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BACKGROUND: Schistosomiasis is a parasitic infection that can cause pulmonary hypertension (PH). Th2 CD4 T cells are necessary for experimental Schistosoma-PH. However, if T cells migrate to the lung to initiate, the localized inflammation that drives vascular remodeling and PH is unknown. METHODS: Mice were sensitized to Schistosoma mansoni eggs intraperitoneally and then challenged using tail vein injection. FTY720 was administered, which blocks lymphocyte egress from lymph nodes. T cells were quantified using flow cytometry, PH severity via heart catheterization, and cytokine concentration through ELISA. RESULTS: FTY720 decreased T cells in the peripheral blood, and increased T cells in the mediastinal lymph nodes. However, FTY720 treatment resulted in no change in PH or type 2 inflammation severity in mice sensitized and challenged with S. mansoni eggs, and the number of memory and effector CD4 T cells in the lung parenchyma was also unchanged. Notably, intraperitoneal Schistosoma egg sensitization alone resulted in a significant increase in intravascular lymphocytes and T cells, including memory T cells, although there was no significant change in parenchymal cell density, IL-4 or IL-13 expression, or PH. CONCLUSION: Blocking T cell migration did not suppress PH following Schistosoma egg challenge. Memory CD4 T cells, located in the lung intravascular space following egg sensitization, appear sufficient to cause type 2 inflammation and PH.

Exaggerated airway constriction triggered by repeated exposure to allergen, also called hyperreactivity, is a hallmark of asthma. Whereas vagal sensory neurons are known to function in allergen-induced hyperreactivity1-3, the identity of downstream nodes remains poorly understood. Here we mapped a full allergen circuit from the lung to the brainstem and back to the lung. Repeated exposure of mice to inhaled allergen activated the nuclei of solitary tract (nTS) neurons in a mast cell-, interleukin-4 (IL-4)- and vagal nerve-dependent manner. Single-nucleus RNA sequencing, followed by RNAscope assay at baseline and allergen challenges, showed that a Dbh+ nTS population is preferentially activated. Ablation or chemogenetic inactivation of Dbh+ nTS neurons blunted hyperreactivity whereas chemogenetic activation promoted it. Viral tracing indicated that Dbh+ nTS neurons project to the nucleus ambiguus (NA) and that NA neurons are necessary and sufficient to relay allergen signals to postganglionic neurons that directly drive airway constriction. Delivery of noradrenaline antagonists to the NA blunted hyperreactivity, suggesting noradrenaline as the transmitter between Dbh+ nTS and NA. Together, these findings provide molecular, anatomical and functional definitions of key nodes of a canonical allergen response circuit. This knowledge informs how neural modulation could be used to control allergen-induced airway hyperreactivity.

Our previous work demonstrated that basophils regulate a suite of malaria phenotypes, including intestinal mastocytosis and permeability, the immune response to infection, gametocytemia, and parasite transmission to the malaria mosquito Anopheles stephensi. Given that activated basophils are primary sources of the regulatory cytokines IL-4 and IL-13, we sought to examine the contributions of these mediators to basophil-dependent phenotypes in malaria. We generated mice with basophils depleted for IL-4 and IL-13 (baso IL-4/IL-13 (-)) and genotype controls (baso IL-4/IL-13 (+)) by crossing mcpt8-Cre and Il4/Il13fl/fl mice and infected them with Plasmodium yoelii yoelii 17XNL. Conditional deletion was associated with ileal mastocytosis and mast cell (MC) activation, increased intestinal permeability, and increased bacterial 16S levels in blood, but it had no effect on neutrophil activation, parasitemia, or transmission to A. stephensi. Increased intestinal permeability in baso IL-4/IL-13 (-) mice was correlated with elevated plasma eotaxin (CCL11), a potent eosinophil chemoattractant, and increased ileal MCs, proinflammatory IL-17A, and the chemokines MIP-1α (CCL3) and MIP-1β (CCL4). Blood bacterial 16S copies were positively but weakly correlated with plasma proinflammatory cytokines IFN-γ and IL-12p40, suggesting that baso IL-4/IL-13 (-) mice failed to control bacterial translocation into the blood during malaria infection. These observations suggest that basophil-derived IL-4 and IL-13 do not contribute to basophil-dependent regulation of parasite transmission, but these cytokines do orchestrate protection of intestinal barrier integrity after P. yoelii infection. Specifically, basophil-dependent IL-4/IL-13 control MC activation and prevent infection-induced intestinal barrier damage and bacteremia, perhaps via regulation of eosinophils, macrophages, and Th17-mediated inflammation.

Background/Objectives: Despite its long-standing recognition, the etiopathogenesis of idiopathic granulomatous mastitis (IGM) remains poorly understood. This study aims to investigate the relationship between IGM and food intolerance, allergies, and immunological factors to shed light on its etiology. Materials and Methods: This case–control study included 32 patients with IGM and 32 healthy women. In order to examine their potential relevance to allergy and immunology, serum interleukin (IL)-4, IL-4 receptor, histamine, and histamine-releasing factor (HRF) were measured by ELISA. Furthermore, serum IgG antibodies against specific food allergens were measured to evaluate food intolerance. Results: The patient group exhibited significantly higher intolerance values for lentils and curry compared to the control group (p = 0.023 and p = 0.012, respectively). Histamine (p < 0.001) and IL-4 (p = 0.003) levels were elevated in IGM patients compared to the control group, while HRF and IL-4R outcomes did not show any significant differences (p > 0.05). Conclusions: Elevated histamine and IL-4 levels may suggest the involvement of allergy and immunological factors in IGM's etiopathogenesis. The integration of anti-histamine medications for IGM patients with elevated histamine levels could provide an alternative therapeutic strategy. [ABSTRACT FROM AUTHOR]

Objective: Reactivity of microglia, the resident cells of the brain, underlies innate immune mechanisms (e.g., injury repair), and disruption of microglial reactivity has been shown to facilitate psychiatric disorder dysfunctions. Although cellular analyses based on cultured microglia have been conducted, the molecular mechanism regulating microglial polarization remains elusive. We established a primary microglia culture that enabled manipulation of the substate of cells. This allowed us to investigate the expression levels of psychiatric disorder-related Kifs messenger RNA (mRNA) in each condition. Kifs encode molecular motor proteins that transport cargo along microtubules, which are thought to dynamically reorganize during a substate change. Results: As a candidate for a crucial Kifs gene that is associated with microglia polarization, we selected psychiatric disorder-related Kifs including Kif17. We found that the relative amounts of Kif3a, Kif17, and Kif13a mRNA were potentiated in alternatively activated microglia, whereas there were no significant changes in activated microglia. Furthermore, the microglia derived from a mouse line which possesses a mutation inducing truncated KIF17 indicated disrupted morphological phenotype of alternatively activated microglia. These results suggest that the potentiation of specific molecular motor expression is required to maintain the function of alternatively activated microglia. [ABSTRACT FROM AUTHOR]

Mitochondrial electron transport chain (ETC) function modulates macrophage biology; however, mechanisms underlying mitochondria ETC control of macrophage immune responses are not fully understood. Here, we report that mutant mice with mitochondria ETC complex III (CIII)-deficient macrophages exhibit increased susceptibility to influenza A virus (IAV) and LPS-induced endotoxic shock. Cultured bone marrow-derived macrophages (BMDMs) isolated from these mitochondria CIII-deficient mice released less IL-10 than controls following TLR3 or TLR4 stimulation. Unexpectedly, restoring mitochondrial respiration without generating superoxide using alternative oxidase (AOX) was not sufficient to reverse LPS-induced endotoxic shock susceptibility or restore IL-10 release. However, activation of protein kinase A (PKA) rescued IL-10 release in mitochondria CIII-deficient BMDMs following LPS stimulation. In addition, mitochondria CIII deficiency did not affect BMDM responses to interleukin-4 (IL-4) stimulation. Thus, our results highlight the essential role of mitochondria CIII-generated superoxide in the release of anti-inflammatory IL-10 in response to TLR stimulation. [ABSTRACT FROM AUTHOR]

