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Skeletal muscle tissue has the critical function of mechanical support protecting the body. In addition, its functions are strongly influenced by the balanced synthesis and degradation processes of structural and regulatory proteins. The inhibition of protein synthesis and/or the activation of catabolism generally determines a pathological state or condition called muscle atrophy, a reduction in muscle mass that results in partial or total loss of function. It has been established that many pathophysiological conditions can cause a decrease in muscle mass. Skeletal muscle innervation involves stable and functional neural interactions with muscles via neuromuscular junctions and is essential for maintaining normal muscle structure and function. Loss of motor innervation induces rapid skeletal muscle fiber degeneration with activation of atrophy-related signaling and subsequent disassembly of sarcomeres, altering normal muscle function. After denervation, an inflammation stage is characterized by the increased expression of pro-inflammatory cytokines that determine muscle atrophy. In this review, we highlighted the impact of some soluble factors on the development of muscle atrophy by denervation.

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The ability of Heteroctenus junceus scorpion venom to modulate the concentration of cytokines related to its antitumoral effect is unknown. F3II cells were treated with » IC50, ½ IC50 and the IC50 of H. junceus scorpion venom. Tumor growth kinetics in F3II-bearing mice were evaluated after 24 days of oral administration of venom doses. The effect of tumor lysates on F3II cell viability was evaluated by MTT assay, while cytokines present in each sample were determined by ELISA. In supernatant, H. junceus scorpion venom decreased the concentration of IL-6 (p < 0.001), IFN-γ (p < 0.001), IL-1ß (p < 0.01); meanwhile IL-12 (p < 0.001) and TNF-α (p < 0.001) levels increased significantly, according to the concentration and the time of incubation. Heteroctenus junceus scorpion venom effectively inhibits in vivo tumor progression. In the sera, a significant decrease was observed in TNF-α levels (p < 0.05). In tumor lysates, IL-6 decreased significantly in the groups treated with 12.5 mg/kg (p < 0.001) and 25 mg/kg (p < 0.05). Heteroctenus junceus scorpion venom is capable of modulating other proinflammatory and protumoral cytokines involved in the inflammation associated with cancer.

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Abstract Introduction: The therapeutic benefits of the brown algae fucoidan in the treatment of breast cancer have attracted considerable interest in recent years. However, research using spheroids which provide relevant results in trials for antitumor and immunomodulatory products because they adequately simulate the tumor microenvironment, is limited. Objective: To evaluate the antitumor and immunomodulatory activity of Lessonia trabeculata fucoidan (LtF), native to the Peruvian Sea, on two types of multicellular tumor spheroids. Methods: The study was conducted from January to December 2021. Two types of spheroides were elaborated: from 4T1 tumor cells (MTS), and from 4T1 tumor cells+mouse splenocytes (MTSs). The antitumor activity of LtF was evaluated in MTS by quantifying cell viability with MTT. Immunomodulatory activity was determined in MTSs using the IC50 for two types of treatment: simple, fucoidan alone (LtF) and combined, fucoidan+doxorubicin (LtF+Dox). Pro-inflammatory (TNF-α, IL-6) and anti-inflammatory (IL-10, TGF-β) cytokine production was quantified by sandwich ELISA 72 h after treatment. Dox was used as positive control in all assays. Results: LtF exerted antitumor activity as evidenced by increased necrotic zone and cell debris formation compared to the untreated control. Antitumor activity was concentration dependent between 100 and 6 000 μg/ml. In MTSs, simple treatment increased IL-6 and decreased IL-10 and TGF-β production. The combined treatment significantly reduced TGF-β production. In both treatments and Dox, there was an increase in IL-6 compared to the untreated control. The highest production of IL-10 and TGF-β was observed in the untreated control, compatible with a highly immunosuppressive tumor microenvironment. Conclusions: LtF is a good candidate for the treatment of breast cancer and can immunomodulate the tumor microenvironment alone or in combination with Dox.

