Microplastics caused embryonic growth retardation and placental dysfunction in pregnant mice by activating GRP78/IRE1α/JNK axis induced apoptosis and endoplasmic reticulum stress.

Microplastics (MPs), a brand-new class of worldwide environmental pollutant, have received a lot of attention. MPs are consumed by both humans and animals through water, food chain and other ways, which may cause potential health risks. However, the effects of MPs on embryonic development, especially placental function, and its related mechanisms still need to be further studied. We investigated the impact on fetal development and placental physiological function of pregnant mice by consecutive gavages of MPs at 0, 25, 50, 100 mg/kg body weight during gestational days (GDs 0-14). The results showed that continuous exposure to high concentrations of MP significantly reduced daily weight gain and impaired reproductive performance of pregnant mice. In addition, MPs could significantly induce oxidative stress and placental dysfunction in pregnant mice. On the other hand, MPs exposure significantly decreased placental barrier function and induced placental inflammation. Specifically, MPs treatment significantly reduced the expression of tight junction proteins in placentas, accompanied by inflammatory cell infiltration and increased mRNA levels of pro-inflammatory cytokines and chemokines in placentas. Finally, we found that MPs induced placental apoptosis and endoplasmic reticulum (ER) stress through the GRP78/IRE1α/JNK axis, leading to placental dysfunction and decreased reproductive performance in pregnant mice. We revealed for the first time that the effects of MPs on placental dysfunction in pregnant animals. Blocking the targets of MPs mediated ER stress will provide potential therapeutic ideas for the toxic effects of MPs on maternal pregnancy.

LncRNA PKD1P6 modulates ovarian granulosa cell survival of hyperandrogenic polycystic ovary syndrome by targeting miR-135b-5p and inhibiting ERK1/2 signaling.

Polycystic ovary syndrome (PCOS) is the most common and multifactorial endocrine disease among women of reproductive age. Aberrant folliculogenesis is a common pathological characteristic of PCOS, but the underlying molecular mechanism remains unclear. Emerging evidence indicated that aberrant expression of long noncoding RNAs (lncRNAs) may contribute to the pathogenesis of PCOS. In this study, we found that lncRNA PKD1P6 expression was remarkably down-regulated in ovarian granulosa cells (GCs) of hyperandrogenic PCOS (HA-PCOS) patients and negatively correlated with serum testosterone (T) levels. We further showed that overexpression of PKD1P6 markedly reduced cell viability, attenuated DNA synthesis capacity, arrested the cell cycle at G0/G1 phase and promoted apoptosis of KGN cells. Exosomes derived from PKD1P6 overexpression cells exerted similar effects to PKD1P6 overexpression on the function of KGN cells. Mechanistically, PKD1P6 could act as a competing endogenous RNA (ceRNA) by directly binding with miR-135b-5p. Overexpression of PKD1P6 significantly suppressed ERK1/2 activation, whereas up-regulation of miR-135b-5p exerted an opposing effect. Additionally, excessive androgen was showed to diminish PKD1P6 expression while promote miR-135b-5p expression of PCOS models in vitro and vivo. Collectively, our findings delineate the clinical significance of PKD1P6 in HA-PCOS and the new regulatory mechanisms involved in abnormal folliculogenesis, providing a promising therapeutic target for HA-PCOS.

Emerging roles of cannabinoid receptor CB2 receptor in the central nervous system: therapeutic target for CNS disorders.

RATIONALE: The endocannabinoid system (ECS) belongs to the G protein-coupled receptor family of cell membranes and is associated with neuropsychiatric conditions, and neurodegenerative diseases. Cannabinoid 2 receptors (CB2) are expressed in the central nervous system (CNS) on microglia and subgroups of neurons and are involved in various behavioural processes via immunological and neural regulation. OBJECTIVE: The objective of this paper is to summarize and explore the impact of CB2 receptors on neuronal modulation, their involvement in various neurological disorders, and their influence on mood, behavior, and cognitive function. RESULTS: The activation of CB2 appears to protect the brain and its functions from damage under neuroinflammatory actions, making it an attractive target in a variety of neurological conditions such as Parkinson's disease (PD), multiple sclerosis (MS), Alzheimer's disease (AD), and Huntington's disease (HD). During inflammation, there is an overexpression of CB2 receptors, and CB2 agonists show a strong anti-inflammatory effect. These results have sparked interest in the CB2 receptors as a potential target for neurodegenerative and neuroinflammatory disease treatment. CONCLUSION: In conclusion, CB2 receptors signalling shows promise for developing targeted interventions that could positively affect both immune and neuronal functions, ultimately influencing behavioral outcomes in both health and disease.