Background: Wound healing is a restoration process of tissue integrity and function targeting reducing the healing time and complications with priority of available, acceptable and affordable medication. The study aimed to evaluate wound healing of aloe vera gel as raw or ethanol extract on a dorsal full thickness circular wound in Wistar rats. Rats subjected to the excision surgery were grouped into: control (+ ve), without treatment. and Kenacomb, aloe raw gel and aloe ethanol extract applied groups for 3, 7, 14 and 21 days for treatment evaluation. The study chromatographically quantified anthraquinones and identified the raw gel and extract' compounds. The evaluation was through the assessment of the wound contraction and complete blood count, serum interleukin-4 and skin tissue proline, hydroxyproline, glycine, malondialdehyde, nitric oxide contents and skin histopathology investigation at tested intervals. Results: Raw gel and extract contained in μg/ml, aloin A (9.23 and 17.22), aloin B (8.87 and 10.31) and emodin (11.66 and 12.66), respectively. The predominates identified percentage in raw gel were coumarins (34.93), fatty acids (28.45), phytosterols (7.77) and tocopherols (8.44) and in gel extract were phytosterols (49.39), fatty acids (29.16) and tocopherols (3.70). Results after 21 days were recorded in + ve control 80.50% wound contraction and showed significantly decreased values of IL-4, lymphocytes, Hb, RBCs and skin glycine, proline, hydroxyproline and NO. Neutrophils, monocytes, platelets and MDA were significantly increased. Histologically revealed epidermal acanthosis, inflammatory infiltration, fibrosis with hair follicles and sebaceous glands loss and dermal hemorrhage. Aloe raw gel revealed incomplete healing (91.79%) and failed to normalize IL-4, lymphocytes, neutrophils and the skin glycine and NO contents. Skin showed moderate epidermal acanthosis, and dermis had fibrosis, hemorrhage and loss of sebaceous glands and hair follicles. The extract group acquired 100% healing, normalized tested parameters and showed skin tissue thinning epidermis and intact dermal tissue with sebaceous glands and hair follicles. Conclusion: Results revealed aloe gel ethanol extract advantage over raw gel for wound healing which may be related to chemical constituents' variation interpreted in interest to the extract as an efficient therapeutic, cost-effective, available wound healing material. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the association between smell loss and other aspects of disease, and evaluate dupilumab efficacy in patients with severe chronic rhinosinusitis with nasal polyps (CRSwNP) and moderate or severe smell loss. Methods: This post-hoc analysis of the SINUS-24/52 studies (NCT02912468/NCT02898454) analyzed nasal polyp score (NPS, 0−8), nasal congestion/obstruction (NC, 0−3), Lund-Mackay CT-scan score (LMK-CT, 0−24), rhinosinusitis severity visual analog scale (RS-VAS, 0-10), and 22-item Sinonasal Outcome Test (SNOT-22, 0−110) according to baseline monthly average patient-reported loss of smell scores (LoS, 0−3) of >1 to 2 (moderate) or >2 to 3 (severe) in patients randomized to dupilumab 300 mg or placebo every 2 weeks. Results: Of 724 patients randomized, baseline LoS was severe in 601 (83%) and moderate in 106 (15%). At baseline, severe versus moderate LoS was associated with 1-point greater severity of NC (odds ratio [OR] 6.01 [95% confidence interval, (CI) 3.95, 9.15]), 5-point greater severity of LMK-CT (OR 2.19 [1.69, 2.85]), and 8.9-point greater severity of SNOT-22 (OR 1.35 [1.20, 1.49]). At Week 24, least squares mean differences (95% CI) dupilumab versus placebo in change from baseline were: NPS −1.90 (−2.56, −1.25) and −1.95 (−2.20, −1.70) in the moderate and severe baseline LoS subgroups, respectively; NC −.35 (−.64, −.06) and −1.00 (−1.13, −.87); LMK-CT −6.30 (−7.88, −4.72) and −6.22 (−6.82, −5.63); RS-VAS −1.18 (−2.20, −.16) and −3.47 (−3.90, −3.03); and SNOT-22 −7.52 (−14.55, −.48) and −21.72 (−24.63, −18.82); all nominal P <.05 versus placebo. Improvements with dupilumab in NC, RS-VAS, and SNOT-22 were statistically greater in patients with severe versus moderate baseline LoS. Conclusion: Significant smell impairment in severe CRSwNP is associated with significant disease (NC, RS-VAS, LMK), health-related quality of life impairment (SNOT-22), asthma, and non-steroidal anti-inflammatory drug-exacerbated respiratory disease. Dupilumab significantly improved NPS, NC, LMK-CT, RS-VAS, and SNOT-22 in subjects with moderate and severe baseline smell loss. [ABSTRACT FROM AUTHOR]

Background: Impaired clearance of amyloid-β protein (Aβ) in the peripheral system is a crucial event in the pathogenesis of sporadic Alzheimer's disease (AD). Dysfunctional monocytes with deficient clearance of Aβ and increased secretion of pro-inflammatory factors in the periphery are considered to contribute to AD development. Multiple studies suggest that IL-4 can inhibit the inflammatory response and enhance the expression and activity of cathepsin protease associated with intracellular clearance of Aβ by monocytes. Objective: To investigate the effects of interleukin-4 (IL-4) on Aβ clearance and inflammatory response of monocytes in vitro. Methods: In this study, flow cytometry, confocal microscopy and ELISA techniques were used for measurement of Aβ clearance and its related mechanisms of monocytes. Results: We found that the mean intracellular content and uptake ratios of Aβ42 in total monocytes, as well as in the CD14 + CD16− subset, were enhanced by IL-4, concomitant with the degradation of Aβ42 by monocytes. And IL-4 treatment also increased expression of scavenger receptor CD36 and Macrophage scavenger receptor 1 (MSR1) on monocytes. It was shown that IL-4 increased the Aβ immunoreactive area within lysosomal markers, including early endosome antigen 1 (EEA1), lysosome-associated membrane glycoprotein 1 and 2 (LAMP1 and 2) and Aβ degradative enzymes cathepsin B and S in monocytes, but reduced secretion of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and interferon-γ (IFN-γ) by monocytes. Conclusions: Our study supports the role of IL-4 in regulating Aβ clearance and inflammatory response by monocytes, suggesting that IL-4 may have therapeutic potential for AD. [ABSTRACT FROM AUTHOR]

BACKGROUND: Diabetic ulcers are a common complication of diabetes mellitus, which is manifested as foot ulcers complicated with infection, long treatment cycle, high disability rate and mortality rate, and brings a heavy burden to patients and social care. OBJECTIVE: To review the mechanism of action and the latest treatment progress of traditional Chinese medicine (TCM) in the treatment of diabetic ulcers, and to provide a basis for further theoretical research and clinical application. METHODS: CNKI, WanFang Database and PubMed database were searched for relevant literature using the keywords of “diabetic ulcer, medicinal herb, inflammation, interleukin-1β, interleukin-6, tumor necrosis factor, hypersensitive C-reactive protein, γ-interferon, interleukin-4, interleukin-10” in Chinese and English, respectively. The relevant literature in recent years was searched, and finally 75 articles were included for review. RESULTS AND CONCLUSION: The high glucose environment of the body will increase the level of pro-inflammatory cytokines, so that diabetic ulcer wounds are in a state of chronic inflammatory response for a long time, and difficult to heal or even not heal. TCM has summed up a lot of experience in the long-term struggle with diabetic ulcer. At present, TCM divides diabetic ulcers into four syndrome types: dampness and heat poison syndrome, blood and blood stasis obstruction pattern, heat poison injury Yin pattern, and Qi and blood deficiency syndrome, as well as representative prescriptions for treatment. According to their clinical characteristics, diabetic ulcers can be also divided into three stages: primary, middle and late stages. Different treatment methods are proposed: “clear method,” “warm and clear combined use” and “maintenance method.” Under the guidance of dialectical typing and staging of TCM, TCM monomers, extracts and compounds inhibit the inflammatory response and promote the healing of diabetic ulcers by down-regulating the expression of pro-inflammatory factors and/or up-regulating the expression of anti-inflammatory factors. Compared with modern medicine, TCM has significant advantages in the treatment of diabetic ulcers. There are many TCM monomers, extracts and compounds for the treatment of diabetic ulcers, such as angelica, curcumin, improved Chonghe ointment, Sanhuang blood exhaustion prescription and sore-ulcer I. formula, etc. It has been found that TCM for the treatment of diabetic ulcers is mainly heatclearing and detoxifying, invigorating blood circulation and removing blood stasis, and amassing sores and muscle-building drugs, and the frequency of use, treatment scope and therapeutic effect of TCM compounds are obviously better than those of TCM monomers and extracts. Among them, the most commonly used are the Sanhuang blood exhaustion prescription and the sore-ulcer I as well as prescription for the treatment of damp heat toxicity syndrome and Zizhu ointment for the treatment of non-ischemic diabetic ulcers. However, there are also some shortcomings in the treatment of diabetic ulcers with TCM. First, there are few clinical syndrome studies on diabetic ulcers. Secondly, there are a wide variety of TCM monomers, extracts and compounds for the treatment of diabetic ulcers, and the relevant research is insufficiently in-depth. Finally, the research on the mechanism underlying TCM treatment of diabetic ulcers is still in the preliminary exploration stage, and the mechanism of action still needs to be further explored. In the future, it is necessary to strengthen the research on the pharmacology of TCM and the clinical syndrome of diabetic ulcers, analyze the potential targets and related signaling pathways of TCM in the treatment of diabetic ulcers, give full play to the therapeutic advantages of TCM with multiple targets, multiple pathways, multiple levels and multiple systems, and develop TCM with significant efficacy, active ingredients and clear targets. [ABSTRACT FROM AUTHOR]