Resumen Introduccción: Los beneficios terapéuticos del fucoidan de algas pardas en el tratamiento del cáncer de mama han despertado gran interés en los últimos años. Sin embargo, las investigaciones con esferoides son limitadas, éstos proporcionan resultados relevantes en ensayos de productos antitumorales e inmunomoduladores porque simulan adecuadamente el microambiente tumoral. Objetivo: Evaluar la actividad antitumoral e inmunomoduladora del fucoidan de Lessonia trabeculata (LtF), nativa del Mar Peruano, en dos tipos de esferoides tumorales multicelulares. Métodos: El estudio se realizó de enero a diciembre de 2021. Se elaboraron dos tipos de esferoides: con células tumorales 4T1 (MTS) y con células tumorales 4T1+esplenocitos de ratón (MTSs). La actividad antitumoral de LtF se evaluó en MTS cuantificando la viabilidad celular con MTT. La inmunomodulación se determinó en MTSs utilizando la IC50 para dos tipos de tratamiento: simple, fucoidan solo (LtF) y combinado, fucoidan+doxorubicina (LtF+Dox). La producción de citoquinas proinflamatorias (TNF-α, IL-6) y antiinflamatorias (IL-10, TGF-β) se cuantificó mediante ELISA sándwich 72 h post-tratamiento. En todos los ensayos se utilizó Dox como control positivo. Resultados: En los MTS, el LtF ejerció actividad antitumoral evidenciada por aumento de la zona necrótica y formación de restos celulares respecto al control no tratado. La actividad antitumoral fue concentración-dependiente entre 100 y 6 000 μg/ml. En los MTSs, con el tratamiento simple se incrementó IL-6 y disminuyeron IL-10 y TGF-β. El tratamiento combinado redujo significativamente la producción de TGF-β. Los dos tratamientos y Dox incrementaron IL-6 respecto al control no tratado. La mayor producción de IL-10 y TGF-β se observó en los no tratados, compatible con un microambiente tumoral altamente inmunosupresor. Conclusiones: El LtF es un buen candidato para tratar el cáncer de mama y puede inmunomodular el microambiente tumoral solo o en combinación con Dox.

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Lupus nephritis (LN) is the most frequent and severe complication of systemic lupus erythematosus (SLE). A prospective cohort with a six-month follow-up was performed. Twelve SLE patients diagnosed with LN Class III, twelve NL Class IV patients, and twelve healthy control subjects (HC) were included. SLE data, renal function, oxidants, antioxidants, and inflammation were determined at baseline and six-month follow-up. During the six-month follow-up, the SLE Disease Activity Index (SLEDAI-2K) decreased in both LN Class III (20.08 ± 6.92 vs. 11.92 ± 5.87, p < 0.001) and LN Class IV (25.33 ± 6.01 vs. 13.83 ± 5.52, p < 0.001) patients. Furthermore, the values of the C4 component also increased during follow-up for LN Class III (25.36 ± 6.34 vs. 30.91 ± 9.22, p = 0.027) and LN Class IV (12.18 ± 3.90 vs. 20.33 ± 8.95, p = 0.008) groups. Regarding inflammation markers, both groups presented decreased C-reactive protein (CRP), but this was only significant for patients with LN class III (7.93 ± 1.77 vs. 4.72 ± 3.23, p = 0.006). Renal function remained stable in both groups, with no changes in eGFR. Patients with LN Class III and Class IV showed higher baseline levels for lipoperoxides (Class III p < 0.01, Class IV p < 0.1) and carbonyl groups in proteins (Class III p < 0.01, Class IV p < 0.1) compared to HC. Moreover, both groups presented lower baseline values of total antioxidant capacity (Class III p < 0.01, Class IV p < 0.1) and catalase (Class III p < 0.01, Class IV p < 0.1) compared to HCs. However, antioxidant and oxidant markers did not show significant differences between baseline values and at six months for either of the two study groups. In conclusion, patients show an imbalance in the oxidative state characterized by the increase in the oxidants LPO and protein carbonyl groups and the decrease in the activity of the antioxidant enzymes TAC and CAT compared to HC. However, the patients did not present an increase in disease activity and renal function improvement. The glomerular filtration rate did not change during the length of the study, and SLEDAI -2K, C3, and C4 improved. The early co-management between Rheumatologists and Nephrologists is essential to prevent the rapid progression of LN. It would be interesting to administer antioxidant supplements to patients with a recent diagnosis of LN and evaluate its effect in a follow-up study.

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This report presents the case of a 47-year-old male patient who worked as a mathematics teacher and experienced the sudden onset of disorientation, aphasia, and acalculia during an online class. The current study reveals the first documented case of HIV and progressive multifocal leukoencephalopathy with the detection of SARS-CoV-2 and human polyomavirus 2 (previously known as John Cunningham virus) in the cerebrospinal fluid. Furthermore, serum analysis revealed elevated concentrations of interleukin (IL)-6, IL-17, and IL-8, which are potential factors known to reduce the expression of tight junctions and adhesion molecules in the extracellular matrix, thereby affecting the permeability of the blood-brain barrier. Finally, the study discusses whether SARS-CoV-2 triggers or exacerbates progressive multifocal leukoencephalopathy.

