Systemic immune response of burns from the acute to chronic phase.

Immune responses that occur following burn injury comprise a series of reactions that are activated in response to damaged autologous tissues, followed by removal of damaged tissues and foreign pathogens such as invading bacteria, and tissue repair. These immune responses are considered to be programmed in living organisms. Developments of modern medicine have led to the saving of burned patients who could not be cured previously; however, the programmed response is no longer able to keep up, and various problems have arisen. This paper describes the mechanism of immune response specific to burn injury and the emerging concept of persistent inflammation, immunosuppression, and catabolism syndrome.

Antifungal efficacy and immunomodulatory effect of PLGA nanoparticle-encapsulated itraconazole in histoplasmosis in vivo model.

INTRODUCTION: Histoplasma capsulatum is the etiological agent of histoplasmosis, the most common endemic pulmonary mycosis. Itraconazole (ITZ) is the choice for mild disease and a step-down therapy in severe and disseminated clinical presentations. Drug encapsulation into nanoparticles (NPs) is an alternative to improve drug solubility and bioavailability, reducing undesirable interactions and drug degradation and reaching the specific therapeutic target with lower doses. OBJECTIVE: evaluate the antifungal and immunomodulatory effect of ITZ encapsulated into poly(lactic-co-glycolic acid) (PLGA) NPs, administrated orally and intraperitoneally in an in vivo histoplasmosis model. RESULTS: After intranasal infection and treatment of animals with encapsulated ITZ by intraperitoneal and oral route, fungal burden control, biodistribution, immune response, and histopathology were evaluated. The results showed that the intraperitoneal administered and encapsulated ITZ has an effective antifungal effect, significantly reducing the Colony-Forming-Units (CFU) after the first doses and controlling the infection dissemination, with a higher concentration in the liver, spleen, and lung compared to the oral treatment. In addition, it produced a substantial immunomodulatory effect on pro- and anti-inflammatory cytokines and immune cell infiltrates confirmed by histopathology. CONCLUSIONS: Overall, results suggest a synergistic effect of the encapsulated drug and the immunomodulatory effect contributing to infection control, preventing their dissemination.

Carboxymethyl cellulose/sodium alginate hydrogel with anti-inflammatory capabilities for accelerated wound healing; In vitro and in vivo study.

Recently, managing the chronic skin wounds has become increasingly challenging for healthcare professionals due to the intricate orchestration of cellular and molecular processes involved that lead to the uncontrollable inflammatory reactions which hinder the healing process. Therefore, different types of wound dressings with immunomodulatory properties have been developed in recent years to effectively regulate the immune responses, enhance angiogenesis, promote re-epithelialization, and accelerate the wound healing process. This study aims to develop a new type of immunomodulatory wound dressing utilizing carboxymethyl cellulose (CMC)/sodium alginate (Alg)-simvastatin (SIM) to simultaneously enhance the inflammatory responses and the wound healing ratio. The CMC/Alg-SIM hydrogels exhibited appropriate swelling ratio, water vapor transmission rate, and desirable degradation rate, depending on the SIM content. The fabricated dressing showed sustained release of SIM (during 5 days) that improved the proliferation of skin cells. According to the in vitro findings, the CMC/Alg-SIM hydrogel exhibited controlled pro-inflammatory responses (decreased 2.5- and 1.6-times IL-6 and TNF-α, respectively) and improved secretion of anti-inflammatory cytokines (increased 1.5- and 1.3-times IL-10 and TGF-ß, respectively) in comparison with CMC/Alg. Furthermore, the CMC/Alg-SIM hydrogel facilitated rapid wound healing in the rat model with a full-thickness skin defect. After 14 days post-surgery, the wound healing ratio in the CMC/Alg hydrogel group (∼93%) was significantly greater than the control group (∼58%). Therefore, the engineered CMC/Alg-SIM hydrogel with desired immunomodulatory properties possesses the potential to enhance and accelerate skin regeneration for the management of chronic wound healing.

