Navigating the Neuroimmunomodulation Frontier: Pioneering Approaches and Promising Horizons-A Comprehensive Review.

The research in neuroimmunomodulation aims to shed light on the complex relationships that exist between the immune and neurological systems and how they affect the human body. This multidisciplinary field focuses on the way immune responses are influenced by brain activity and how neural function is impacted by immunological signaling. This provides important insights into a range of medical disorders. Targeting both brain and immunological pathways, neuroimmunomodulatory approaches are used in clinical pain management to address chronic pain. Pharmacological therapies aim to modulate neuroimmune interactions and reduce inflammation. Furthermore, bioelectronic techniques like vagus nerve stimulation offer non-invasive control of these systems, while neuromodulation techniques like transcranial magnetic stimulation modify immunological and neuronal responses to reduce pain. Within the context of aging, neuroimmunomodulation analyzes the ways in which immunological and neurological alterations brought on by aging contribute to cognitive decline and neurodegenerative illnesses. Restoring neuroimmune homeostasis through strategies shows promise in reducing age-related cognitive decline. Research into mood disorders focuses on how immunological dysregulation relates to illnesses including anxiety and depression. Immune system fluctuations are increasingly recognized for their impact on brain function, leading to novel treatments that target these interactions. This review emphasizes how interdisciplinary cooperation and continuous research are necessary to better understand the complex relationship between the neurological and immune systems.

The Next Chapter in Cancer Diagnostics: Advances in HPV-Positive Head and Neck Cancer.

Human papillomavirus (HPV)-associated head and neck squamous cell carcinoma (HNSCC), particularly oropharyngeal squamous cell carcinoma (OPSCC), is an increasingly prevalent pathology worldwide, especially in developed countries. For diagnosing HPV in HNSCC, the combination of p16 immunohistochemistry (IHC) and polymerase chain reaction (PCR) offers high sensitivity and specificity, with p16 IHC being a reliable initial screen and PCR confirming HPV presence. Advanced techniques like next-generation sequencing (NGS) and RNA-based assays provide detailed insights but are primarily used in research settings. Regardless of HPV status, standard oncological treatments currently include surgery, radiation, and/or chemotherapy. This conventional approach does not account for the typically better prognosis of HPV-positive HNSCC patients, leading to increased chemo/radiation-induced secondary morbidities and reduced quality of life. Therefore, it is crucial to identify and detect HPV positivity and other molecular characteristics of HNSCC to personalize treatment strategies. This comprehensive review aims to summarize current knowledge on various HPV detection techniques and evaluate their advantages and disadvantages, with a focus on developing methodologies to identify new biomarkers in HPV-positive HNSCC. The review discusses direct and indirect HPV examination in tumor tissue, DNA- and RNA-based detection techniques, protein-based markers, liquid biopsy potentials, immune-related markers, epigenetic markers, novel biomarkers, and emerging technologies, providing an overall insight into the current state of knowledge.

The Role of Biomarkers in HPV-Positive Head and Neck Squamous Cell Carcinoma: Towards Precision Medicine.

Head and neck cancer (HNC) represents a significant global health challenge, with squamous cell carcinomas (SCCs) accounting for approximately 90% of all HNC cases. These malignancies, collectively referred to as head and neck squamous cell carcinoma (HNSCC), originate from the mucosal epithelium lining the larynx, pharynx, and oral cavity. The primary risk factors associated with HNSCC in economically disadvantaged nations have been chronic alcohol consumption and tobacco use. However, in more affluent countries, the landscape of HNSCC has shifted with the identification of human papillomavirus (HPV) infection, particularly HPV-16, as a major risk factor, especially among nonsmokers. Understanding the evolving risk factors and the distinct biological behaviors of HPV-positive and HPV-negative HNSCC is critical for developing targeted treatment strategies and improving patient outcomes in this complex and diverse group of cancers. Accurate diagnosis of HPV-positive HNSCC is essential for developing a comprehensive model that integrates the molecular characteristics, immune microenvironment, and clinical outcomes. The aim of this comprehensive review was to summarize the current knowledge and advances in the identification of DNA, RNA, and protein biomarkers in bodily fluids and tissues that have introduced new possibilities for minimally or non-invasive cancer diagnosis, monitoring, and assessment of therapeutic responses.