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Secondary fungal infections are frequently observed in COVID-19 patients. However, the occurrence of candiduria in these patients and its risk factors are underexplored. We evaluated the risk factors of candiduria in COVID-19 patients, including inflammatory mediators that could be used as prognostic markers. Clinical information, laboratory test results, and outcomes were collected from severely ill COVID-19 patients with and without candiduria. Candida species identification, antifungal susceptibility, and plasma inflammatory mediators' measurements were performed. Regression logistic and Cox regression model were used to evaluate the risk factors. A higher risk of longer hospitalization and mortality were observed in patients with candiduria compared to those with COVID-19 only. Candiduria was caused by Candida albicans, C. glabrata, and C. tropicalis. Isolates with intermediate susceptibility to voriconazole and resistant to caspofungin were identified. Classic factors such as the use of corticosteroids and antibacterials, the worsening of renal function, and hematological parameters (hemoglobin and platelets) were found to predispose to candiduria. The mediators IL-1ß, IL-1ra, IL-2, CXCL-8, IL-17, IFN-γ, basic FGF, and MIP-1ß were significantly increased in patients with COVID-19 and candiduria. Furthermore, IFN-γ, IL-1ra, and CXCL-8 were associated with the occurrence of candiduria in COVID-19 patients, whereas basic FGF, IL-1ß, and CXCL-8 were associated with the risk of death in these patients. Classical and immunological factors were associated with worse prognosis among patients with COVID-19 and candiduria. Some mediators, especially CXCL-8, can be a reliable biomarker of fungal coinfection and may guide the diagnostic and the treatment of these patients.

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Diabetic cardiomyopathy (DCM) is a serious complication of diabetes caused by oxidative stress, inflammation, insulin resistance, myocardial fibrosis, and lipotoxicity; its nature is insidious, complex and difficult to treat. NLRP3 inflammasome triggers the maturation and release of pro-inflammatory cytokines, participates in pathophysiological processes such as insulin resistance and myocardial fibrosis, in addition to being closely related to the development and progression of diabetic cardiomyopathy. The development of inhibitors targeting specific aspects of inflammation suggests that NLRP3 inflammasome can be used to treat diabetic cardiomyopathy. This paper aims to summarize NLRP3 inflammasome mechanism and therapeutic targets in diabetic cardiomyopathy, and to provide new suggestions for the treatment of this disease.

La cardiomiopatía diabética es una complicación grave de la diabetes causada por estrés oxidativo, inflamación, resistencia a la insulina, fibrosis miocárdica y lipotoxicidad. Se trata de un padecimiento insidioso, complejo y difícil de tratar. El inflamasoma NLRP3 desencadena la maduración y liberación de citoquinas proinflamatorias, participa en procesos fisiopatológicos como la resistencia a la insulina y la fibrosis miocárdica, además de estar estrechamente relacionado con la aparición y progresión de la cardiomiopatía diabética. El desarrollo de inhibidores dirigidos a aspectos específicos de la inflamación sugiere que el inflamasoma NLRP3 puede utilizarse para tratar la cardiomiopatía diabética. Este artículo pretende resumir el mecanismo y las dianas terapéuticas del inflamasoma NLRP3 en la cardiomiopatía diabética, así como aportar nuevas sugerencias para el tratamiento de esta enfermedad.

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Resumen La cardiomiopatía diabética es una complicación grave de la diabetes causada por estrés oxidativo, inflamación, resistencia a la insulina, fibrosis miocárdica y lipotoxicidad. Se trata de un padecimiento insidioso, complejo y difícil de tratar. El inflamasoma NLRP3 desencadena la maduración y liberación de citoquinas proinflamatorias, participa en procesos fisiopatológicos como la resistencia a la insulina y la fibrosis miocárdica, además de estar estrechamente relacionado con la aparición y progresión de la cardiomiopatía diabética. El desarrollo de inhibidores dirigidos a aspectos específicos de la inflamación sugiere que el inflamasoma NLRP3 puede utilizarse para tratar la cardiomiopatía diabética. Este artículo pretende resumir el mecanismo y las dianas terapéuticas del inflamasoma NLRP3 en la cardiomiopatía diabética, así como aportar nuevas sugerencias para el tratamiento de esta enfermedad.

Abstract Diabetic cardiomyopathy (DCM) is a serious complication of diabetes caused by oxidative stress, inflammation, insulin resistance, myocardial fibrosis, and lipotoxicity; its nature is insidious, complex and difficult to treat. NLRP3 inflammasome triggers the maturation and release of pro-inflammatory cytokines, participates in pathophysiological processes such as insulin resistance and myocardial fibrosis, in addition to being closely related to the development and progression of diabetic cardiomyopathy. The development of inhibitors targeting specific aspects of inflammation suggests that NLRP3 inflammasome can be used to treat diabetic cardiomyopathy. This paper aims to summarize NLRP3 inflammasome mechanism and therapeutic targets in diabetic cardiomyopathy, and to provide new suggestions for the treatment of this disease.