Conserved signaling modules regulate filamentous growth in fungi: a model for eukaryotic cell differentiation.

Eukaryotic organisms are composed of different cell types with defined shapes and functions. Specific cell types are produced by the process of cell differentiation, which is regulated by signal transduction pathways. Signaling pathways regulate cell differentiation by sensing cues and controlling the expression of target genes whose products generate cell types with specific attributes. In studying how cells differentiate, fungi have proved valuable models because of their ease of genetic manipulation and striking cell morphologies. Many fungal species undergo filamentous growth-a specialized growth pattern where cells produce elongated tube-like projections. Filamentous growth promotes expansion into new environments, including invasion into plant and animal hosts by fungal pathogens. The same signaling pathways that regulate filamentous growth in fungi also control cell differentiation throughout eukaryotes and include highly conserved mitogen-activated protein kinase (MAPK) pathways, which is the focus of this review. In many fungal species, mucin-type sensors regulate MAPK pathways to control filamentous growth in response to diverse stimuli. Once activated, MAPK pathways reorganize cell polarity, induce changes in cell adhesion, and promote the secretion of degradative enzymes that mediate access to new environments. However, MAPK pathway regulation is complicated because related pathways can share components with each other yet induce unique responses (i.e. signal specificity). In addition, MAPK pathways function in highly integrated networks with other regulatory pathways (i.e. signal integration). Here, we discuss signal specificity and integration in several yeast models (mainly Saccharomyces cerevisiae and Candida albicans) by focusing on the filamentation MAPK pathway. Because of the strong evolutionary ties between species, a deeper understanding of the regulation of filamentous growth in established models and increasingly diverse fungal species can reveal fundamentally new mechanisms underlying eukaryotic cell differentiation.

Terminalia bellirica (Gaertn.) Roxb. Extracts reshape the perifollicular microenvironment and regulate the MAPK pathway for androgenetic alopecia treatment.

ETHNOPHARMACOLOGICAL RELEVANCE: Terminalia bellirica (Gaertn.) Roxb. (TBR), a popular herbal remedy in India and Southeast Asia, has been demonstrated to possess multiple pharmacological activities. However, systematic studies on the medicinal effects and mechanism of TBR for the androgenetic alopecia (AGA) treatment are deficient. MATERIALS AND METHODS: Human Umbilical Vein Endothelial Cells (HUVECs) and testosterone-induced AGA mice were used to evaluate the hair regrowth activity of TBR extracts. Chemical constituents and potential active components of TBR extracts were analyed by UPLC-Q-TOF-MS in vitro/vivo. The hair regrowth mechanisms of TBR were elucidated through network pharmacology and experimental validation. RESULTS: Totally 28 chemical constituents in TBR were identified, of which 15 were predicted as potential active components for AGA therapy. TBR could significantly scavenge ROS, promote VEGF level/cell migration of HUVECs, and inhibiting type II 5α-reductase activity (the inhibit rate: 82.35 ± 1.02 %). Pharmacodynamic evaluation suggested that TBR effectively led to hair regrowth in C57BL6 mice compared to minoxidil. TBR promoted the hair follicle (HF) transition from the telogen phase to anagen phase by decreasing MDA levels, increasing VEFG expression and up-regulating phosphorylated P38/ERK protein levels in the MAPK signalling pathway. CONCLUSIONS: TBR reversed AGA via inhibiting SRD5A2 activity and stimulating the MAPK pathway. Meantime, TBR could remodel the follicle microenvironment by reducing oxidative stress and increasing angiogenesis.

Vasorin (VASN) overexpression promotes pulmonary metastasis and resistance to adjuvant chemotherapy in patients with locally advanced rectal cancer.