Joint Inflammation Correlates with Joint GPR30 Expression in Males and Hippocampal GPR30 Expression in Females in a Rat Model of Rheumatoid Arthritis.

It is not entirely clear how the interaction between joint inflammation and the central nervous system (CNS) response in rheumatoid arthritis (RA) works, and what pathophysiology underlies the sex differences in coexisting neuropsychiatric comorbidities. It is known that estrogen hormones reduce inflammation in RA and that this occurs mainly via the stimulation of G protein-coupled receptor-30 (GPR30), also known as G protein-coupled estrogen receptor (GPER) 1. However, changes in GPR30 expression and sex differences induced by local and systemic inflammation in RA are not yet known. Our aim was to reveal sex differences in the expression and association of joint GPR30 with local and systemic inflammation, clinical course and furthermore with hippocampal GPR30 expression during pristane-induced arthritis (PIA) in Dark Agouti (DA) rats, an animal model of RA. Furthermore, we demonstrated sex-specific differences in the association between joint and systemic inflammation and hippocampal microglia during PIA. Our results suggest sex-specific differences not only in the clinical course and serum levels of pro-inflammatory cytokines but also in the expression of GPR30. Female rats show greater synovial inflammation and greater damage to the articular cartilage compared to males during PIA attack. Male rats express higher levels of synovial and cartilaginous GPR30 than females during PIA, which correlates with a less severe clinical course. The correlation between synovial and cartilaginous GPR30 and joint inflammation scores (Krenn and Mankin) in male rats suggests that the more severe the joint inflammation, the higher the GPR30 expression. At the same time, there is no particular upregulation of hippocampal GPR30 in males. On the other hand, female rats express higher levels of neuroprotective GPR30 in the hippocampus than male rats at the basic level and during PIA attack. In addition, females have a higher number of Iba-1+ cells in the hippocampus during PIA attack that strongly correlates with the clinical score, serum levels of IL-17A, and Krenn and Mankin scores. These results suggest that male rats are better protected from inflammation in the joints and female rats are better protected from the inflammation in the hippocampus during a PIA attack, independently of microglia proliferation. However, in the remission phase, synovial GPR30 expression suddenly increases in female rats, as does hippocampal GPR30 expression in males. Further experiments with a longer remission period are needed to investigate the molecular background of these sex differences, as well as microglia phenotype profiling.

Insights into the Molecular Mechanism of Endothelial Glycocalyx Dysfunction during Heart Surgery.

The endothelial glycocalyx (EGC) is a layer of proteoglycans (associated with glycosaminoglycans) and glycoproteins, which adsorbs plasma proteins on the luminal surface of endothelial cells. Its main function is to participate in separating the circulating blood from the inner layers of the vessels and the surrounding tissues. Physiologically, the EGC stimulates mechanotransduction, the endothelial charge, thrombocyte adhesion, leukocyte tissue recruitment, and molecule extravasation. Hence, severe impairment of the EGC has been implicated in various pathological conditions, including sepsis, diabetes, chronic kidney disease, inflammatory disorders, hypernatremia, hypervolemia, atherosclerosis, and ischemia/reperfusion injury. Moreover, alterations in EGC have been associated with altered responses to therapeutic interventions in conditions such as cardiovascular diseases. Investigation into the function of the glycocalyx has expanded knowledge about vascular disorders and indicated the need to consider new approaches in the treatment of severe endothelial dysfunction. This review aims to present the current understanding of the molecular mechanisms underlying cardiovascular diseases and to elucidate the impact of heart surgery on EGC dysfunction.

Comprehensive molecular and clinical insights into non-small cell lung cancer transformation to small cell lung cancer with an illustrative case report.