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Infectious keratitis is a vision-threatening microbial infection. The increasing antimicrobial resistance and the fact that severe cases often evolve into corneal perforation necessitate the development of alternative therapeutics for effective medical management. Genipin, a natural crosslinker, was recently shown to exert antimicrobial effects in an ex vivo model of microbial keratitis, highlighting its potential to serve as a novel treatment for infectious keratitis. This study aimed to evaluate the antimicrobial and anti-inflammatory effects of genipin in an in vivo model of Staphylococcus aureus (S. aureus) and Pseudomonas aeruginosa (P. aeruginosa) keratitis. Clinical scores, confocal microscopy, plate count, and histology were carried out to evaluate the severity of keratitis. To assess the effect of genipin on inflammation, the gene expression of pro- and anti-inflammatory factors, including matrix metalloproteinases (MMPs), were evaluated. Genipin treatment alleviated the severity of bacterial keratitis by reducing bacterial load and repressing neutrophil infiltration. The expression of interleukin 1B (IL1B), interleukin 6 (IL6), interleukin 8 (IL8), interleukin 15 (IL15), tumor necrosis factor-α (TNF-α), and interferon γ (IFNγ), as well as MMP2 and MMP9, were significantly reduced in genipin-treated corneas. Genipin promoted corneal proteolysis and host resistance to S. aureus and P. aeruginosa infection by suppressing inflammatory cell infiltration, regulating inflammatory mediators, and downregulating the expression of MMP2 and MMP9.

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BACKGROUND: Type I Diabetes mellitus (T1D) is characterized by a specific destruction of ß-cells by the immune system. During this process pro-inflammatory cytokines are released in the pancreatic islets and contribute for ß-cells demise. Cytokine-induced iNOS activation, via NF-κB, is implicated in induction of ß-cells death, which includes ER stress activation. Physical exercise has been used as an adjunct for better glycemic control in patients with T1D, since it is able to increase glucose uptake independent of insulin. Recently, it was observed that the release of IL-6 by skeletal muscle, during physical exercise, could prevent ß-cells death induced by pro-inflammatory cytokines. However, the molecular mechanisms involved in this beneficial effect on ß-cells are not yet completely elucidated. Our aim was to evaluate the effect of IL-6 on ß-cells exposed to pro-inflammatory cytokines. RESULTS: Pre-treatment with IL-6 sensitized INS-1E cells to cytokine-induced cell death, increasing cytokine-induced iNOS and Caspase-3 expression. Under these conditions, however, there was a decrease in cytokines-induced p-eIF2-α but not p-IRE1expression, proteins related to ER stress. To address if this prevention of adequate UPR response is involved in the increase in ß-cells death markers induced by IL-6 pre-treatment, we used a chemical chaperone (TUDCA), which improves ER folding capacity. Use of TUDCA increased cytokines-induced Caspase-3 expression and Bax/Bcl-2 ratio in the presence of IL-6 pre-treatment. However, there is no modulation of p-eIF2-α expression by TUDCA in this condition, with increase of CHOP expression. CONCLUSION: Treatment with IL-6 alone is not beneficial for ß-cells, leading to increased cell death markers and impaired UPR activation. In addition, TUDCA has not been able to restore ER homeostasis or improve ß-cells viability under this condition, suggesting that other mechanisms may be involved.

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OBJECTIVES: This study aimed to investigate the effect of cannabidiol (CBD) on type 4 Toll-like receptors (TLR4), glial cells and pro-inflammatory cytokines during the neuropathic pain induced by the chemotherapy agent paclitaxel (PTX), as well as the involvement of the endocannabinoid system in this process. METHODS: Male C57BL6 mice were subjected to PTX-induced neuropathic pain. To evaluate the involvement of the TLR4, glial cells and cannabinoid CB2 receptor, specific inhibitors or antagonists were intrathecally administered. The western blotting and immunofluorescence assay was performed to evaluate the spinal expression of TLR4, microglia, astrocytes and cannabinoid CB2 receptor. The levels of spinal pro-inflammatory cytokines and endocannabinoids were determined by enzyme-linked immunosorbent assay and liquid chromatography-mass spectrometry analysis, respectively. KEY FINDINGS: CBD prevented PTX-induced neuropathic pain, and the cannabinoid CB2 receptor antagonist AM630 reversed this effect. In addition, CBD treatment inhibited the spinal expression of TLR4 and Iba1 in mice with neuropathic pain. CBD also increased spinal levels of endocannabinoids anandamide and 2-arachidonoylglycerol, and reduced levels of cytokines in mice with neuropathic pain. CONCLUSIONS: CBD was efficient in preventing PTX-induced neuropathic pain, and this effect may involve inhibition of the TLR4 on microglia spinal with activation of the endocannabinoid system.