Cryptosporidiosis is a zoonotic disease caused by a protozoan parasite of the genus Cryptosporidium. It is widespread worldwide and is among the four main diarrhoea pathogens in children and adults. The present study aimed to investigate infection with the cryptosporidiosis in children under the age of eight years in both sexes who suffered from diarrhoea, and to evaluate the relationship of Interlukin-4 to parasitic infection and the changes in some serological parameters that included lipid profile and total protein. Two hundred fecal samples were collected from Ramadi Teaching Hospital for Women and Children. Microscopic examination of the samples stained with Ziehl-Neelsen stain and ELISA test indicated the presence of egg cysts in 23 samples, with a total percentage of (11.5%). The shape of the parasite was spherical, tending to oval, with a size of (4.8 to 5.7 micrometres). The lipid profile results showed that there was a significant increase in cholesterol (Ch.), triglycerides (TG.), low density lipoprotein (LDL), very low-density lipoprotein (vLDL), and for high-density lipoproteins (HDL) of the patient's group, there was no significant difference between the control group and the infected group at the (P ≤0.05). There was a significant increase in the level of blood proteins (Total Protein, Albumin, Globulin) for the infected group at a significant level (P≤0.05). The study also showed significant differences in interleukin-4 between patients and healthy people, which was 0.0444 ± 0.01141 pg/ml for patients (P≤0.05). Due to the increasing spread, seriousness, and epidemiology of the parasite, considered environmental pollution, and because of its lack of diagnosis in health departments (such as hospitals), and because its entry significantly stimulates the immune system, causes dehydration and death in children with weak immunity, and affects the absorption of fats, proteins, and vitamins significantly, a new factor IL-4 related to the infection was identified. It was also known how significant the effect of injury is on the amount of fats and proteins that are involved in the structure of living cell membranes. [ABSTRACT FROM AUTHOR]

Background: Chronic rhinosinusitis (CRS) is a disease characterized by persistent sinonasal mucosal inflammation. Fibroblasts play a crucial role in extracellular matrix production and inflammation. We investigated the heterogeneity of fibroblasts in patients with CRS. Methods: Fibroblasts were isolated from nasal polyp tissues. RNA sequencing was then performed. We also analyzed the GSE136825 dataset obtained from the Gene Expression Omnibus database. Alternatively, fibroblasts were stimulated in vitro. Results: Hierarchical clustering of samples indicated ADGRB3-high and POSTN-high fibroblasts. A Gene Set Enrichment Analysis (GSEA) revealed that cytotoxic immune responses were enriched in ADGRB3-high fibroblasts, while cell cycle pathways were enriched in POSTN-high fibroblasts. Similar GSEA results were observed in the GSE136825 dataset. Additionally, type 1 and type 3 inflammation-related genes were highly expressed in ADGRB3-high samples, whereas type 2-related genes were highly expressed in POSTN-high samples. In vitro, ADGRB3 expression increased in fibroblasts stimulated with IFN-γ, while POSTN increased in those stimulated with IL-4 and IL-13. Conclusions: Our study demonstrates that type 1 inflammation induces ADGRB3-high fibroblasts, associated with the cytotoxic immune response, while type 2 inflammation induces POSTN-high fibroblasts, linked to CRS progression via an elevated cell cycle. The further characterization of fibroblasts could provide insights into the stromal networks in the CRS microenvironment. [ABSTRACT FROM AUTHOR]

The experiment aimed to study the effects of Eucommia ulmoides extract on the growth performance and serum indexes of calves. A single-factor randomized block design was used, selecting 30 healthy newborn Holstein calves delivered naturally, randomly divided into a control group and an experimental group, with 15 replicates in each group, and one calf per replicate. The control group was fed a basic diet, while the experimental group was fed a basic diet plus 2 kg/t of Eucommia ulmoides extract for 62 days trial period. The results showed that the average daily weight gain of the calves in the experimental group increased compared to the control group (P>0.05). The frequency of mild diarrhea and total diarrhea in the experimental group were extremely reduced compared to the control group (P<0.01). The levels of serum albumin (ALP), interleukin-4 (IL-4), interleukin-10 (IL-10), and activity of glutathione peroxidase (GSH-Px) in the experimental group were significantly higher than those in the control group ( P<0.05), while the contant of tumor necrosis factor-α (TNF-α) was significantly lower than that in the control group (P<0.05). The study indicates that adding 2 kg/t of Eucommia ulmoides extract to the feed of calves can enhance their anti-inflammatory and antioxidant capabilities, reduce the incidence of diarrhea, and improve growth performance. [ABSTRACT FROM AUTHOR]

The experiment aimed to explore the effects of starter feed with different proportions of alfalfa on the growth performance, serum indexes, and intestinal development of Hu sheep lambs aged 15 to 54 days. A total of 48 Hu sheep lambs with an average body weight of (4.22±0.35) kg from the second parity twins were randomly divided into three groups, with four replicates per group and four sheep per replicate. Each group was fed starter feed containing 10%, 20%, and 30% alfalfa, respectively. The experiment lasted for 40 days. The results showed that at 54 days of age, the body weight of lambs in the 30% alfalfa group was higher than that of the other groups (P>0.05). From 45 to 49 days of age, the average daily feed intake (ADFI) of the 20% alfalfa group was significantly higher than that of the 10% alfalfa group (P<0.05). The levels of tumor necrosis factor-α (TNF-α), interleukin-4 (IL-4), and interleukin-6 (IL-6) in the 20% and 30% alfalfa groups were significantly lower than those in the 10% alfalfa group (P<0.05), and the serum total antioxidant capacity (T-AOC) and glutathione peroxidase (GSH-Px) activity in the 20% and 30% alfalfa groups were significantly higher than those in the 10% alfalfa group (P<0.05). The total antioxidant capacity (T-AOC) and superoxide dismutase (SOD) activity in the intestines of the 10% alfalfa group were significantly higher than those in the other groups (P<0.05). The creatine kinase (CK) activity in the 20% and 30% alfalfa groups was significantly lower than that in the 10% alfalfa group (P<0.05), and the lactate dehydrogenase (LDH) activity in the 20% and 30% alfalfa groups was significantly higher than that in the 10% alfalfa group (P<0.05). The villus length of the duodenum in the 20% alfalfa group and the crypt depth in the duodenum of the 30% alfalfa group were significantly higher than those in the other groups (P<0.05). The study indicates that feeding starter feed containing 10% and 20% alfalfa can enhance the body's immune and antioxidant capabilities, and promote the development of duodenal tissue. It is recommended that the content of alfalfa in the starter feed for lambs aged 15 to 54 days should not exceed 20%. [ABSTRACT FROM AUTHOR]

