, MCP-1, iNOS, and 12-LO in the kidney tissues. However, SKI and rhein showed the stronger inhibitory effect on the significantly downregulated anti-inflammatory and anti-oxidative protein expression nuclear Nrf2 and its target gene products including HO-1, catalase, GCLC, and NQO1 in the Keap1/Nrf2 signaling pathway than chrysophanol and emodin. This study first demonstrated that SKI and its major components protected against renal fibrosis by inhibiting oxidative stress and inflammation via simultaneous targeting IƙB/NF-ƙB and Keap1/Nrf2 signaling pathways, which illuminated the potential molecular mechanism of anti-oxidative and anti-inflammatory effects of SKI.

Protective Effect of Melatonin Administration against SARS-CoV-2 Infection: A Systematic Review.

Introduction: according to the World Health Organization (WHO), COVID-19 is an infectious disease caused by the SARS-CoV-2 virus, responsible for an increasing number of cases and deaths. From a preventive and therapeutic point of view, there are two concerns that affect institutions and healthcare professionals: global immunization (which is still far from being achieved) and the availability of drugs capable of preventing its consequences in the infected patient. In this sense, the role that melatonin can play is has been assessed in the recent literature. Justification and Objectives: the serious health, social and economic consequences of COVID-19 have forced an urgent search for preventive methods, such as vaccines, among others, and therapeutic methods that could be alternatives to the drugs currently used. In this sense, it must be accepted that one of the most recommended has been the administration of melatonin. The present study proposes to carry out a systematic review of its possible role in the treatment and/or prevention of COVID-19. Material and methods: a systematic review of the literature related to the prevention of COVID-19 through the administration of melatonin was carried out, following the sequence proposed by the Prisma Declaration regarding the identification and selection of documents, using the specialized health databases Trip Medical Database, Cochrane Library, PubMed, Medline Plus, BVS, Cuiden and generic databases such as Dialnet, Web of Science and Google Scholar for their retrieval. Appropriate inclusion and exclusion criteria are described for the articles assessed. The main limitation of the study has been the scarcity of works and the lack of defining a specific protocol in terms of dosage and administration schedule. Results: once the selection process was completed, and after an in-depth critical analysis, 197 papers were selected, and 40 of them were finally used. The most relevant results were: (1) melatonin prevents SARS-CoV-2 infection, (2) although much remains to be clarified, at high doses, it seems to have a coadjuvant therapeutic effect in the treatment of SARS-CoV-2 infection and (3) melatonin is effective against SARS-CoV-2 infection. Discussion: until group immunization is achieved in the population, it seems clear that we must continue to treat patients with SARS-CoV-2 infection, and, in the absence of a specific and effective antiviral therapy, it is advisable to continue researching and providing drugs that demonstrate validity based on the scientific evidence. In this regard, we believe that the available studies recommend the administration of melatonin for its anti-inflammatory, antioxidant, immunomodulatory, sleep-inducing, CD147, Mpro, p65 and MMP9 protein suppressing, nephrotoxicity-reducing and highly effective and safe effects. Conclusions: (1) melatonin has anti-inflammatory, antioxidant, immunomodulatory, and Mpro and MMP9 protein-inhibitory activity. (2) It has been shown to have a wide margin of safety. (3) The contributions reviewed make it an effective therapeutic alternative in the treatment of SARS-CoV-2 infection. (4) Further clinical trials are recommended to clearly define the administration protocol.

The role of cellular senescence in female reproductive aging and the potential for senotherapeutic interventions.