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ETHNOPHARMACOLOGICAL RELEVANCE: Alternanthera brasiliana L. is a flowering plant belonging to the family Amaranthaceae and is popularly known as "penicillin". It is used in folk medicine to treat infections, coughs, wound healing, and inflammatory diseases. AIM OF THE STUDY: We investigated the effect of Alternanthera brasiliana L. leaves hydroalcoholic extract (AB) against oxidative stress, inflammation, and fibrotic changes in an experimental model of carbon tetrachloride (CCl4)-induced liver injury and fibrosis in mice. MATERIALS AND METHODS: Thirty-six male Balb/C mice were randomized into five groups: normal control, AB control, CCl4 control, CCl4 + AB-200 mg/kg, and CCl4 + AB-400 mg/kg. In mice, liver injury was induced by intraperitoneal injection of CCl4 (20% in corn oil, 5 ml/kg body weight) thrice a week for six consecutive weeks. AB extract at two doses (200 mg/kg and 400 mg/kg body weight) was administered orally for six consecutive weeks. Liver injury-related serum markers (ALT, AST, ALP), antioxidants (GSH, GST, SOD, and vitamin C), pro-inflammatory cytokines including tumor necrosis factor-α (TNF-α), interleukin (IL)-1ß, and IL-18, ultrasonographic and histological alterations, proteins of matrix metalloproteinases (MMPs) and tissue inhibitors of matrix metalloproteinase-1 (TIMP-1), nuclear factor-κB (p65) (NF-κB), nod-like receptor protein 3 (NLRP3), and TGF-ß/Smad signaling were accessed. LC-Q-TOF-MS/MS analysis of AB was performed. RESULTS: AB treatment significantly decreased the CCl4-induced rise in serum ALT, AST, and ALP activities and improved the histological alterations. Compared with the CCl4-treated group, treatment with AB significantly restored the hepatic antioxidants and reduced the pro-inflammatory cytokines in the liver. The antioxidant activity of AB may be attributed to its terpenoid constituents, which was confirmed by LC-Q-TOF-MS/MS analysis. The CCl4-induced rise in expression of MMP-2 and MMP-9 and decrease in TIMP-1 were markedly restored in the AB-treated groups. Further findings revealed a significant reduction in the protein levels of phospho-NF-κB (p65), NLRP3, TGF-ß, pSmad2/3, collagen I, and α-smooth muscle actin (α-SMA) in the AB treatment groups. CONCLUSIONS: The hepatoprotective effect of AB may be attributed to the high content of terpenoid compounds and alleviates liver injury and associated fibrotic changes through modulating MMPs, NF-κB (p65), and the TGF-ß/Smad axis.

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Painmanagement after oral surgeries is essential to enhance recovery, reduce negative outcomes and improve the experience of the patient. Naltrexone (NTX) is a non-selective opioid receptor antagonist that has been shown to modulate neuro-inflammation when employed in low to ultra-low doses. In addition, ultra-low dose naltrexone (ULDN) has been shown to potentiate opioids' analgesia and to have opioid-sparing effects. Herein it was investigated the effect of ULDN in a model of postoperative orofacial pain in rats, and it was tested the hypothesis that blockade of TLR4-signalling pathway contributes to its antinociceptive effect. Systemic NTX reduced heat hyperalgesia in female rats and heat and mechanical hyperalgesia in male rats after incision surgery. Combined treatment with NTX and morphine, both at ineffective doses, resulted in a significant reduction of heat hyperalgesia in male rats. NTX injection at the incision site failed to change heat hyperalgesia, but injection at the trigeminal ganglion (TG) or subnucleus caudalis (Sp5C) caused a significant reduction in heat hyperalgesia. At these sites, blockade of TLR4 impeded NTX effect. Lipopolysaccharide (LPS) injection in the intraoral mucosa resulted in facial heat hyperalgesia an increase in IL-1ß levels in the TG, which were reduced by systemic NTX. Stimulation of macrophages with LPS resulted in increase of nitric oxide, IL-1ß and CXCL-2 levels which were reduced by NTX. Altogether, these results provide evidence for an antinociceptive effect of ULDN in postoperative orofacial pain and suggest that blockade of TLR4 and downstream signaling pathway contribute to its effect.

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Preconditioning episodes of ischemia/reperfusion (IR) induce protection against acute kidney injury (AKI), however their long-term effect still unknown. We evaluated AKI to chronic kidney disease (CKD) transition, after three-mild or three-severe episodes of IR. AKI was induced by single bilateral IR (1IR), or three episodes of IR separated by 10-day intervals (3IR) of mild (20 min) or severe (45 min) ischemia. Sham-operated rats served as controls. During 9-months, the 1IR group (20 or 45 min) developed CKD evidenced by progressive proteinuria and renal fibrosis. In contrast, the long-term adverse effects of AKI were markedly ameliorated in the 3IR group. The acute response in 3IR, contrasted with the 1IR group, that was characterized by an increment in heme oxygenase-1 (HO-1) and an anti-inflammatory response mediated by a NFkB-p65 phosphorylation and IL-6 decrease, together with an increase in TGF-ß, and IL-10 expression, as well as in M2-macrophages. In addition, three episodes of IR downregulated endoplasmic reticulum (ER) stress markers expression, CHOP and BiP. Thus, repeated episodes of IR with 10-day intervals induced long-term renal protection accompanied with HO-1 overexpression and M2-macrophages increase.