Therapeutic Effects of a Novel Aptamer on Coronaviral Infection-Induced Lung Injury and Systemic Inflammatory Responses.

BACKGROUND: Coronaviral infection-induced acute lung injury has become a major threat to public health, especially through the ongoing pandemic of COVID-19. Apta-1 is a newly discovered Aptamer that has anti-inflammatory effects on systemic septic responses. The therapeutic effects of Apta-1 on coronaviral infection-induced acute lung injury and systemic responses were evaluated in the present study. METHODS: Female A/J mice (at 12-14 weeks of age) were challenged with murine hepatitis virus 1 (MHV-1), a coronavirus, at 5000 PFU intranasally, followed by Apta-1 intravenously administered (100 mg/kg, twice) 1.5 h or 2 days after viral delivery. Animals were sacrificed at Day 2 or Day 4. Lung tissues were examined with H&E, immunohistochemistry staining, and western blotting. RT-qPCR was used for cytokine gene expression. Serum and plasma were collected for laboratory assessments. RESULTS: Apta-1 treatment reduced viral titers, prevented MHV-1-induced reduction of circulating blood volume and hemolysis, reduced alveolar space hemorrhage, and protease-activated receptor 1 (PAR-1) cleavage. Apta-1 treatment also significantly reduced chemokine (MKC, MCP-1, and RANTES) levels, as well as AST, ALT, total bilirubin, and reduced unconjugated bilirubin levels in the serum. CONCLUSION: Apta-1 showed therapeutic benefits in coronaviral infection-induced hemorrhage and PAR-1 cleavage in the lung. It also has anti-inflammatory effects systemically.

Major low-energy trauma results in non-specific immunoglobulin generation without evidence for specific autoantibody production: A prospective cohort study.

Cellular debris resulting from large trauma might overwhelm the scavenger mechanisms and lead to autoimmune reactions. We analysed whether a major well-defined trauma in humans induces laboratory signs of transient autoimmunity in the months after the insult. We included 50 patients with pertrochanteric femur fracture undergoing intramedullary nail osteosynthesis in a prospective cohort study and followed them at 3-4 days, 6 weeks, 12 weeks and 12 months postoperatively. By standard techniques, we assessed levels of total immunoglobulins, anti-nuclear antibodies (ANA), anti-cardiolipin antibodies, anti-dsDNA antibodies and anti-C1q antibodies, as well as antibodies against cytomegalovirus (CMV) as a control. Blood leukocyte differential and lymphocyte subpopulations were determined at baseline and in the first two postoperative samples. The mean age of the patients reached 80.1 years, and 23 (46%) completed all visits. Serum concentrations of total IgG, IgM and IgA increased at all follow-up time points. The ANA fluorescence light intensity units increased at 12 weeks and 12 months postoperatively (p < 0.0001), but the proportion of ANA-positive patients did not change (35%). The values of anti-C1q mildly increased at all follow-up visits, but not the ratio to total IgG. Anti-dsDNA remained negative in all patients, and anti-cardiolipin IgG/IgM antibodies did not change. Anti-CMV IgG antibodies increased significantly at all follow-up visits, without change in the ratio to total IgG. Flow cytometry showed an increased proportion of B-cells 3-4 days postoperatively. In conclusion, major musculoskeletal trauma in elderly patients induces a generalized non-specific increase in immunoglobulin production without laboratory signs for enhanced systemic autoimmunity.

MbovP0725, a secreted serine/threonine phosphatase, inhibits the host inflammatory response and affects metabolism in Mycoplasma bovis.