BACKGROUNDAdvanced maternal age is associated with decreased oocyte quantity and quality as well as uterine and placental dysfunctions. These changes lead to infertility, pregnancy complications and birth defects in the offspring. As the mean age of giving birth is increasing worldwide, prevention of age-associated infertility and pregnancy complications, along with the more frequent use of ART, become extremely important. Currently, significant research is being conducted to unravel the mechanisms underlying female reproductive aging. Among the potential mechanisms involved, recent evidence has suggested a contributing role for cellular senescence, a cellular state of irreversible growth arrest characterized by a hypersecretory and pro-inflammatory phenotype. Elucidating the role of senescence in female reproductive aging holds the potential for developing novel and less invasive therapeutic measures to prevent or even reverse female reproductive aging and increase offspring wellbeing.OBJECTIVE AND RATIONALEThe review will summarize the positive and negative implications of cellular senescence in the pathophysiology of the female reproductive organs during aging and critically explore the use of novel senotherapeutics aiming to reverse and/or eliminate their detrimental effects. The focus will be on major senescence mechanisms of the ovaries, the uterus, and the placenta, as well as the potential and risks of using senotherapies that have been discovered in recent years.SEARCH METHODSData for this review were identified by searches of MEDLINE, PubMed and Google Scholar. References from relevant articles using the search terms ‘Cellular Senescence’, ‘Aging’, ‘Gestational age’, ‘Maternal Age’, ‘Anti-aging’, ‘Uterus’, ‘Pregnancy’, ‘Fertility’, ‘Infertility’, ‘Reproduction’, ‘Implant’, ‘Senolytic’, ‘Senostatic’, ‘Senotherapy’ and ‘Senotherapeutic’ where selected. A total of 182 articles published in English between 2005 and 2020 were included, 27 of which focus on potential senotherapies for reproductive aging. Exclusion criteria were inclusion of the terms ‘male’ and ‘plants’.OUTCOMESAging is a major determinant of reproductive wellbeing. Cellular senescence is a basic aging mechanism, which can be exploited for therapeutic interventions. Within the last decade, several new strategies for the development and repurposing of drugs targeting senescent cells have emerged, such as modulators of the anti-inflammatory response, oxidative stress, DNA damage, and mitochondria and protein dysfunctions. Several studies of female reproductive aging and senotherapies have been discussed that show promising results for future interventions.WIDER IMPLICATIONSIn most countries of the Organization for Economic Co-operation and Development, the average age at which women give birth is above 30 years. Currently, in countries such as the Netherlands, Australia, Spain, Finland, Germany and the UK, birth rates among 30- to 34-year-olds are now higher than in any other age groups. This review will provide new knowledge and scientific advancement on the senescence mechanisms during female reproductive aging, and benefit fundamental and clinical scientists and professionals in the areas of reproduction, cancer, immunobiology and fibrosis.

Immunological Effects of Adding Bovine Lactoferrin and Reducing Iron in Infant Formula: A Randomized Controlled Trial.

ABSTRACTObjectives:Compared to formula-fed infants, breastfed infants have a lower risk of infections. Two possible reasons for this are the presence of the anti-infective and anti-inflammatory protein lactoferrin and the lower level of iron in breast milk. We explored how adding bovine lactoferrin and reducing the iron concentration in infant formula affect immunology and risk of infections in healthy infants.Methods:In a double-blind controlled trial, term formula-fed (FF) Swedish infants (n = 180) were randomized to receive, from 6 weeks to 6 months of age, a low-iron formula (2 mg/L) with added bovine lactoferrin (1.0 g/L) (Lf+; n = 72); low-iron formula with no added lactoferrin (Lf−; n = 72); and standard formula at 8 mg/L iron and no added lactoferrin (control formula [CF]; n = 36). Cytokines, infections, and infection related treatments were assessed until 12 months of age.Results:No adverse effects were observed. There were no apparent effects on transforming growth factor beta (TGF-β)1, TGF-β2, tumor necrosis factor alfa (TNF-α) or interleukin2 (IL-2) at 4, 6, or 12 months, except of higher TGF-β2 at 6 months in the CF group in comparison to the low iron groups combined (P = 0.033). No significant differences in otitis, respiratory infections, gastroenteritis, or other monitored infections and treatments were detected for any of the study feeding groups during the first 6 months and only a few and diverging effects were observed between 6 and 12 months.Conclusions:Adding bovine lactoferrin and reducing iron from 8 to 2 mg/L in infant formula was safe. No clinically relevant effects on cytokines or infection related morbidity were observed in this well-nourished and healthy population.