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Abstract Objectives: Diabetes Mellitus (DM) causes an increase in oxidative stress that leads to deterioration in auditory functions. Astaxanthine (AST) is known to have strong antioxidant effects. In this study, the aim is to investigate the effect of AST against hearing loss that is due to DM. Methods: This study is an experimental animal study. The study was designed in four groups with 8 animals (n = 8) in each group. The groups were as follows; Control Group (CNT), Diabetic Group (DM), AST applied diabetic group (DM+AST), and AST applied non-diabetic group (AST). Streptozotocin was applied in rats to induce DM. AST was administered by oral gavage. Auditory Brainstem Responses (ABR) and Distortion Product Otoacoustic Emissions (DPOAE) tests were performed on several days of the study. At the end of the study, pro-inflammatory cytokine levels were analyzed in cochlear tissue samples, and Glutathione Peroxidase (GPx), Superoxide Dismutase (SOD), Catalase (CAT) and Malondialdehyde (MDA) levels were measured. Results: When the findings obtained in the ABR and DPOAE tests in the DM group, it was observed that there was a significant deterioration in the hearing sense. This deterioration was not observed in the DM+AST group. In the DM group, GPx, SOD and CAT levels decreased and MDA levels increased in blood and cochlear tissue. Compared to the DM group, it was noted that antioxidant enzyme levels increased and MDA levels decreased in the DM+AST group. Cochlear tissue pro-inflammatory cytokine levels, which increased with DM, were significantly decreased in the DM+AST group. Conclusion: Even though the effects of AST were investigated in a diabetic experimental animal model, if this molecule is proven to be effective in diabetic humans, it can be considered an adjunct therapeutic option with its antioxidant effects. Level of evidence: The level of evidence of this article is 5. This article is an experimental animal and laboratory study.

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Nowadays, macrophages are recognized as key cells involved in chronic inflammatory conditions, and play central roles in all inflammatory diseases and cancer. Due to their extensive involvement in the pathogenesis of inflammatory diseases, they are now considered a relevant therapeutic target in the development of new therapeutic strategies. 2-Iminothiazolidines are associated with important anti-inflammatory activity and represent a rich source for the development of new drugs and treatments. Our research focuses on evaluating the anti-inflammatory capacity of these compounds and their relationship with M1/M2 macrophage polarization. The results demonstrate that 2-iminothiazolidines have the capacity to decrease the levels of anti-inflammatory biomarkers, such as cytokines (IL-1ß, TNF-α, and IL-6), nitric oxide synthase (with impact on NOx production), and COX-2, following a significant decline in NF-kB activation. We also observed an increase in levels of anti-inflammatory cytokines (IL-4 and IL-13) in the in vitro model of RAW 264.7 macrophages induced by LPS. Moreover, this is the first report, suggesting that the anti-inflammatory activity of 2-iminothiazolidines is associated with the ability to enhance phagocytosis, increase Arginase-1 and CD206 expression, and increase the secretion of IL-10. Furthermore, an in vivo study using the acute lung injury model induced by LPS proved the anti-inflammatory activity of a selected 2-iminothiazolidine, named methyl 2-(benzoylimino)-3-methyl-4-(4-nitrobenzyl)-1,3-thiazolidine-4-carboxylate. All these results, taken together, lead us to hypothesize that the mechanism of anti-inflammatory effect observed with this compound is closely related to the ability of this compound to produce macrophage repolarization, from the M1 to the M2 phenotype.

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BACKGROUND: Endometriosis is an estrogen-dependent and chronic inflammatory disease affecting up to 10% of women. It is the result of a combined interaction of genetic, epigenetic, environmental, lifestyle, reproductive and local inflammatory factors. In this study, we investigated whether single nucleotide polymorphisms (SNPs) mapping to TNF-alpha (TNF, rs1800629) and IL-1beta (IL1B, rs1143634) and variable number tandem repeat polymorphism mapping to IL1-Ra (IL1RN intron 2, rs2234663) genetic loci are associated with risk for endometriosis in a Mexican mestizo population. METHODS: This study included 183 women with confirmed endometriosis (ENDO) diagnosed after surgical laparoscopy and 186 women with satisfied parity and without endometriosis as controls (CTR). PCR/RFLP technique was used for genotyping SNPs (rs1800629 and rs1143634); PCR for genotyping rs2234663. RESULTS: We found no statistical differences in age between groups nor among stages of endometriosis and the CTR group. We observed no difference in genotype and allele frequencies, nor carriage rate between groups in none of the three studied polymorphisms. The prevalence of TNF*2-allele heterozygotes (p = 0.025; OR 3.8), TNF*2-allele (p = 0.029; OR 3.4), IL1B*2-allele heterozygotes (p = 0.044; OR 2.69) and its carriage rate (p = 0.041; OR 2.64) in endometriosis stage IV was higher than the CTR group. Surprisingly, the carriage rate of IL1RN*2-allele (ENDO: p = 0.0004; OR 0.4; stage I: p = 0.002, OR 0.38; stage II: p = 0.002, OR 0.35; stage III: p = 0.003, OR 0.33), as well as the IL1RN*2-allele frequencies (ENDO: p = 0.0008, OR 0.55; I: p = 0.037, OR 0.60; II: p = 0.002, OR 0.41; III: p = 0.003, OR 0.38) were lower than the CTR group. Women with endometriosis stage IV (severe) had frequencies more alike to the CTR group in the IL1RN*2 allele frequency (31.2% vs. 27.2%) and carriage rate (37.5% vs. 41.9%). CONCLUSION: Although these polymorphisms are not associated with the risk of endometriosis, Mexican mestizo women with severe stage of endometriosis have higher frequencies of TNF*2-, IL1B*2- and IL1RN*2-alleles, which may explain a possible correlation with disease severity rather than predisposition or risk.