Mycoplasma species are able to produce and release secreted proteins, such as toxins, adhesins, and virulence-related enzymes, involved in bacteria adhesion, invasion, and immune evasion between the pathogen and host. Here, we investigated a novel secreted protein, MbovP0725, from Mycoplasma bovis encoding a putative haloacid dehalogenase (HAD) hydrolase function of a key serine/threonine phosphatase depending on Mg2+ for the dephosphorylation of its substrate pNPP, and it was most active at pH 8 to 9 and temperatures around 40°C. A transposon insertion mutant strain of M. bovis HB0801 that lacked the protein MbovP0725 induced a stronger inflammatory response but with a partial reduction of adhesion ability. Using transcriptome sequencing and quantitative reverse transcription polymerase chain reaction analysis, we found that the mutant was upregulated by the mRNA expression of genes from the glycolysis pathway, while downregulated by the genes enriched in ABC transporters and acetate kinase-phosphate acetyltransferase pathway. Untargeted metabolomics showed that the disruption of the Mbov_0725 gene caused the accumulation of 9-hydroxyoctadecadienoic acids and the consumption of cytidine 5'-monophosphate, uridine monophosphate, and adenosine monophosphate. Both the exogenous and endogenous MbvoP0725 protein created by purification and transfection inhibited lipopolysaccharide (LPS)-induced IL-1ß, IL-6, and TNF-α mRNA production and could also attenuate the activation of MAPK-associated pathways after LPS treatment. A pull-down assay identified MAPK p38 and ERK as potential substrates for MbovP0725. These findings define metabolism- and virulence-related roles for a HAD family phosphatase and reveal its ability to inhibit the host pro-inflammatory response. IMPORTANCE: Mycoplasma bovis (M. bovis) infection is characterized by chronic pneumonia, otitis, arthritis, and mastitis, among others, and tends to involve the suppression of the immune response via multiple strategies to avoid host cell immune clearance. This study found that MbovP0725, a haloacid dehalogenase (HAD) family phosphatase secreted by M. bovis, had the ability to inhibit the host pro-inflammatory response induced by lipopolysaccharide. Transcriptomic and metabolomic analyses were used to identify MbovP0725 as an important phosphatase involved in glycolysis and nucleotide metabolism. The M. bovis transposon mutant strain T8.66 lacking MbovP0725 induced a higher inflammatory response and exhibited weaker adhesion to host cells. Additionally, T8.66 attenuated the phosphorylation of MAPK P38 and ERK and interacted with the two targets. These results suggested that MbovP0725 had the virulence- and metabolism-related role of a HAD family phosphatase, performing an anti-inflammatory response during M. bovis infection.

Genipin crosslinking promotes biomechanical reinforcement and pro-regenerative macrophage polarization in bioartificial tubular substitutes.

Traumatic nerve injuries are nowadays a significant clinical challenge and new substitutes with adequate biological and mechanical properties are in need. In this context, fibrin-agarose hydrogels (FA) have shown the possibility to generate tubular scaffolds with promising results for nerve repair. However, to be clinically viable, these scaffolds need to possess enhanced mechanical properties. In this line, genipin (GP) crosslinking has demonstrated to improve biomechanical properties with good biological properties compared to other crosslinkers. In this study, we evaluated the impact of different GP concentrations (0.05, 0.1 and 0.2% (m/v)) and reaction times (6, 12, 24, 72 h) on bioartificial nerve substitutes (BNS) consisting of nanostructured FA scaffolds. First, crosslinked BNS were studied histologically, ultrastructurally and biomechanically and then, its biocompatibility and immunomodulatory effects were ex vivo assessed with a macrophage cell line. Results showed that GP was able to improve the biomechanical resistance of BNS, which were dependent on both the GP treatment time and concentration without altering the structure. Moreover, biocompatibility analyses on macrophages confirmed high cell viability and a minimal reduction of their metabolic activity by WST-1. In addition, GP-crosslinked BNS effectively directed macrophage polarization from a pro-inflammatory (M1) towards a pro-regenerative (M2) phenotype, which was in line with the cytokines release profile. In conclusion, this study considers time and dose-dependent effects of GP in FA substitutes which exhibited increased biomechanical properties while reducing immunogenicity and promoting pro-regenerative macrophage shift. These tubular substitutes could be useful for nerve application or even other tissue engineering applications such as urethra.

Bioglass/ceria nanoparticle hybrids for the treatment of seroma: a comparative long-term study in rats.