Histologic transformation to small cell lung cancer (tSCLC) is a rare but increasingly recognised mechanism of acquired resistance to tyrosine kinase inhibitors (TKI) in patients with epidermal growth factor receptor (EGFR)-positive non-small cell lung cancer (NSCLC). Beyond its acknowledged role in TKI resistance, histologic transformation to SCLC might be an important, yet under-recognised, mechanism of resistance in NSCLC treated with immunotherapy. Our review identified 32 studies that investigated tSCLC development in patients with EGFR-mutated NSCLC treated with TKI therapy and 16 case reports of patients treated with immunotherapy. It revealed the rarity of tSCLC, with a predominance of EGFR exon 19 mutations and limited therapeutic options and outcomes. Across all analysed studies in EGFR-mutated NSCLC treated with TKI therapy, the median time to tSCLC development was ∼17 months, with a median overall survival of 10 months. Histologic transformation of EGFR-mutated NSCLC to SCLC is a rare, but challenging clinical problem with a poor prognosis. A small number of documented cases of tSCLC after immunotherapy highlight the need for rebiopsies at progression to diagnose this potential resistance mechanism. Further research is needed to better understand the mechanisms underlying this phenomenon and to develop more effective treatment strategies for patients with tSCLC.

Postprandial Dysmetabolism and Its Medical Implications.

An unbalanced diet increases the risk of developing a variety of chronic diseases and cancers, leading to higher morbidity and mortality rates worldwide. Low-grade systemic chronic inflammation mediated by the activation of the innate immune system is common to all these pathologies. Inflammation is a biological response of the body and a normal part of host defense to combat the effects of bacteria, viruses, toxins and macronutrients. However, when the innate immune system is constantly activated, it can promote the development of low-grade systemic chronic inflammation, which could play an important role in the development of chronic diseases and cancer. Since most chronic inflammatory diseases are associated with diet, a balanced healthy diet high in anti-inflammatory food components could prevent chronic diseases and cancer. The cells of the body's immune system produce chemokines and cytokines which can have pro-inflammatory and tumor-promoting as well as anti-inflammatory and tumor-fighting functions. A challenge in the future will be to assess whether polymorphisms in immune-related genes may play a role in promoting pro-inflammatory activity. Thanks to this duality, future research on immune regulation could focus on how innate immune cells can be modified to convert a pro-inflammatory and tumor-friendly microenvironment into an anti-inflammatory and anti-tumor one. This review describes inflammatory responses mediated by the innate immune system in various diseases such as hyperglycemia and/or hyperlipemia, obesity, type II diabetes, cardiovascular disease and cancer.

Innate Immunity in Autoimmune Thyroid Disease during Pregnancy.

Autoimmune thyroid disease (AITD) is the most common organ-specific autoimmune disorder clinically presented as Hashimoto thyroiditis (HT) and Graves' disease (GD). The pathogenesis of AITD is caused by an inappropriate immune response related to genetic, non-genetic, and environmental factors. Pregnancy is one of the factors that have a great influence on the function of the thyroid gland because of the increased metabolic demand and the effects of hormones related to pregnancy. During pregnancy, an adaptation of the maternal immune system occurs, especially of the innate immune system engaged in maintaining adaptive immunity in the tolerant state, preventing the rejection of the fetus. Pregnancy-related hormonal changes (estrogen, progesterone, hCG) may modulate the activity of innate immune cells, potentially worsening the course of AITD during pregnancy. This especially applies to NK cells, which are associated with exacerbation of HD and GD. On the other hand, previous thyroid disorders can affect fertility and cause adverse outcomes of pregnancy, such as placental abruption, spontaneous abortion, and premature delivery. Additionally, it can cause fetal growth retardation and may contribute to impaired neuropsychological development of the fetus. Therefore, maintaining the thyroid equilibrium in women of reproductive age and in pregnant women is of the highest importance.

Small Cell Lung Carcinoma: Current Diagnosis, Biomarkers, and Treatment Options with Future Perspectives.

Small cell lung cancer (SCLC) is an aggressive malignancy characterized by rapid proliferation, early dissemination, acquired therapy resistance, and poor prognosis. Early diagnosis of SCLC is crucial since most patients present with advanced/metastatic disease, limiting the potential for curative treatment. While SCLC exhibits initial responsiveness to chemotherapy and radiotherapy, treatment resistance commonly emerges, leading to a five-year overall survival rate of up to 10%. New effective biomarkers, early detection, and advancements in therapeutic strategies are crucial for improving survival rates and reducing the impact of this devastating disease. This review aims to comprehensively summarize current knowledge on diagnostic options, well-known and emerging biomarkers, and SCLC treatment strategies and discuss future perspectives on this aggressive malignancy.