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High-risk human papillomavirus (HR-HPV) infection, followed by chronic inflammation and oxidative stress, is a major risk factor of male infertility. In this study, we explored the potential impact of high-risk (HR) HPV genotypes in single infection (SI) and multiple infections (MI) that promote CYP2E1 expression, oxidative damage and pro-inflammatory cytokines, possibly contributing to sperm damage and male infertility. Semen samples from 101 infertile military men were studied. We analyzed seminal parameters, namely, HPV genotyping, cytochrome P450 2E1 (CYP2E1), oxidative stress biomarkers (total antioxidant capacity (TAC), catalase (CAT) and superoxide dismutase (SOD)), lipid peroxidation (LPO), 8-hydroxiguanosine (8-OHdG) and pro-inflammatory cytokines (IFN-γ, IL-1ß, IL-4, IL-6 and IL-8). Eighty-one men (80.2%, 81/101) were positive for HPV infection, and MI-HR-HPV was higher than SI-HR-HPV (63% vs. 37%). HPV-52 was the most frequently detected type (18.5%), followed by HPV-33 (11.1%), and the most frequent combination of genotypes detected was HPV-33,52 (11.1%), followed by HPV-18,31 (6.2%). The group with infected samples presented lower normal morphology and antioxidant levels compared to non-infected samples. In concordance, the infected group showed high levels of LPO, IFN-γ, IL-1ß, IL-4 and IL-6 and downregulation of CAT and SOD enzymes. Interestingly, changes in motility B, low levels of TAC, overexpression of CYP2E1, LPO and IL-8 levels were higher in MI-HR-HPV than SI-HR-HPV, suggesting that HPV infection promotes a chronic inflammatory process and a toxic and oxidative microenvironment, which increases with MI-HPV infections.

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ABSTRACT Background: Polysaccharides from edible mushrooms possess immunomodulatory, anti-inflammatory, and anti-tumor activities. Recent studies indicated that necroptosis plays a role in the pathogenesis of inflammatory diseases and mediates increased expression of inflammatory cytokines. Objective: Therefore, it is imperative to determine the impact of polysaccharide extract from Lentinula edodes (L. edodes) on inflammatory cytokines in experimental model of colitis in mice. Methods: Female C57BL/6 mice divided into three or four mice per group were used for this study. Polysaccharide sample was orally administered to mice prior to (7 days) and during colitis induction with 2.5% dextran sodium sulfate (7 days), followed by additional 3 days of administration. Changes in body weight and colon length were used as markers for colitis, and pro-inflammatory cytokines and tumor necrosis factor receptor 1 (TNFR1) expressions, as well as necroptosis were analyzed in the colon of colitis mice. Data obtained were analysed by Tukey-Kramer and two-tailed standard t tests. Results: The results indicated that the polysaccharide sample suppressed colitis in mice using effects on the body weight and colon length as markers. Also, it was demonstrated that necrostatin-1, a specific inhibitor of necroptosis, suppressed the expression of interleukin (IL)-8, a pro-inflammatory chemokine, in Caco-2 cells induced necroptosis induced by zVAD and TNF-α, an indication that necroptosis may be involved in the expression of pro-inflammatory cytokines. Moreover, the polysaccharide sample suppressed the expression of pro-inflammatory cytokines such as tumor necrosis factor (TNF)-α, IL-6, IL-1β, and interferon (IFN)-γ in the colon of mice. Conclusion: These results suggested that the suppressive effects of the polysaccharide sample on inflammatory cytokines expression may contribute to its anti-colitis effect, and so may serve as a potent therapeutic agent against inflammatory bowel disease.