Background: Seroma formation is a common postoperative complication. Fibrin-based glues are typically employed in an attempt to seal the cavity. Recently, the first nanoparticle (NP)-based treatment approaches have emerged. Nanoparticle dispersions can be used as tissue glues, capitalizing on a phenomenon known as 'nanobridging'. In this process, macromolecules such as proteins physically adsorb onto the NP surface, leading to macroscopic adhesion. Although significant early seroma reduction has been shown, little is known about long-term efficacy of NPs. The aim of this study was to assess the long-term effects of NPs in reducing seroma formation, and to understand their underlying mechanism. Methods: Seroma was surgically induced bilaterally in 20 Lewis rats. On postoperative day (POD) 7, seromas were aspirated on both sides. In 10 rats, one side was treated with NPs, while the contralateral side received only NP carrier solution. In the other 10 rats, one side was treated with fibrin glue, while the other was left untreated. Seroma fluid, blood and tissue samples were obtained at defined time points. Biochemical, histopathological and immunohistochemical assessments were made. Results: NP-treated sides showed no macroscopically visible seroma formation after application on POD 7, in stark contrast to the fibrin-treated sides, where 60% of the rats had seromas on POD 14, and 50% on POD 21. At the endpoint (POD 42), sides treated with nanoparticles (NPs) exhibited significant macroscopic differences compared to other groups, including the absence of a cavity, and increased fibrous adhesions. Histologically, there were more macrophage groupings and collagen type 1 (COL1) deposits in the superficial capsule on NP-treated sides. Conclusion: NPs not only significantly reduced early manifestations of seroma and demonstrated an anti-inflammatory response, but they also led to increased adhesion formation over the long term, suggesting a decreased risk of seroma recurrence. These findings highlight both the adhesive properties of NPs and their potential for clinical therapy.

A functional chicken-liver hydrolysate-based supplement ameliorates alcohol liver disease via regulation of antioxidation, anti-inflammation, and antiapoptosis.

Tons of broiler livers are produced yearly in Taiwan but always considered waste. Our team has successfully patented and characterized a chicken-liver hydrolysate (CLH) with several biofunctions. Chronic alcohol consumption causes hepatosteatosis or even hepatitis, cirrhosis, and cancers. This study was to investigate the hepatoprotection of CLH-based supplement (GBHP01™) against chronic alcohol consumption. Results showed that GBHP01™ could reduce (p < .05) enlarged liver size, lipid accumulation/steatosis scores, and higher serum AST, ALT, γ-GT, triglyceride, and cholesterol levels induced by an alcoholic liquid diet. GBHP01™ reduced liver inflammation and apoptosis in alcoholic liquid-diet-fed mice via decreasing TBARS, interleukin-6, interleukin-1ß, and tumor necrosis factor-α levels, increasing reduced GSH/TEAC levels and activities of SOD, CAT and GPx, as well as downregulating CYP2E1, BAX/BCL2, Cleaved CASPASE-9/Total CASPASE-9 and Active CASPASE-3/Pro-CASPASE-3 (p < .05). Furthermore, GBHP01™ elevated hepatic alcohol metabolism (ADH and ALDH activities) (p < .05). In conclusion, this study prove the hepatoprotection of GBHP01™ against alcohol consumption.

Exploring the Effect of Deep-Sea Water on the Therapeutic Potential of the Anti-Inflammatory Response in an Indomethacin-Induced Gastric Ulcer Rat Model.

Gastric ulcers are often exacerbated by factors such as nonsteroidal anti-inflammatory drugs (NSAIDs) and inflammation, and they have a substantial impact on a significant portion of the population. Notably, indomethacin is recognized as a prominent contributor to ulcers. This study investigated this potential method, with normalization to the anti-inflammatory and antiulcer properties of deep-sea water (DSW)-derived mineral water, using an indomethacin-induced gastric ulcer model in rats. The study involved four groups (n = 6 rats/group): normal control group (CON), indomethacin-only group (IND), indomethacin with trace mineral water group (TM), and indomethacin with high magnesium low sodium water group (HMLS). For three weeks, the CON and IND groups consumed tap water, while the TM and HMLS groups had access to mineral water. Gastric ulcers were induced on the final day using indomethacin, for all groups except the CON group. The results demonstrated that HMLS intake significantly improved gastric mucosal damage, preserved mucin stability, and increased gastric thickness, indicating its potential to prevent and alleviate indomethacin-induced gastric ulcers. Furthermore, HMLS consumption led to the upregulation of key genes associated with inflammation and a reduction in inflammatory cytokines. These findings suggest that DSW-derived mineral water, and particularly its high Mg2+ content, may offer promising health benefits including anti-inflammatory and anti-ulcer properties.