Endothelial Dysfunction in Patients Undergoing Cardiac Surgery: A Narrative Review and Clinical Implications.

Cardiac surgery is one of the highest-risk procedures, usually involving cardiopulmonary bypass and commonly inducing endothelial injury that contributes to the development of perioperative and postoperative organ dysfunction. Substantial scientific efforts are being made to unravel the complex interaction of biomolecules involved in endothelial dysfunction to find new therapeutic targets and biomarkers and to develop therapeutic strategies to protect and restore the endothelium. This review highlights the current state-of-the-art knowledge on the structure and function of the endothelial glycocalyx and mechanisms of endothelial glycocalyx shedding in cardiac surgery. Particular emphasis is placed on potential strategies to protect and restore the endothelial glycocalyx in cardiac surgery. In addition, we have summarized and elaborated the latest evidence on conventional and potential biomarkers of endothelial dysfunction to provide a comprehensive synthesis of crucial mechanisms of endothelial dysfunction in patients undergoing cardiac surgery, and to highlight their clinical implications.

Sinomenine mitigates cisplatin-induced kidney injury by targeting multiple signaling pathways.

Sinomenine is a pharmacologically active alkaloid with antioxidant and anti-inflammatory properties. We aimed to investigate the mechanism of renoprotective activity of sinomenine in kidney injury induced by cisplatin (CP). Sinomenine (5 mg/kg) was administered to mice orally in two doses, the second day after intraperitoneal application of CP (13 mg/kg). Sinomenine ameliorated kidney injury and decreased serum levels of urea and creatinine and renal expression of NGAL and KIM-1. The increase in HO-1, 4-HNE, 3-NT and TNF-α renal expression was mitigated by sinomenine. Additionally, sinomenine reduced the expression of p21, Bax, Noxa, caspase-3 and -8 and PARP1 cleavage in mice kidneys as well as the number of TUNEL-positive cells. Sinomenine attenuated CP-induced activation of ERK1/2, Akt, FOXO3a, STAT3 and NF-κB and restored Sirtuin 6 expression. In the human proximal tubular cell line HK2, sinomenine 100 µM reduced the toxic effect of CP 30 µM. Our current findings suggest that sinomenine suppresses CP-induced oxidative stress, inflammation and apoptosis in mice kidneys by targeting multiple signaling pathways.

Significance of the Lung Immune Prognostic Index for Assessment of the Reliability of the Clinical Treatment Outcome for Advanced Non-Small-Cell Lung Cancer in Patients with COVID-19 Infection.

Introduction: Lung cancer is one of the most diagnosed malignancies with increasing incidence worldwide. Immunotherapy is the main oncological treatment for advanced non-small cell lung cancer (NSCLC), for which the discovery of new efficient biomarkers is crucial. Scientific evidence points to the importance of the Lung Immune Prognostic Index (LIPI), but its predictive significance is unclear. Aim: The aim of this study was to investigate the clinical significance and predictive role of LIPI in patients with advanced NSCLC and PD-L1 mutation who are eligible for immunotherapy in combination with chemotherapy. In addition, to our knowledge, this is the first time that the association between COVID-19 infection and the course and outcome of oncologic treatment of NSCLC has been investigated. Patients and Methods: Patients were divided into four study groups according to strictly defined clinical parameters, therapeutic approach, and COVID-19 infection. LIPI was determined and its predictive power was evaluated in all studied groups, as well as overall survival (OS), progression-free survival (PFS), and disease control rate (DCR). Results: This study confirmed the understudied and uncertain predictive power and clinical relevance of LIPI as a biomarker in patients with advanced NSCLC. Patients infected with COVID-19 had a higher survival rate than uninfected patients despite the therapeutic approach, which may be attributed to their hospitalization and intensive medical management during the pandemic. Conclusions: Findings obtained in this study may help to determine treatment options according to the clinical condition of the patient by using LIPI values as a non-invasive, readily available and economically acceptable predictive biomarker in lung oncology.

Oleanolic acid induces HCT116 colon cancer cell death through the p38/FOXO3a/Sirt6 pathway.