Allergic dermatitis (AD) is a skin disease characterized by a chronic inflammation caused by immune dysregulation. In the histopathology of patients with AD, there are several features, such as accumulation of eosinophils and mast cells, hyperkeratosis, and dermal fibrosis which are related to the exacerbation of AD. Mast cells and eosinophils are thought to be involved in fibrosis, but the details are unknown. Yama mouse is an inbred mouse showing genetically eosinophilia. If eosinophils have significant effect on fibrosis, it may be possible to establish a new AD model with severe fibrosis. In this study, AD was induced by applying dinitrofluorobenzene to mice auricle. Yama mice showed AD lesion with more severe dermal fibrosis with severe eosinophil infiltration than Balb/c and Nc/nga mice. The expression of transforming growth factor-β (TGF-β), a cytokine important for fibrosis, was not significantly different among Yama, Balb/c, and Nc/nga mice, while the expression of interleukin-4 (IL-4), which is also mediator of tissue fibrosis, was increased only in Yama mice. The results of this study showed that AD with more severe fibrosis could be induced in Yama mice than in Balb/c and Nc/nga mice. In Yama mice, it can be concluded that the severe fibrosis is TGF-β independent, and IL-4 would be the main mediator of severe fibrosis. This mouse model may be useful for elucidating the mechanism of fibrosis in chronic AD, and for conducting research leading to the development of new therapies. [ABSTRACT FROM AUTHOR]

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Abstract It was a general belief that drug resistance in Mycobacterium tuberculosis (Mtb) was associated with lesser virulence, particularly rifampicin resistance, which is usually produced by mutations in the RNA polymerase Beta subunit (RpoB). Interestingly, this kind of bacterial mutations affect gene transcription with significant effects on bacterial physiology and metabolism, affecting also the bacterial antigenic constitution that in consequence can produce diverse immune responses and disease outcome. In the present study, we show the results of the Mtb clinical isolate A96, which is resistant to rifampicin and when used to infect BALB/c mice showed hypervirulence, apparently by rapidly polarization of the Th2 immune response through early and high production of IL-4. The 2D-PAGE analysis of the secretome of Mtb A96 showed 204 spots, and by immunoproteome, seven proteins that were differentially recognized with the sera of infected mice on day 28 were identified by LC-MS/MS. The proteins correspond to surface antigens, virulence factors, and energy metabolism enzymes. Some of them are immunodominant antigens, such as LpqH lipoprotein that induces IL-4 secretion in cell suspensions from the lung and spleen of mice infected with Mtb A96 at 28 days postinfection, suggesting that LpqH could be one of the main antigens involved in the Th2 polarization. The reduction of Mtb A96 hypervirulence in IL-4Rα−/− BALB/c mice highlights the importance of IL-4 induction and Th2 response polarization and the immunopathological response. Thus, high and rapid bias to Th2 response is a mechanism of Mtb virulence, which could be mediated by rifampicin-resistant Mtb isolates, probably by high production and secretion of specific antigens.

Abstract Background Wound healing is a restoration process of tissue integrity and function targeting reducing the healing time and complications with priority of available, acceptable and affordable medication. The study aimed to evaluate wound healing of aloe vera gel as raw or ethanol extract on a dorsal full thickness circular wound in Wistar rats. Rats subjected to the excision surgery were grouped into: control (+ ve), without treatment. and Kenacomb, aloe raw gel and aloe ethanol extract applied groups for 3, 7, 14 and 21 days for treatment evaluation. The study chromatographically quantified anthraquinones and identified the raw gel and extract’ compounds. The evaluation was through the assessment of the wound contraction and complete blood count, serum interleukin-4 and skin tissue proline, hydroxyproline, glycine, malondialdehyde, nitric oxide contents and skin histopathology investigation at tested intervals. Results Raw gel and extract contained in μg/ml, aloin A (9.23 and 17.22), aloin B (8.87 and 10.31) and emodin (11.66 and 12.66), respectively. The predominates identified percentage in raw gel were coumarins (34.93), fatty acids (28.45), phytosterols (7.77) and tocopherols (8.44) and in gel extract were phytosterols (49.39), fatty acids (29.16) and tocopherols (3.70). Results after 21 days were recorded in + ve control 80.50% wound contraction and showed significantly decreased values of IL-4, lymphocytes, Hb, RBCs and skin glycine, proline, hydroxyproline and NO. Neutrophils, monocytes, platelets and MDA were significantly increased. Histologically revealed epidermal acanthosis, inflammatory infiltration, fibrosis with hair follicles and sebaceous glands loss and dermal hemorrhage. Aloe raw gel revealed incomplete healing (91.79%) and failed to normalize IL-4, lymphocytes, neutrophils and the skin glycine and NO contents. Skin showed moderate epidermal acanthosis, and dermis had fibrosis, hemorrhage and loss of sebaceous glands and hair follicles. The extract group acquired 100% healing, normalized tested parameters and showed skin tissue thinning epidermis and intact dermal tissue with sebaceous glands and hair follicles. Conclusion Results revealed aloe gel ethanol extract advantage over raw gel for wound healing which may be related to chemical constituents’ variation interpreted in interest to the extract as an efficient therapeutic, cost-effective, available wound healing material.

Background It is believed that genetic factors play a role in the development and severity of neural injury among people with distal symmetrical polyneuropathy (DSP), because some genes are involved in specific biological pathways, acting in different ways in the pathogenic process.

The motility of macrophages in response to microenvironment stimuli is a hallmark of innate immunity, where macrophages play pro-inflammatory or pro-reparatory roles depending on their activation status during wound healing. Cell size and shape have been informative in defining macrophage subtypes. Studies show pro and anti-inflammatory macrophages exhibit distinct migratory behaviors, in vitro, in 3D and in vivo but this link has not been rigorously studied. We apply both morphology and motility-based image processing approaches to analyze live cell images consisting of macrophage phenotypes. Macrophage subtypes are differentiated from primary murine bone marrow derived macrophages using a potent lipopolysaccharide (LPS) or cytokine interleukin-4 (IL-4). We show that morphology is tightly linked to motility, which leads to our hypothesis that motility analysis could be used alone or in conjunction with morphological features for improved prediction of macrophage subtypes. We train a support vector machine (SVM) classifier to predict macrophage subtypes based on morphology alone, motility alone, and both morphology and motility combined. We show that motility has comparable predictive capabilities as morphology. However, using both measures can enhance predictive capabilities. While motility and morphological features can be individually ambiguous identifiers, together they provide significantly improved prediction accuracies (75%) from a training dataset of 1000 cells tracked over time using only phase contrast time-lapse microscopy. Thus, the approach combining cell motility and cell morphology information can lead to methods that accurately assess functionally diverse macrophage phenotypes quickly and efficiently. This can support the development of cost efficient and high through-put methods for screening biochemicals targeting macrophage polarization.

BACKGROUND: Many recent studies have shown a close relationship between inflammatory cytokines and osteoporosis and bone mineral density (BMD). However, the causal relationship between inflammatory cytokines and BMD has not been fully revealed. OBJECTIVE: To explore the potential causal relationship between inflammatory cytokines and BMD using a two-sample Mendelian randomization analysis. METHODS: The single nucleotide polymorphisms associated with 41 circulating inflammatory cytokines were selected from the open database of genome-wide association studies (GWAS) as instrumental variables. The GWAS data about BMD were from the Genetic Factors for Osteoporosis Consortium, involving a total of 32 735 individuals of European ancestry. Inverse variance weighting was used as the primary analysis to evaluate the causal effect. Weighted median, MR Egger regression, simple mode, and weighted mode methods were used to supplement the explanation. We used the MR-Egger intercept and MR-PRESSO method to conduct a pleiotropy test, the Cochran’s Q test was used to determine whether there was heterogeneity in the results, and the leave-one-out method was used to evaluate the stability of the results. In addition, to more accurately assess the causality, the Bonferroni-corrected test was used to identify inflammatory cytokines that have a strong causal relationship with BMD. RESULTS AND CONCLUSION: (1) According to the results of the inverse variance weighting method, we found a positive causal relationship between interleukin-8 and lumbar spine BMD [β=0.075, 95% confidence interval (CI): 0.033-0.117, P=0.000 5), while a negative causal relationship between interleukin-17 and lumbar spine BMD (β=-0.083, 95% CI: -0.152 to -0.014, P=0.018). There might be a negative causal relationship between tumor necrosis factor b and femoral neck BMD (β=-0.053, 95% CI: -0.088 to -0.018, P=0.003), while a positive causal relationship between basic fibroblast growth factor and femoral neck BMD (β=0.085, 95% CI: 0.016-0.154, P=0.015). There might be a negative causal relationship between macrophage inflammatory protein-1a and total body BMD (β=-0.056, 95% CI: -0.105 to -0.007, P=0.025). There was a negative causal relationship between interleukin-5 (β=-0.019, 95% CI: -0.031 to -0.006, P=0.004), stromal cell-derived factor-1a (β=-0.022, 95% CI: -0.038 to -0.005, P=0.010), hepatocyte growth factor (β=-0.021, 95% CI: -0.041 to -0.002, P=0.030), interleukin-4 (β=-0.016, 95% CI: -0.032 to -0.001, P=0.034) and heel BMD, while a positive causal relationship between nerve growth factor (β=0.019, 95% CI: 0.002-0.036, P=0.033), granulocyte colony-stimulating factor (β=0.011, 95% CI: 0.000-0.022, P=0.050), and heel BMD. Meanwhile, after the Bonferroni-corrected test, there was a strong positive causal effect between interleukin-8 and lumbar spine BMD (P=0.000 5). And consistent directional effects for all analyses were observed in MR Egger, weighted median, simple mode, and weighted mode methods. (2) Sensitivity analyses revealed no heterogeneity, pleiotropy, or outliers for the causal effect of circulating inflammatory cytokines on BMD. [ABSTRACT FROM AUTHOR]