Cholinergic Polarization of Human Macrophages.

Macrophages serve as vital defenders, protecting the body by exhibiting remarkable cellular adaptability in response to invading pathogens and various stimuli. These cells express nicotinic acetylcholine receptors, with the α7-nAChR being extensively studied due to its involvement in activating the cholinergic anti-inflammatory pathway. Activation of this pathway plays a crucial role in suppressing macrophages' production of proinflammatory cytokines, thus mitigating excessive inflammation and maintaining host homeostasis. Macrophage polarization, which occurs in response to specific pathogens or insults, is a process that has received limited attention concerning the activation of the cholinergic anti-inflammatory pathway and the contributions of the α7-nAChR in this context. This review aims to present evidence highlighting how the cholinergic constituents in macrophages, led by the α7-nAChR, facilitate the polarization of macrophages towards anti-inflammatory phenotypes. Additionally, we explore the influence of viral infections on macrophage inflammatory phenotypes, taking into account cholinergic mechanisms. We also review the current understanding of macrophage polarization in response to these infections. Finally, we provide insights into the relatively unexplored partial duplication of the α7-nAChR, known as dup α7, which is emerging as a significant factor in macrophage polarization and inflammation scenarios.

Protaetia Brevitarsis-Derived Protein Hydrolysate Reduces Obesity-Related Colitis Induced by High-Fat Diet in Mice through Anti-Inflammatory Pathways.

Ulcerative colitis is an inflammatory bowel disease characterized by inflammation in the mucosal and submucosal layers of the colon. Obesity is closely related to the occurrence and progression of colitis. The most plausible mechanism linking obesity and colitis is an excessive adipogenesis-related inflammatory response, which causes mucosal dysfunction. Obesity and colitis are linked by several etiologic mechanisms, including excessive adipogenesis, lipotoxicity, pro-inflammatory adipokines/cytokines, macrophage polarization, oxidative stress, endoplasmic reticulum (ER) stress, and gut microbiota. These low-grade enteric inflammations cause mucosal layer damage, especially goblet cell dysfunction through mucin 2 (MUC2) misfolding, ultimately leading to colitis. Inhibiting the inflammatory response can be the most effective approach for treating obesity-related colitis. We focused on the anti-inflammatory effects of polyphenols in Protaectia brevitas larvae. The P. brevitas was prepared as a low molecular protein hydrolysate (PHPB) to increase the concentration of anti-inflammatory molecules. In the current study, we investigated the anti-inflammatory effect of PHPB in an obesity-induced colitis mouse model. Compared with the high-fat diet (HFD) group, the group treated with PHPB exhibited reduced body/organ/fat weight, appetite/food intake inhibition, hypolipidemic effect on ectopic fat, and anti-adipogenic mechanism through the AMPK signaling pathway. Furthermore, we observed attenuated expression of PPARγ and C/EBPα, inhibition of pro-inflammatory molecules, stimulation of anti-inflammatory molecules, probiotic-like effect against obesogenic gut microbiota, inhibition of macrophage polarization into M1, suppression of oxidative/ER stress, and reduction of Muc2 protein misfolding in colon. These diverse anti-inflammatory responses caused histological and functional recovery of goblet cells, eventually improving colitis. Therefore, our findings suggest that the protein hydrolysate of Protaetia brevitarsis can improve obesity-related colitis through its anti-inflammatory activities.

Sulforaphane Reduces the Chronic Inflammatory Immune Response of Human Dendritic Cells.