Oleanolic acid (OA) is a natural compound that possesses numerous beneficial health effects, including anticancer activity. The current study aimed to investigate the role of forkhead box O3a (FOXO3a) in autophagy/mitophagy by OA in HCT116 cell line. OA dose-dependently reduced viability of HCT116 cells, with IC50 = 29.8 µΜ. The expression of cleaved caspase-3 and poly (ADP-ribose) polymerase 1 increased after OA treatment, suggesting induction of apoptosis. Concurrently, OA induced autophagy, evidenced by increased expression of Beclin-1, autophagy-related protein 5 and microtubule-associated protein1A/1B-light chain 3 beta (LC3B), which played a prosurvival role. The induction of mitophagy was suggested by increased expression of p62 and PTEN-induced kinase 1 and reduced expression of translocase of outer mitochondrial membrane 20, which colocalized with LC3B. OA also induced nuclear accumulation of forkhead box O3a (FOXO3a). The cytotoxic activity of OA coincided with upregulation of p38. Inhibition of p38 led to increase in FOXO3a and NAD+-dependent deacetylase sirtuin 6 expression. In vivo, OA inhibited tumor growth in colon cancer xenograft mice. Our results suggest concomitant induction of apoptosis and prosurvival mitophagy by OA in colon cancer via p38/FOXO3a/Sirt6 signaling. Additionally, our data demonstrate that OA can chemosensitize colon cancer cells to 5-fluorouracil (5-FU).

CD26 Deficiency Controls Macrophage Polarization Markers and Signal Transducers during Colitis Development and Resolution.

Ulcerative colitis (UC) is a multifactorial condition characterized by a destructive immune response that failed to be attenuated by common regulatory mechanisms which reduce inflammation and promote mucosa healing. The inhibition of CD26, a multifunctional glycoprotein that controls the immune response via its dipeptidyl peptidase (DP) 4 enzyme activity, was proven to have beneficial effects in various autoimmune inflammatory diseases. The polarization of macrophages into either pro-inflammatory M1 or anti-inflammatory M2 subclass is a key intersection that mediates the immune-inflammatory process in UC. Hence, we hypothesized that the deficiency of CD26 affects that process in the dextran sulfate sodium (DSS)-induced model of UC. We found that mRNA expression of M2 markers arginase 1 and Fizz were increased, while the expression of M1 marker inducible NO synthase was downregulated in CD26-/- mice. Decreased STAT1 mRNA, as well as upregulated pSTAT6 and pSTAT3, additionally support the demonstrated activation of M2 macrophages under CD26 deficiency. Finally, we investigated DP8 and DP9, proteins with DP4-like activity, and found that CD26 deficiency is not a key factor for the noted upregulation of their expression in UC. In conclusion, we demonstrate that CD26 deficiency regulates macrophage polarization toward the anti-inflammatory M2 phenotype, which is driven by STAT6/STAT3 signaling pathways. This process is additionally enhanced by the reduction of M1 differentiation via the suppression of proinflammatory STAT1. Therefore, further studies should investigate the clinical potential of CD26 inhibitors in the treatment of UC.

Gender-Related Differences in BMP Expression and Adult Hippocampal Neurogenesis within Joint-Hippocampal Axis in a Rat Model of Rheumatoid Arthritis.

BMPs regulate synovial quiescence and adult neurogenesis in the hippocampus in non-stress conditions. However, changes in BMP expression that are induced by inflammation during rheumatoid arthritis (RA) have not yet been reported. Here, we show that signalling with synovial BMPs (BMP-4 and -7) mediates the effect of systemic inflammation on adult neurogenesis in the hippocampus during pristane-induced arthritis (PIA) in Dark Agouti (DA) rats, an animal model of RA. Moreover, we show gender differences in BMP expressions and their antagonists (Noggin and Gremlin) during PIA and their correlations with the clinical course and IL-17A and TNF-α levels in serum. Our results indicate gender differences in the clinical course, where male rats showed earlier onset and earlier recovery but a worse clinical course in the first two phases of the disease (onset and peak), which correlates with the initial increase of serum IL-17A level. The clinical course of the female rats worsened in remission. Their prolonged symptoms could be a reflection of an increased TNF-α level in serum during remission. Synovial inflammation was greater in females in PIA-remission with greater synovial BMP and antagonist expressions. More significant correlations between serum cytokines (IL-17A and TNF-α), and synovial BMPs and their antagonists were found in females than in males. On the other hand, males showed an increase in hippocampal BMP-4 expression during the acute phase, but both genders showed a decrease in antagonist expressions during PIA in general. Both genders showed a decrease in the number of Ki-67+ and SOX-2+ and DCX+ cells and in the ratio of DCX+ to Ki67+ cells in the dentate gyrus during PIA. However, in PIA remission, females showed a faster increase in the number of Ki67+, SOX-2+, and DCX+ cells and a faster increase in the DCX/Ki67 ratio than males. Both genders showed an increase of hippocampal BMP-7 expression during remission, although males constantly showed greater BMP-7 expression at all time points. Our data show that gender differences exist in the BMP expressions in the periphery-hippocampus axis and in the IL-17A and TNF-α levels in serum, which could imply differences in the mechanisms for the onset and progression of the disease, the clinical course severity, and adult neurogenesis with subsequent neurological complications between genders.