Background: Thymic stromal lymphopoietin (TSLP) plays an important role in mediating the type-2-inflammatory response. This study examined how TSLP and interleukin (IL)-4 levels in patients with chronic rhinosinusitis with nasal polyps (CRSwNP) correlated with clinical and postoperative outcomes. Methods: Solid-phase sandwich ELISA was used to analyze TSLP and IL-4 levels in mucus (n = 47), plasma (n = 17), polyp (n = 30), inferior (n = 25), and middle (n = 26) turbinate tissue collected during functional endoscopic sinus surgery (FESS) in CRSwNP patients (n = 76) and controls (n = 11). Inclusion criteria includes patients with medical treatment refractory CRSwNP confirmed by endoscopy or maxillofacial CT. Exclusion criteria include history of immunodeficiency, coagulation disorders, fungal sinusitis, or cystic fibrosis. Levels of TSLP and IL-4 were correlated with SNOT-22, UPSIT, and fractional exhaled nitric oxide (FeNO) using MannWhitney U two-tailed test and linear regression with Spearman correlation coefficient test. Results: TSLP is elevated in the inferior turbinates (effect size = 2.695, p = 0.0007) of CRSwNP patients compared to controls. IL-4 is expressed at elevated levels in the inferior (effect size = 3.092, p < 0.0001) and middle turbinates (effect size = 2.041, p = 0.019) compared to controls. Mucus TSLP (r = 0.4013, p = 0.0153) and IL-4 (r = 0.6138, p < 0.0001) positively correlate with preoperative FeNO levels. Lower TSLP in the inferior (r = −0.5179, p = 0.0231) and middle turbinates (r = −0.5075, p = 0.0224) and lower IL-4 in the inferior turbinates (r = −0.5205, p = 0.0223) correlate with a greater improvement in SNOT-22 post-FESS. Conclusion: TSLP and IL-4 are elevated in patients with CRSwNP and correlated with increased preoperative FeNO levels and decreased sinonasal quality of life benefit after FESS. Expression of TSLP and IL-4 may play a role in guiding postoperative expectations in patients with treatment refractory CRSwNP. [ABSTRACT FROM AUTHOR]

Fractional exhaled nitric oxide （FeNO） is a biomarker of type 2 inflammation， and produced by nitric oxide synthase （NOS） expressed on the airway epithelial cells， with the substrates of L-arginine and oxygen. Type 2 cytokines such as interleukin （IL）-4 and IL-13 can up-regulate inducible NOS， which results in the abundant production of NO. NO plays an important role in the pathogenesis of bronchial asthma， and is closely associated with the airway inflammation and remodeling， reduction of lung function and eosinophil infiltration， etc. The technique of FeNO test is applied in the clinical diagnosis of asthma， predicting the response to steroids and evaluating the compliance of asthmatic patients. In recent years， it also plays a guiding role in choosing the optimal biologics for individual therapy for patients of asthma. As a non-invasive， convenient， and economical method， the role of FeNO in the diagnosis and treatment of asthma will be better understood and applied.

Rabies remains a global health threat despite being preventable with post-exposure prophylaxis (PEP). This study assessed one-year humoral and T cell immunity in PEP recipients of the Insitut Pasteur du Cambodge (IPC) regimen, recommended by WHO. We analyzed rabies virus (RABV) neutralizing antibodies (nAbs) and T cell responses at baseline, 7 and 14 days, 6 and 12 months after PEP. A total of 148 patients were included, with 78 bitten by confirmed RABV-positive dogs receiving PEP and equine rabies immunoglobulins (eRIG), and 70 bitten by RABV-negative dogs receiving only PEP. Fourteen days after PEP, all but two individuals seroconverted for nAbs (≥ 0.5 IU/mL) with 87% maintaining this response even after 12 months. Interleukin-4 (IL-4) and interferon-gamma (IFN-γ)-secreting T cells were significantly elevated after 14 days and sustained for one year. No differences were observed between the RABV-exposed and -unexposed groups. This study demonstrates robust one-year immunity after IPC PEP. [ABSTRACT FROM AUTHOR]

Introduction: Postoperative strabismus inflammation can lead to fibrotic tissue formation. Dexamethasone, while generally effective as an anti-inflammatory post-surgery medication, can increase IOP and blood sugar levels. Research on asiatic acid suggests its potential as an anti-inflammatory and anti-fibrotic agent. Methods: Superior rectus recession was conducted on 20 rabbits, which were divided into five groups based on the subconjunctival injection substance: aquadest, dexamethasone, asiatic acid at a concentration of 0.4 mg/0.5 mL, 0.8 mg/0.5 mL, and 1.6 mg/0.5 mL. After three days, exenteration was performed, and an immunohistochemical examination was performed to assess interleukin-4 expression. Hematoxylin and eosin staining was performed to assess eosinophile cell count. SPSS 26.0 facilitated the data analysis using the Kruskal-Wallis and Wilcoxon Mann-Whitney tests. P<0.05 was considered significant statistically. Results: This study showed that interleukin-4 expression in the asiatic acid 0.4 mg/0.5 mL group was significantly decreased compared to the aquadest group (P = 0.029) and dexamethasone group (P = 0.029). Higher-dose groups did not exhibit a significant decrease. Dexamethasone also did not exhibit a significant decrease compare to aquadest. There was no significant reduction of eosinophile cell count among all groups. Conclusions: This study highlighted the potential of asiatic acid, particularly at the concentration of 0.4 mg/0.5 mL, in reducing the inflammatory response, specifically interleukin-4 expression, after strabismus surgery in New Zealand rabbits. [ABSTRACT FROM AUTHOR]

Chronic spontaneous urticaria (CSU) is a complex dermatological condition characterized by recurrent wheals and/or angioedema lasting for more than six weeks, significantly impairing patients' quality of life. According to European guidelines, the first step in treatment involves second-generation H1-antihistamines (sgAHs), which block peripheral H1 receptors to alleviate symptoms. In cases with inadequate responses, the dose of antihistamines can be increased by up to fourfold. If symptoms persist despite this adjustment, the next step involves the use of omalizumab, a monoclonal anti-IgE antibody, which has shown efficacy in the majority of cases. However, a subset of patients remains refractory, necessitating alternative treatments such as immunosuppressive agents like cyclosporine or azathioprine. To address these unmet needs, several new therapeutic targets are being explored. Among them, significant attention is being given to drugs that block Bruton's tyrosine kinase (BTK), such as remibrutinib, which reduces mast cell activation. Therapies like dupilumab, which target the interleukin-4 (IL-4) and IL-13 pathways, are also under investigation. Additionally, molecules targeting the Mas-related G protein-coupled receptor X2 (MRGPRX2), and those inhibiting the tyrosine kinase receptor Kit, such as barzolvolimab, show promise in clinical studies. These emerging treatments offer new options for patients with difficult-to-treat CSU and have the potential to modify the natural course of the disease by targeting key immune pathways, helping to achieve longer-term remission. Further research is essential to better elucidate the pathophysiology of CSU and optimize treatment protocols to achieve long-term benefits in managing this condition. Altogether, the future of CSU treatments that target pathogenetic mechanisms seems promising. [ABSTRACT FROM AUTHOR]