BACKGROUND: Sulforaphane (SFN) is an isothiocyanate of vegetable origin with potent antioxidant and immunomodulatory properties. The characterization of its pleiotropic activity in human dendritic cells (DCs) is poorly summarized. The aim of this work was to study the immunomodulatory power of SFN in response to an inflammatory microenvironment on human monocyte-derived DCs (moDCs). METHODS: We studied the immunological response induced by SFN. Apoptosis and autophagy assays were performed using flow cytometry on moDCs and a cancer cell line (THP-1). These included moDC maturation, lymphocyte proliferation and cytokine production under different experimental conditions. We investigated whether these results were associated with an inflammatory microenvironment induced by lipopolysaccharides (LPSs). RESULTS: Our results demonstrated that SFN could interact with moDCs, significantly reducing the autophagy process and enhancing apoptosis similarly to cancer cell line THP-1 cells in a chronic inflammatory microenvironment. Under chronic inflammation, SFN modulated the phenotypical characteristics of moDCs, reducing the expression of all markers (CD80, CD83, CD86, HLA-DR and PD-L1). SFN significantly reduced the Th2 proliferative response, with a decrease in the IL-9 and IL-13 levels. Although we did not observe any changes in the regulatory proliferative response, we noted an increase in the IL-10 levels. CONCLUSIONS: These findings demonstrate that SFN exerts protective effects against LPS-induced inflammation via the modulation of moDCs/T cells towards a regulatory profile. SFN may be a potential candidate for the treatment of pathologies with an inflammatory profile.

During Sepsis and COVID-19, the Pro-Inflammatory and Anti-Inflammatory Responses Are Concomitant.

The most severe forms of COVID-19 share many features with bacterial sepsis and have thus been considered to be a viral sepsis. Innate immunity and inflammation are closely linked. While the immune response aims to get rid of the infectious agent, the pro-inflammatory host response can result in organ injury including acute respiratory distress syndrome. On its side, a compensatory anti-inflammatory response, aimed to dampen the inflammatory reaction, can lead to immunosuppression. Whether these two key events of the host inflammatory response are consecutive or concomitant has been regularly depicted in schemes. Initially proposed from 2001 to 2013 to be two consecutive steps, the concomitant occurrence has been supported since 2013, although it was proposed for the first time in 2001. Despite a consensus was reached, the two consecutive steps were still recently proposed for COVID-19. We discuss why the concomitance view could have been initiated as early as 1995.

Tulsi (Ocimum sanctum) mediated Co nanoparticles with their anti-inflammatory, anti-cancer, and methyl orange dye adsorption properties.

Nanotechnology is an emerging technology that uses medicinal plants to extract nanoparticles for conventional applications. In the present investigation, the medical plant Tulsi (Ocimum sanctum) has used in the synthesis of cobalt (Co) nanoparticles in a cost-effective, feasible process. The efficiency of nanoparticles in removing methyl orange dye was evaluated by analyzing their applications in wastewater treatment. An analysis of the anti-inflammatory and anti-cancer properties of Tulsi-mediated Co nanoparticles was conducted to examine their medical application. Morphological analysis of Co nanoparticles showed that the synthesized nanoparticles were in crystal shape with a mean particle size of 110 nm. A batch adsorption study has shown that incubation periods of 5 h, pH 2, temperatures of 70 °C, and adsorbent dosage of 125 µg/mL are optimal for removing methyl orange dye from wastewater. To examine the anti-inflammatory properties of Tulsi-mediated Co nanoparticles, protein denaturation and nitric oxide scavenging assays were performed. The maximum anti-inflammatory response was recorded at a concentration of 250 µg/mL of Co nanoparticles. MTT assays against MDA-MB-231 human breast cancer cells were used to evaluate the anti-cancer properties of Co nanoparticles. This study investigates the economical extraction of Co nanoparticles from tulsi and its potential use in wastewater purification and biomedical applications.

Suppression of NASH-Related HCC by Farnesyltransferase Inhibitor through Inhibition of Inflammation and Hypoxia-Inducible Factor-1α Expression.