Diagnostic accuracy of three SARS-CoV2 antibody detection assays, neutralizing effect and longevity of serum antibodies.

Evidence is currently insufficient to know whether SARS-CoV-2 antibodies (Abs) protect from future infection and how long immunity will last. The kinetics of the immune response to SARS-CoV-2 infection and role of serology in estimating individual protective immunity is yet to be established. We evaluated diagnostic performances of three serological assays - Abbott Architect CMIA IgG, bioMerieux VIDAS ELFA IgG/IgM, and Diesse Chorus ELISA IgG/IgM, and analyzed longevity and potential neutralizing effect of SARS-CoV-2 Abs in COVID-19 patients. Clinical sensitivities of assessed IgG tests two to three weeks post symptom onset (PSO) were very high: 96.77 % for Architect, 96.77 % for Chorus, and 100.00 % for VIDAS. Sensitivities of two assessed IgM assays were moderate: 74.07 % for Chorus, and 76.92 % for VIDAS. Specificities were excellent for all assessed IgG assays: 99.01 % for Architect and 100 % for Chorus and VIDAS. Chorus and VIDAS IgM assays also achieved excellent specificity of 99.01 % and 100 %, respectively. In most cases IgG Abs were still present eight months PSO. Neutralizing antibodies were detected in majority of serum samples from convalescent patients. Serum samples from severe COVID-19 patients had higher antibody titers and higher neutralizing activity. We observed a strong positive correlation among SARS-CoV-2 IgG antibody titer and neutralizing activity. The strongest positive correlation to neutralizing activity was found for VIDAS IgG assay.

Profiling Colorectal Cancer in the Landscape Personalized Testing-Advantages of Liquid Biopsy.

Drug-specific therapeutic approaches for colorectal cancer (CRC) have contributed to significant improvements in patient health. Nevertheless, there is still a great need to improve the personalization of treatments based on genetic and epigenetic tumor profiles to maximize the quality and efficacy while limiting cytotoxicity. Currently, CEA and CA 19-9 are the only validated blood biomarkers in clinical practice. For this reason, laboratories are trying to identify new specific prognostics and, more importantly, predictive biomarkers for CRC patient profiling. Thus, the unique landscape of personalized biomarker data should have a clinical impact on CRC treatment strategies and molecular genetic screening tests should become the standard method for diagnosing CRC. This review concentrates on recent molecular testing in CRC and discusses the potential modifications in CRC assay methodology with the upcoming clinical application of novel genomic approaches. While mechanisms for analyzing circulating tumor DNA have been proven too inaccurate, detecting and analyzing circulating tumor cells and protein analysis of exosomes represent more promising options. Blood liquid biopsy offers good prospects for the future if the results align with pathologists' tissue analyses. Overall, early detection, accurate diagnosis and treatment monitoring for CRC with specific markers and targeted molecular testing may benefit many patients.

Luteolin ameliorates experimental colitis in mice through ERK-mediated suppression of inflammation, apoptosis and autophagy.