Dupilumab, an anti‐interleukin (IL)‐4 receptor α‐antibody, was approved in 2018 for the treatment of moderate‐to‐severe atopic dermatitis (AD) in Japan. Although real‐world data have accumulated on the effectiveness and safety of dupilumab in patients with AD in the short term, real‐world data on its long‐term use are limited. In this study, we retrospectively investigated its effectiveness, safety and laboratory data in patients with AD who received dupilumab for 3 years. All adult patients with moderate‐to‐severe AD who were administered dupilumab between June 2018 and December 2020 and were treated with dupilumab for more than 3 years were included in this study. Sixty Japanese patients with AD (male, 48; female, 12) were included in this study. Their mean age was 36.6 ± 11.0 (standard deviation) years. The mean Eczema Area and Severity Index (EASI) was 29.9 ± 9.2. The clinical severity scales, including Investigator's Global Assessment (IGA), EASI and affected body surface area (BSA), and patient‐reported outcomes, such as Dermatology Quality Life Index (DLQI), Patient‐Oriented Eczema Measure (POEM) and visual analogue scale (VAS) of pruritus, significantly improved at 3 months, and at 1, 2 and 3 years after initiating dupilumab. The total EASI score significantly decreased by a mean of 66.8% at 3 months, 81.0% at 1 year, 85.3% at 2 years and 90.0% at 3 years after initiating dupilumab. The serum levels of thymus and activation‐regulated chemokine (TARC), immunoglobulin E (IgE) and lactate dehydrogenase (LDH) significantly decreased at 1, 2 and 3 years. A slight decrease in circulating neutrophils was observed in patients with AD treated with dupilumab over periods from 3 months to 3 years. The number of circulating eosinophils significantly decreased at 2 and 3 years after initiating dupilumab. The most common adverse event was ocular disorders observed in 23 patients (38.3%). Our study shows the sustained effectiveness and tolerable safety of 3‐year usage of dupilumab in Japanese patients with atopic dermatitis. Furthermore, dupilumab decreased neutrophil values at 3 months and later, and reduced the number of circulating eosinophils after long‐term use (≧ 2 years). [ABSTRACT FROM AUTHOR]

Introduction: Anaphylaxis is a globally increasing allergic reaction that is often fatal. Recently, our previous study reported the possibility of using the modified natural products "sodium R-lipoate (NaRLA) and enzymatically modified isoquercitrin (EMIQ)" as potential novel safe agents against the non-immunological-degranulation of mast cells. Methods: Here, we extended our previous findings by determining the antianaphylactic activity of 50 and 100 mg/kg body weight of NaRLA and EMIQ (given orally and prior to local or systemic challenge) in mice models of ovalbumin (OVA)-induced IgE-dependent active cutaneous anaphylaxis (ACA) and active systemic anaphylaxis (ASA) in comparison with sulfasalazine (SSZ, amast cell stabilizer). Results: The pre-treatment of mice with NaRLA or EMIQ completely succeeded, as SSZ, in suppression of the increased vascular permeability associated with IgE-dependent ACA and protected the OVA-sensitized mice from fatal ASA by reducing (p <.001) the skin mast cell degranulation, the elevated peritoneal histamine and interleukin-4 levels, along with decreasing the associated sever gastrointestinal and lung histopathological alterations and inflammation. The high dose of EMIQ prevented death in 70% of mice with anaphylactic shock, better than SSZ. Discussion: Our data indicated that NaRLA and EMIQ may be potential prophylactic and therapeutic candidates for the alleviation of atopic and systemic anaphylaxis. [ABSTRACT FROM AUTHOR]

Aim: This work investigated the difference of serum cytokine levels in children with bronchial asthma (BA) in acute attack and clinical remission and the relationship between them. Material and methods: A hundred children with BA were included and enrolled into an acute attack group (AA group) and a clinical remission group (CR group) according to their medical history and clinical characteristics, with 50 children in each group. Then, another 50 healthy children in the same hospital for physical examination were randomly selected as controls. Results: Interleukin (IL) 4 (IL-4) and interferon-γ (IFN-γ) levels in the AA group were significantly higher than those in controls (p < 0.05), but the IL-4 and IFN-γ levels in the clinical remission phase group were not remarkably different from those in controls (p > 0.05). The IL-15 level in the AA group was much higher than that in children with BA in the clinical remission stage and controls, and the IL-15 level in the CR control was higher than that in controls (p < 0.05). IL-4 level was positively linked with INF-γ level (r = 15.621, p = 0.002) and IL-15 level (r = 9.581, p = 0.008). IL-15, IL-4, and IFN-γ were related to the incidence of BA of children and played a role in the exacerbation of respiratory inflammation during acute attacks. IL-4 was associated with IL-15 and INF-γ, and there was a synergistic relationship in promoting inflammation of BA. [ABSTRACT FROM AUTHOR]

• Developed a novel, reproducible cellular assay to directly quantify non-specific endocytosis of therapeutic proteins. • A previous clinical candidate monoclonal antibody with rapid target-independent clearance in mice and humans possessed extensive non-specific endocytosis that was due to exposed positive charge features. • Demonstration of distinct rates of endocytosis into mammalian cells for disparate monoclonal antibodies, even those with common specificity for targets or isoelectric points. • Cell-based assay to quantify the potential impact of non-specific endocytosis on target-independent clearance and/or subcutaneous bioavailability of monoclonal antibodies. Past studies have demonstrated higher clearance for monoclonal antibodies possessing increased rates of non-specific endocytosis. However, this metric is oftentimes evaluated indirectly using biophysical techniques or cell surface binding studies that may not provide insight into the specific rates of cellular turnover. Furthermore, few examples evaluating non-specific endocytosis have been reported for a therapeutic antibody that reached clinical assessment. In the current report, we evaluated a therapeutic human immunoglobulin G2 monoclonal antibody targeted against the interleukin-4 receptor alpha chain (IL-4Rα) that exhibited elevated target independent clearance in previous Phase 1 and 2 studies. We confirmed high non-specific clearance of the anti-IL-4Rα antibody as compared to a reference antibody during pharmacokinetic assessments in wild type mice where target-mediated disposition was absent. We then developed a cell-based method capable of measuring cellular protein endocytosis and demonstrated the anti-IL-4Rα antibody exhibited marked non-specific uptake relative to the reference compound. Antibody homology modeling identified the anti-IL-4Rα antibody possessed positive charge patches whose removal via targeted mutations substantially reduced its non-specific endocytosis. We then expanded the scope of the study by evaluating panels of both preclinical and clinically relevant monoclonal antibodies and demonstrate those with the highest rates of non-specific uptake in vitro exhibited elevated target independent clearance, low subcutaneous bioavailability, or both. Our results support the observation that high non-specific endocytosis is a negative attribute in monoclonal antibody development and demonstrate the utility of a generic cell-based screen as a quantitative tool to measure non-specific endocytosis of protein therapeutics at the single-cell level. [ABSTRACT FROM AUTHOR]

Allergic disorders, including asthma, rhinitis and atopic dermatitis, are significant global health concerns, primarily driven by dysregulated immune responses. Key cytokines, such as interleukin-4 (IL-4), interleukin-5 (IL-5) and interleukin-13 (IL-13), play a pivotal role in orchestrating allergic inflammation. Conventional treatments, although effective in symptom management, often have side effects and do not adequately address the immune dysregulation. As a result, there is growing interest in exploring natural alternatives with fewer adverse effects. This study investigates the in vitro anti-allergic potential of Croton bonplandianum ethanolic extract (CBEE) by evaluating its effect on IL-5 and IL-13 production in stimulated THP-1 cell cultures. The results demonstrate that CBEE significantly downregulates IL-5 and IL-13 production, indicating its potential as a natural anti-allergic agent. These findings suggest that Croton bonplandianum could provide a novel approach to managing allergic disorders by targeting key mediators of inflammation. [ABSTRACT FROM AUTHOR]