Inflammatory processes play major roles in carcinogenesis and the progression of hepatocellular carcinoma (HCC) derived from non-alcoholic steatohepatitis (NASH). But, there are no therapies for NASH-related HCC, especially focusing on these critical steps. Previous studies have reported that farnesyltransferase inhibitors (FTIs) have anti-inflammatory and anti-tumor effects. However, the influence of FTIs on NASH-related HCC has not been elucidated. In hepatoblastoma and HCC cell lines, HepG2, Hep3B, and Huh-7, we confirmed the expression of hypoxia-inducible factor (HIF)-1α, an accelerator of tumor aggressiveness and the inflammatory response. We established NASH-related HCC models under inflammation and free fatty acid burden and confirmed that HIF-1α expression was increased under both conditions. Tipifarnib, which is an FTI, strongly suppressed increased HIF-1α, inhibited cell proliferation, and induced apoptosis. Simultaneously, intracellular interleukin-6 as an inflammation marker was increased under both conditions and significantly suppressed by tipifarnib. Additionally, tipifarnib suppressed the expression of phosphorylated nuclear factor-κB and transforming growth factor-ß. Finally, in a NASH-related HCC mouse model burdened with diethylnitrosamine and a high-fat diet, tipifarnib significantly reduced tumor nodule formation in association with decreased serum interleukin-6. In conclusion, tipifarnib has anti-tumor and anti-inflammatory effects in a NASH-related HCC model and may be a promising new agent to treat this disease.

Zinc (Zn) and adipose-derived mesenchymal stem cells (AD-MSCs) on MPTP-induced Parkinson's disease model: A comparative evaluation of behavioral and immunohistochemical results.

Parkinson's disease (PD) is characterized by the loss of dopaminergic neurons and sustained neuroinflammation due to microglial activation. Adipose tissue-derived mesenchymal stem cells (AD-MSCs) secrete neuroprotective factors to prevent neuronal damage. Furthermore, Zn regulates stem cell proliferation and differentiation and has immunomodulatory functions. Our in vivo study aimed to investigate whether Zn affects the activities of AD-MSCs in the MPTP-induced mouse model. Male C57BL/6 mice were randomly divided into six groups (n = 6): Control, Zn, PD, PD+Zn, PD+ (AD-MSC), PD+ (AD-MSC)+Zn. MPTP toxin (20 mg/kg) was dissolved in saline and intraperitoneally injected into experimental groups for two days with 12 h intervals. On the 3rd day, AD-MSCs were given to the right lateral ventricle of the PD+ (AD-MSC) and PD+ (AD-MSC)+Zn groups by stereotaxic surgery. Then, ZnSO4H2O was administered intraperitoneally for 4 days at 2 mg/kg. Seven days post MPTP injection, the motor activities of the mouse were evaluated. Then immunohistochemical analyzes were performed in SNpc. Our results showed that motor activity was lower in Group PD. AD-MSC and Zn administration have improved this impairment. MPTP caused a decrease in TH and BDNF expressions in dopaminergic neurons in Group PD. However, TH and BDNF expressions were more intense in the other groups. MCP-1, TGF-ß, and IL-10 expressions increased in administered groups compared to the Group PD. The present study indicates that Zn's individual and combined administration with AD-MSCs reduces neuronal damage in the MPTP-induced mouse model. In addition, anti-inflammatory responses that emerge with Zn and AD-MSCs may have a neuroprotective effect.

Linoleic acid stimulation results in TGF-ß1 production and inhibition of PEDV infection in vitro.