Ulcerative colitis (UC) is a chronic inflammatory disease with increasing incidence and prevalence worldwide. Currently used treatments of UC are unsatisfactory, while natural bioactive compounds are considered to be emerging therapeutic agents. Luteolin (Lut) is a natural compound with beneficial effects in a variety of diseases, however, its effect in UC has been poorly studied. In this study we investigated the effect of Lut in posttreatment and cotreatment of dextran sulfate sodium (DSS)-induced experimental colitis in mice. In addition, the role of extracellular signal-regulated kinases 1/2 (ERK1/2) in the mechanism of action of Lut in experimental colitis was investigated using the ERK inhibitor PD0325901. Lut attenuated symptoms of DSS-induced colitis in mice, ameliorated colon tissue damage and reduced inflammation, apoptosis and autophagy. The effect was more pronounced if Lut was administered simultaneously with DSS. The administration of ERK inhibitor exacerbated DSS-induced colitis symptoms and prevented the protective effects of Lut. The results provide new mechanistic details underlying the anti-inflammatory, anti-apoptotic and anti-autophagic effects of Lut through the activation of the ERK signaling pathway. This suggested that Lut can be used as a novel therapeutic candidate in the treatment of UC or could be used as a supplement to existing therapy.

Aucubin administered by either oral or parenteral route protects against cisplatin-induced acute kidney injury in mice.

Aucubin is pharmacologically active natural compound which possesses numerous beneficial properties. This study aimed to evaluate the protective effect of aucubin against cisplatin (CP)-induced acute kidney injury in mice and the mechanism of its action. Aucubin was administrated to mice orally or intraperitoneally (ip) (1.5 and 5 mg/kg) for two consecutive days, two days after ip injection of cisplatin (CP), 11 mg/kg. Treatment with aucubin by both routes of administration ameliorated histopathological changes and reduced elevated serum markers of kidney injury. CP administration increased renal expression of heme oxygenase-1 (HO-1) and 4-hydroxynonenal (4-HNE), as well as tumor necrosis factor-alpha (TNF-α), which was dose-dependently ameliorated by aucubin. Moreover, aucubin reduced increased renal expression of cleaved caspase-3 and -9 and decreased poly (ADP-ribose) polymerase (PARP) cleavage. Mechanistically, aucubin suppressed the activation of several signaling pathways involved in inflammation and apoptosis, including nuclear factor-kappa B (NF-κB), signal transducer and activator of transcription 3 (STAT3), Akt, extracellular signal-regulated kinase 1/2 (ERK1/2) and forkhead box O3a (FOXO3a). Parenteral application was marginally but statistically more effective in reducing CP-induced kidney injury than oral administration. The findings of this study suggest that aucubin acts as a protective agent against CP-induced nephrotoxicity, which should be further investigated.

Neuroimmunomodulative properties of dipeptidyl peptidase IV/CD26 in a TNBS-induced model of colitis in mice.

Causal connections between dipeptidyl peptidase IV, also known as CD26 molecule (DPP IV/CD26) and inflammatory bowel disease (IBD) have been shown, but mechanisms of these interactions are unclear. Our hypothesis was that DPP IV/CD26 could affect the neuroimmune response during inflammatory events. Therefore, we aimed to evaluate its possible role and the relevance of the gut-brain axis in a model of IBD in mice. Trinitrobenzenesulfonic acid-induced (TNBS) colitis was induced in CD26-deficient (CD26(-/-) ) and wild-type (C57BL/6) mice. Pathohistological and histomorphometrical measurements were done. Concentrations and protein expressions of DPP IV/CD26 substrates neuropeptide Y (NPY) and vasoactive intestinal peptide (VIP) were determined. Concentrations of IL-6 and IL-10 were evaluated. Investigations were conducted at systemic and local levels. Acute inflammation induced increased serum NPY concentrations in both mice strains, more enhanced in CD26(-/-) mice. Increased NPY concentrations were found in colon and brain of C57BL/6 mice, while in CD26(-/-) animals only in colon. VIP and IL-6 serum and tissue concentrations were increased in both mice strains in acute inflammation, more pronouncedly in CD26(-/-) mice. IL-10 concentrations, after a decrease in serum of both mice strains, increased promptly in CD26(-/-) mice. Decreased IL-10 concentration was found in brain of C57BL/6 mice, while it was increased in colon of CD26(-/-) mice in acute inflammation. DPP IV/CD26 deficiency affects the neuroimmune response at systemic and local levels during colitis development and resolution in mice. Inflammatory changes in the colon reflected on investigated parameters in the brain, suggesting an important role of the gut-brain axis in IBD pathogenesis.