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Leptospirosis is a worldwide zoonotic disease caused by pathogenic Leptospira spp., often occurring in tropical and subtropical regions. Focusing on development of rapid diagnostic methods to facilitate early diagnosis and a universal vaccine are the main critical issues to overcome the burden of leptospirosis. Here, we have studied the immunogenic potential of prepared recombinant Loa22 protein (rLoa22) of local pathogenic Leptospira species in mice and its ability to induce humoral and cellular immunity, being further evaluated by analyzing the immunoglobulin G (IgG) subclasses and cytokines produced through immunization. Based on the results, mice immunized with rLoa22/adjuvant and a trivalent vaccine, induced high titers of total IgG. All immunized groups increased IgG1 almost on the same level; but, IgG2a level was significantly higher in the vaccine and rLoa22/adjuvant groups than rLoa22 alone group. Animals immunized with the vaccine produced more interleukin 4 than rLoa22/adjuvant group. The results of evaluating interferon gamma level showed that the rLoa22/adjuvant and vaccine groups had a significant increase compared to the rLoa22 alone group. The results also demonstrated that the rLoa22 protein, in indirect enzyme-linked immunosorbent assay, was able to detect the anti-Leptospira antibodies in mice serum that can be used as a marker in assessing the seroprevalence of leptospirosis and/or in combination with other leptospiral antigens in development of an effective vaccine against leptospirosis. [ABSTRACT FROM AUTHOR]

Background Interleukin 4 (IL-4), increased in tuberculosis infection, may impair bacterial killing. Blocking IL-4 confers benefit in animal models. We evaluated safety and efficacy of pascolizumab (humanized anti–IL-4 monoclonal antibody) as adjunctive tuberculosis treatment. Methods Participants with rifampicin-susceptible pulmonary tuberculosis received a single intravenous infusion of pascolizumab or placebo, and standard 6-month tuberculosis treatment. Pascolizumab dose increased in successive cohorts: (1) nonrandomized 0.05 mg/kg (n = 4); (2) nonrandomized 0.5 mg/kg (n = 4); (3) randomized 2.5 mg/kg (n = 9) or placebo (n = 3); and (4) randomized 10 mg/kg (n = 9) or placebo (n = 3). Coprimary safety outcome was study-drug–related grade 4 or serious adverse event (G4/SAE) in all cohorts (1–4). Coprimary efficacy outcome was week 8 sputum culture time-to-positivity (TTP) in randomized cohorts (3–4) combined. Results Pascolizumab levels exceeded IL-4 50% neutralizing dose for 8 weeks in 78%–100% of participants in cohorts 3–4. There were no study-drug–related G4/SAEs. Median week-8 TTP was 42 days in pascolizumab and placebo groups (P =.185). Rate of TTP increase was greater with pascolizumab (difference from placebo 0.011 log10 TTP/day; 95% Bayesian credible interval 0.006 to 0.015 log10 TTP/day). Conclusions There was no evidence to suggest blocking IL-4 was unsafe. Preliminary efficacy findings are consistent with animal models. This supports further investigation of adjunctive anti–IL-4 interventions for tuberculosis in larger phase 2 trials. Clinical Trials Registration NCT 01638520. [ABSTRACT FROM AUTHOR]

The aim of this experiment was to investigate the effects of different levels of plant extracts on the growth performance, serum biochemical indexes, and immune function of Xuhuai white goat, and to determine the suitable supplemental level of plant extracts in Xuhuai white goat breeding. A total of 48 healthy Xuhuai white goats were selected and divided into four treatment groups with three replicates per group and four Xuhuai white goats per replicate according to the single-factor experimental design. The control group was fed a basic diet, while the experimental groups were fed diets containing 0.1%, 0.2%, and 0.4% plant extracts. The preliminary trial lasted for one week, and the formal experiment was conducted for eight weeks. After the experiment, the growth performance, biochemical indexes, and immune indexes of the Xuhuai white goats in each group were measured. The results showed that compared with the control group, the final weight and average daily gain of 0.2% and 0.4% plant extract groups were significantly increased (P<0.05), the ratio of feed to gain was significantly decreased (P<0.05). The diarrhea rate was significantly decreased by 33.88% and 41.82% (P<0.05). Compared with control group, the contentrations of serum urea nitrogen and cholesterol of Xuhuai white goats in 0.2% and 0.4% plant extract groups were significantly decreased (P<0.05), while the contentrations of albumin, total protein, high density lipoprotein and growth hormone were significantly increased (P<0.05). The glutamic oxalacetic transaminase activity of Xuhuai white goats in all experimental groups was significantly decreased (P<0.05). Compared with the control group, the serum interleukin-4 concentrations of Xuhuai white goats in 0.2% plant extract group were significantly increased (P<0.05), and the serum interleukin-22 concentrations were significantly decreased (P<0.05), serum interleukin-6 and tumor necrosis factor-α concentrations of Xuhuai white goats in all experimental groups were significantly decreased (P<0.05). The contentrations of serum interleukin-10 and transforming growth factor-β of Xuhuai white goats in 0.2% and 0.4% plant extract groups were significantly increased (P<0.05). The results indicate that feeding an appropriate amount of plant extracts can improve the growth performance, immune function, and health status of Xuhuai white goats, with the better effect at the 0.2% addition level. [ABSTRACT FROM AUTHOR]

Glioblastoma multiforme (GBM) is one of the most aggressive and deadly forms of brain cancer, which has a very complex tumor microenvironment (TME) promoting tumor growth, immune evasion, and resistance to therapy. The main players within this environment are represented by cytokines such as Interleukin-4, Interleukin-6, and Interleukin-13, along with the costimulatory molecule CD40. The paper draws back the curtain on the complex interactions played out by these molecules in contributing to the formation of a TME within GBM. IL-4 and IL-13 induce an immunosuppressive environment through the polarization of tumor-associated macrophages (TAMs) into a pro-tumoral M2 phenotype. In contrast, IL-6 takes part in the activation of the JAK–STAT3 pathway, enhancing survival and proliferation of tumor cells. In this context, CD40 either induces anti-tumor immunity through APC activation or facilitates tumors by angiogenesis and survival pathways. The synergistic actions of these molecules create feedback loops that keep up the malignancy of GBM and present a big problem for therapy. Knowledge of these interactions opens new ways for the development of multi-targeted therapeutic strategies at the other end. This may result in the interruption of the tumor-supportive environment in GBM, reducing tumor growth and improving patient outcomes by targeting IL-4, IL-6, IL-13, and CD40 simultaneously. [ABSTRACT FROM AUTHOR]

BACKGROUND: Interleukin-4 can promote the osteogenic effect of bone substitute materials, but its molecular mechanism is not yet clear. Further elucidating the mechanism of interleukin-4 promoting osteogenic effect can help find safe, economical, and effective methods for the regeneration treatment of alveolar bone defects in patients. OBJECTIVE: To explore the effect of interleukin-4 intervention on polarization transformation of macrophages and osteogenic differentiation of bone marrow mesenchymal stem cells and its possible mechanism. METHODS: RAW264.7 cells in the M1 group were induced with interferon gamma + lipopolysaccharide for 24 hours. RAW264.7 cells in the interleukin-4+M1 group were induced with interferon gamma + lipopolysaccharide for 24 hours and then interleukin-4 was added for 24 hours. RAW264.7 cells in the interleukin4+AG+M1 group were induced with interferon gamma + lipopolysaccharide for 24 hours, and then interleukin-4 and AG-490, a JAK/STAT pathway inhibitor, were added for 24 hours. After intervention, immunofluorescence staining was used to analyze the expression of inducible nitric oxide synthase and CD206, the phenotypic marker protein of macrophages. ELISA kit was used to detect the expression of interleukin-10 and tumor necrosis factor-α in the supernatant of cell culture. The gene expressions of nodular receptor protein-3 (NLRP3), interleukin-1β, and caspase-1 were detected by RT-qPCR. The expression levels of tyrosine protein kinase 1 (JAK1)/ phosphorylated tyrosine protein kinase 1 (p-JAK1), signal transduction and transcription activator 6 (STAT6)/phosphorylated signal transduction and transcription activator 6 (p-STAT6), NLRP3, pro-interleukin-1β and pro-caspase-1 were detected by western blot assay. Then, RAW264.7 cells in the above four groups were indirectly co-cultured with bone marrow mesenchymal stem cells by transwell for 24 hours, followed by alkaline phosphatase staining and alizarin red staining. The mRNA expressions of alkaline phosphatase, collagen type I, and osteocalcin were detected by RT-qPCR. RESULTS AND CONCLUSION: (1) Immunofluorescence and ELISA results showed that interleukin-4 intervention could promote the expression of CD206 and interleukin-10 in M2 macrophages, and inhibit the secretion of inducible nitric oxide synthase and tumor necrosis factor-α. (2) RT-qPCR results showed that interleukin-4 could suppress the expression of NLRP3, interleukin-1β, and caspase-1 mRNAs. (3) Western blot assay showed that interleukin-4 could promote the expression of JAK1/p-JAK1, STAT6/p-STAT6 and NLRP3 proteins. (4) The alkaline phosphatase staining and alizarin red staining of bone marrow mesenchymal stem cells co-cultured with the interleukin-4+M1 group were significantly enhanced, and the mRNA expressions of alkaline phosphatase, collagen type I, and osteocalcin were significantly increased. It is concluded that interleukin-4 may inhibit the activation of NLRP3 by up-regulating JAK1/STAT6 pathway, thus promoting the transformation of macrophages from M1 polarization to M2 polarization, and finally enhancing the osteogenic differentiation ability of bone marrow mesenchymal stem cells. [ABSTRACT FROM AUTHOR]