RESUMO Contexto: Polissacarídeos de cogumelos comestíveis possuem atividades imunomodulatórias, anti-inflamatórias e anti-tumorais. Estudos recentes indicaram que a necroptose desempenha um papel na patogênese de doenças inflamatórias e regula o aumento da expressão de citocinas inflamatórias. Objetivo: Torna-se imprescindível determinar o impacto do extrato de polissacarídeo de Lentinula edodes (L. edodes) em citocinas inflamatórias em modelo experimental de colite em camundongos. Métodos: Foram utilizados para este estudo os camundongos C57BL/6 femininos divididos em três ou quatro camundongos por grupo. A amostra de polissacarídeo foi administrada oralmente em camundongos antes (7 dias) e durante a indução de colite com sulfato de dextran sulfato de sódio (7 dias), seguido por 3 dias adicionais de administração. Alterações no peso corporal e comprimento do cólon foram utilizadas como marcadores para colite, e citocinas pró-inflamatórias e tumores receptor fator 1 (TNFR1), bem como necroptose foram analisadas no cólon de camundongos colite. Os dados obtidos foram analisados por testes Tukey-Kramer e testes padrão t de duas caudas. Resultados: Os resultados indicaram que a amostra de polissacarídeo suprimiu colite em camundongos usando efeitos sobre o peso corporal e o comprimento do cólon como marcadores. Além disso, foi demonstrado que a necrostatina-1, inibidora específica da necroptose, suprimiu a expres são de interleucina (IL)-8, uma quimiocina pró-inflamatória, em células caco-2 induzidas necroptose induzidas por zVAD e TNF-α, uma indicação de que a necroptose pode estar envolvida na expressão de citocinas pro-inflamatórias. Além disso, a amostra de polissacarídeo suprimiu a expressão de citocinas pró-inflamatórias, como o fator de necrose tumoral (TNF)-α, IL-6, IL-1β e interferon (IFN)-γ no cólon dos camundongos. Conclusão: Esses resultados sugeriram que os efeitos supressivos da amostra de polissacarídeo na expressão de citocinas inflamatórias podem contribuir para o seu efeito anti-colite, podendo, portanto, servir como um potente agente terapêutico contra doença inflamatória intestinal.

RESUMO

RESUMEN Introducción: la enfermedad de hígado graso no alcohólico (EHGNA) se caracteriza por la acumulación de gotas lipídicas (GL) y sobre expresión de la proteína de GL Perilipina 1 (PLIN1) en los hepatocitos. En su patogénesis y progresión participan NF-ĸB, caspasa-1 y citoquinas proinflamatorias como IL-1β. La medicina popular del norte de Chile utiliza la planta Lampaya medicinalis Phil. (Verbenaceae) contra enfermedades. Objetivo: evaluar el efecto de un extracto hidroalcohólico de lampaya (EHL) sobre la expresión de marcadores inflamatorios y proteínas asociadas a las GL en hepatocitos tratados con ácidos grasos. Métodos: se incubó hepatocitos HepG2 con 0,66 mM de ácido oleico (AO) y 0,33 mM de ácido palmítico (AP) por 24 o 48 horas en presencia o no de EHL. Se evaluó la expresión proteica de NF-ĸB, PLIN1 y caspasa-1 por Western blot y la expresión de ARNm de IL-1β por qPCR. Resultados: los hepatocitos tratados por 48 h con AO/AP mostraron un aumento en la expresión de IL-1β que fue revertido por la co-incubación con EHL. Conclusión: estos antecedentes aportan nueva evidencia respecto a la actividad biológica del EHL en un modelo de alteraciones metabólicas e inflamatorias, asociadas a la EHGNA, inducidas por AO/AP en hepatocitos humanos.

ABSTRACT Introduction: Nonalcoholic fatty liver disease (NAFLD) is characterized by the accumulation of lipid droplets (LD) and overexpression of the LD-associated protein Perilipin 1 (PLIN1). NF-ĸB, caspase-1 and proinflammatory cytokine such as IL-1β participate in the pathogenesis and progression of NAFLD. Traditional medicine in northern Chile uses the plant Lampaya medicinalis Phil. (Verbenaceae) against diseases. Objective: To evaluate the effect of a hydroalcoholic extract of lampaya (HEL) on the expression of inflammatory markers and LD-associated proteins in hepatocytes treated with fatty acids. Methods: HepG2 hepatocytes were incubated with 0.66 mM oleic acid (OA) and 0.33 mM palmitic acid (PA) for 24 or 48 h in the presence or not of HEL. The protein expression of NF-ĸB, PLIN1 and caspase-1 was evaluated by Western blot while the mRNA expression of IL-1β was assessed by qPCR. Results: hepatocytes treated for 48 h with OA/AP showed an increase in IL-1β expression that was reversed by co-incubation with HEL. Conclusion: These antecedents provide new evidence regarding the biological activity of HEL in a model of metabolic and inflammatory alterations, associated with NAFLD, induced by OA/PA in human hepatocytes.