Linoleic acid (LA) is recommended to improve pork quality. However, whether it affects the intestinal immune response in pigs is still unclear. Our ex vivo experiments demonstrated that LA stimulation resulted in increased frequencies of Tregs in PBMCs but not in Peyer's Patches (PPs). The results of RT-qPCR, flow cytometry, and ELISA indicated that LA increased the TGF-ß1 expression level in DCs isolated from PEDV infected pigs. Furthermore, RT-qPCR and flow cytometry results demonstrated that TGF-ß1 was associated with higher frequencies of Tregs both in PBMCs and PPs. Additional investigations showed that TGF-ß1 inhibited PEDV infection in vitro. Besides, knocking-out TGF-ß1 in IPEC-J2 cells resulted in higher viral load. Taken together, our results demonstrated that LA stimulation resulted in enhanced production of TGF-ß1 by DC, which resulted in higher frequencies of Tregs production and inhibition of PEDV infection.

Thymosin alpha 1 restores the immune homeostasis in lymphocytes during Post-Acute sequelae of SARS-CoV-2 infection.

The complex alterations of the immune system and the immune-mediated multiorgan injury plays a key role in host response to SARS-CoV-2 infection and in the pathogenesis of COVID-19, being also associated with adverse outcomes. Thymosin alpha 1 (Tα1) is one of the molecules used in the treatment of COVID-19, as it is known to restore the homeostasis of the immune system during infections and cancer. The use of Tα1 in COVID-19 patients had been widely used in China and in COVID-19 patients, it has been shown to decrease hospitalization rate, especially in those with greater disease severity, and reduce mortality by restoring lymphocytopenia and more specifically, depleted T cells. Persistent dysregulation with depletion of naive B and T cell subpopulations and expansion of memory T cells suggest a chronic stimulation of the immune response in individuals with post-acute sequelae of SARS-CoV-2 infection (PASC). Our data obtained from an ex vivo study, showed that in PASC individuals with a chronically altered immune response, Tα1 improve the restoration of an appropriate response, most evident in those with more severe illness and who need respiratory support during acute phase, and in those with specific systemic and psychiatric symptoms of PASC, confirming Tα1 treatment being more effective in compromised patients. The results obtained, along with promising reports on recent trials on Tα1 administration in patients with COVID-19, offer new insights into intervention also for those patients with long-lasting inflammation with post-infectious symptoms, some of which have a delayed onset.

Utility of monocyte HLA-DR and rationale for therapeutic GM-CSF in sepsis immunoparalysis.

Sepsis, a heterogeneous clinical syndrome, features a systemic inflammatory response to tissue injury or infection, followed by a state of reduced immune responsiveness. Measurable alterations occur in both the innate and adaptive immune systems. Immunoparalysis, an immunosuppressed state, associates with worsened outcomes, including multiple organ dysfunction syndrome, secondary infections, and increased mortality. Multiple immune markers to identify sepsis immunoparalysis have been proposed, and some might offer clinical utility. Sepsis immunoparalysis is characterized by reduced lymphocyte numbers and downregulation of class II human leukocyte antigens (HLA) on innate immune monocytes. Class II HLA proteins present peptide antigens for recognition by and activation of antigen-specific T lymphocytes. One monocyte class II protein, mHLA-DR, can be measured by flow cytometry. Downregulated mHLA-DR indicates reduced monocyte responsiveness, as measured by ex-vivo cytokine production in response to endotoxin stimulation. Our literature survey reveals low mHLA-DR expression on peripheral blood monocytes correlates with increased risks for infection and death. For mHLA-DR, 15,000 antibodies/cell appears clinically acceptable as the lower limit of immunocompetence. Values less than 15,000 antibodies/cell are correlated with sepsis severity; and values at or less than 8000 antibodies/cell are identified as severe immunoparalysis. Several experimental immunotherapies have been evaluated for reversal of sepsis immunoparalysis. In particular, sargramostim, a recombinant human granulocyte-macrophage colony-stimulating factor (rhu GM-CSF), has demonstrated clinical benefit by reducing hospitalization duration and lowering secondary infection risk. Lowered infection risk correlates with increased mHLA-DR expression on peripheral blood monocytes in these patients. Although mHLA-DR has shown promising utility for identifying sepsis immunoparalysis, absence of a standardized, analytically validated method has thus far prevented widespread adoption. A clinically useful approach for patient inclusion and identification of clinically correlated output parameters could address the persistent high unmet medical need for effective targeted therapies in sepsis.