Trimetazidine (TMZ) is a promising emerging therapeutic piperazine derivative for renal pathologies. However, the nephroprotective mechanism of TMZ against heavy metal-induced toxicity is unknown. This study, therefore, aimed to explore whether TMZ could mitigate mercury-induced nephrotoxicity in rats. Rats were injected TMZ (3 mg/kg bw) and/or mercury chloride (HgCl2) (4 mg/kg bw) for 4 days (n = 6 rats per group). The blood analysis revealed marked increases in creatinine, urea and uric acid levels in HgCl2 group compared to the control. HgCl2 induced prominent decreases in renal superoxide dismutase (SOD), catalase (CAT), glutathione peroxide (GPx) activities compared to the control followed by marked increases in the levels of malondialdehyde (MDA), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), caspase-3 and caspase-9. Whereas the renal levels of anti-inflammatory cytokines interleukin-4 (IL-4) and interleukin-10 (IL-10) reduced considerably compared to the control. Contrarily, it was found that in the rats administered TMZ + HgCl2, levels of renal markers, MDA, TNF-α, IL-6 and caspases-3/-9 were prominently reduced compared to the HgCl2 group. The renal SOD, CAT, GPx, IL-4, and IL-10 were markedly elevated along with ameliorated histopathological lesions. On the whole, therefore, TMZ could be repurposed for blocking HgCl2 nephrotoxicity via inhibition of oxidative inflammation and apoptosis in rats. [ABSTRACT FROM AUTHOR]

Allergic asthma is a chronic inflammatory disease characterized by airway inflammation and hyper-responsiveness. Silymarin is a natural compound recognized for its potential anti-inflammatory properties in various conditions, including asthma. In this study, we investigated the anti-inflammatory effects of silymarin on a mouse model of allergic asthma. Thirty-five mice were categorized into five groups (n = 7 per group). The normal control group received phosphate-buffered saline (PBS), while the remaining four groups were induced with allergic asthma using ovalbumin (OVA). One sensitized group was treated with PBS (Asthma/Baseline), another received beclomethasone, and two groups were administered silymarin (25 mg/kg and 50 mg/kg) intraperitoneally. Subsequently, we quantified the changes in inflammatory cell influx in bronchoalveolar lavage fluid (BALF) and the levels of interferon-γ (IFN-γ) and interleukin-4 (IL-4) in BALF and blood. Histopathological alterations of leukocytes were examined in the lung tissues of all animals. The results showed that silymarin reduced inflammatory cells, including eosinophils and lymphocytes, in the BALF. Additionally, the silymarin-treated groups exhibited decreased IL-4 levels and increased IFN-γ levels in the blood, surpassing the effects of beclomethasone. Furthermore, histopathological analysis demonstrated a significant decrease in leukocyte infiltration following silymarin treatment. Our findings demonstrate the anti-inflammatory effects of silymarin in allergic asthma, likely through the modulation of inflammatory cells. [ABSTRACT FROM AUTHOR]

Psossibility and appropriate timing of discontinuation of dupilumab for atopic dermatitis (AD) remain unclear. We explored the possibility of patients, who could maintain remission with topical therapy alone after withdrawing dupilumab in the real world. Furthermore, we identified their characteristics. All adult AD patients who initiated dupilumab from June 2018 to July 2022 and were treated with dupilumab for more than 3 months at our hospital were included in this study. The observation period was from June 2018 to July 2023. In 138 patients, 58 (42.0%) discontinued dupilumab at least once. Among them, 18 (13.0%) discontinued dupilumab but reinitiated dupilumab later due to exacerbation. Only seven patients (5.1%) could maintain remission with topical therapy alone after discontinuation of dupilumab, with characteristics of lower POEM, VAS of pruritus, serum levels of TARC and LDH, and neutrophil counts at baseline, and those of longer duration of dupilumab until its discontinuation (24.0 ± 13.3 vs. 12.8 ± 7.3 months) and lower EASI and affected BSA at the discontinuation of dupilumab. In 118 patients treated with dupilumab for at least 1 year, 38 patients (32.2%) discontinued at least once. Only four patients (3.4%) could maintain remission with topical therapy alone after discontinuation of dupilumab, with characteristics of lower POEM at baseline and lower EASI at the discontinuation of dupilumab. In conclusion, maintaining remission after withdrawing dupilumab is challenging. Discontinuation of dupilumab may be considered in patients with low baseline POEM, after more than 2 years of dupilumab treatment, with a substantial decrease in EASI. [ABSTRACT FROM AUTHOR]

ABSTRACT: Purpose: To determine the antiasthmatic potential of salicin in experimental animals. Materials and Methods: The study was undertaken in two phases: clonidine-induced catalepsy (Phase I) and ovalbumin (OVA) induced lung inflammation (Phase II). In Phase I, 36 Swiss Albino mice were pretreated with clonidine (1 mg/kg) subcutaneously for induction of catalepsy. Different doses of salicin (100, 200, and 300 mg/kg) and pheniramine maleate (10 mg/kg) were administered through the oral route, and the cataleptic score was calculated. In Phase II, 36 Albino Wistar rats were sensitized and challenged with 1 mg OVA absorbed on 20 mg aluminum hydroxide (Al(OH)3) intraperitoneally on days 0, 7, and 14 followed by the treatment with salicin doses (100, 200, and 300 mg/kg) and dexamethasone (0.5 mg/kg). Blood parameters, including total cells (TC), eosinophils (EOS), neutrophils (NEU), and macrophages (MAC), were recorded. Levels of tumor necrosis factor-α (TNFα), interleukin-4 (IL-4), interleukin-6 (IL-6), and interleukin-13 (IL-13) were collected from bronchoalveolar lavage fluid. Levels of OVA-specific IgE were estimated from spleens, Peyer's patches, and mesenteric lymph nodes of rats. Results: Animals treated with salicin showed a significant reduction (P- value <0.05) in cataleptic scores. Significant reduction (P- value <0.05) in levels of TC, NEU, EOS, and MAC was observed in animals treated with salicin. Levels of TNF-α, IL-4, IL-6, and IL13 also reduced significantly (P- value <0.05) in salicin-treated animals. The concentration of OVA-specific IgE reduced significantly (P -value <0.05) in salicin-treated animals. Conclusion: Salicin ameliorates catalepsy and lung inflammation in asthmatic conditions. [ABSTRACT FROM AUTHOR]

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Tissue engineering technology offers a promising solution for ear reconstruction; however, it faces the challenge of foreign body reaction and neocartilage malformation. This study investigates the impact of interleukin‐4 (IL‐4), an anti‐inflammatory factor, on cartilage regeneration of hydrogel encapsulating autologous auricular chondrocytes in a rabbit subcutaneous environment. Initially, we assessed the influence of IL‐4 on chondrocyte proliferation and determined the appropriate concentration using the CCK‐8 test in vitro. Subsequently, we loaded IL‐4 into gelatin methacryloyl (GelMA) hydrogel containing chondrocytes and measured its release profile through ELISA. The constructs were then implanted autologously into rabbits' subcutis, and after 3, 7, 14, and 28 days, cartilage matrix formation was evaluated by histological examinations, and gene expression levels were detected by qRT‐PCR. Results demonstrated that IL‐4 promotes chondrocyte proliferation in vitro, and maximum release from constructs occurred during the first week. In the rabbit subcutaneous implantation model, IL‐4‐loaded constructs (20 ng/mL) maintained a superior chondrocytic phenotype compared to controls with increased expression of anti‐inflammatory factors. These findings highlight IL‐4 as a potential strategy for promoting chondrogenesis in a subcutaneous environment and improving ear reconstruction. [ABSTRACT FROM AUTHOR]