BACKGROUND: LARC patients commonly receive adjuvant therapy, however, hidden micrometastases still limit the improvement of OS. This study aims to investigate the impact of VASN in rectal cancer with pulmonary metastasis and understand the underlying molecular mechanisms to guide adjuvant chemotherapy selection. METHODS: Sequencing data from rectal cancer patients with pulmonary metastasis from Sun Yat-sen University Cancer Center (SYSUCC) and publicly available data were meticulously analyzed. The functional role of VASN in pulmonary metastasis was validated in vivo and in vitro. Coimmunoprecipitation (co-IP), immunofluorescence, and rescue experiments were conducted to unravel potential molecular mechanisms of VASN. Moreover, VASN expression levels in tumor samples were examined and analyzed for their correlations with pulmonary metastasis status, tumor stage, adjuvant chemotherapy benefit, and survival outcome. RESULTS: Our study revealed a significant association between high VASN expression and pulmonary metastasis in LARC patients. Experiments in vitro and in vivo demonstrated that VASN could promote the cell proliferation, metastasis, and drug resistance of colorectal cancer. Mechanistically, VASN interacts with the NOTCH1 protein, leading to concurrent activation of the NOTCH and MAPK pathways. Clinically, pulmonary metastasis and advanced tumor stage were observed in 90% of VASN-positive patients and 53.5% of VASN-high patients, respectively, and VASN-high patients had a lower five-year survival rate than VASN-low patients (26.7% vs. 83.7%). Moreover, the Cox analysis and OS analysis indicated that VASN was an independent prognostic factor for OS (HR = 7.4, P value < 0.001) and a predictor of adjuvant therapy efficacy in rectal cancer. CONCLUSIONS: Our study highlights the role of VASN in decreasing drug sensitivity and activating the NOTCH and MAPK pathways, which leads to tumorigenesis and pulmonary metastasis. Both experimental and clinical data support that rectal cancer patients with VASN overexpression detected in biopsies have a higher risk of pulmonary metastasis and adjuvant chemotherapy resistance.

N6­methyladenosine methyltransferase METTL14 is associated with macrophage polarization in rheumatoid arthritis.

Rheumatoid arthritis (RA) is largely caused by the inflammatory response triggered by macrophage polarization. Through epigenetic reprogramming, the inflammatory state of macrophages can be modified. Macrophage polarization is associated with the RNA epigenetic alteration N6-methyladenosine (m6A) RNA methylation. However, the specific function and underlying mechanisms of m6A methylation in the role of macrophage polarization in RA remain to be elucidated. The mRNA expression levels of m6A methylase genes and signaling pathway components associated with RA macrophages were determined in the present study using reverse-transcription quantitative PCR. Methyltransferase 14 (METTL14) protein expression levels were determined using western blot analysis, and the levels of specific cellular secretion factors were determined using ELISA and flow cytometry. The results of the present study demonstrated that elevated METTL14 expression was associated with joint tenderness, and METTL14 expression was positively correlated with both C-reactive protein and rheumatoid factor expression levels. Moreover, METTL14 exhibited potential in the prediction of visual analogue scale. Pro-inflammatory cytokines (TNF-α) and M1 macrophage markers (CD68+CD86+) were also positively associated with METTL14 expression. The results of the Kyoto Encyclopedia of Genes and Genomes analysis revealed that METTL14 was strongly associated with the MAPK signaling pathway. Notably, JNK and ERK2 exhibited a positive correlation with the M1 macrophage marker, CD68+CD86+, which was positively associated with the pro-inflammatory factor, TNF-α. JNK and ERK2 expression levels were markedly increased in the METTL14 high-expression group, compared with in the low-expression group; however, p38 and ERK1 expression levels were not significantly different between these groups. Collectively, the results of the present study demonstrated that METTL14 expression was significantly increased in the peripheral blood and synovial tissue of patients with RA, highlighting the potential association with both immunoinflammatory markers and clinical symptoms. In addition, it was suggested that METTL14 may exacerbate the downstream inflammatory response, through mediating macrophage polarization via the MAPK pathway.

The Role of the MiR-181 Family in Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is the fourth-leading cause of cancer-related death worldwide. Due to the high mortality rate in HCC patients, discovering and developing novel systemic treatment options for HCC is a vital unmet medical need. Among the numerous molecular alterations in HCCs, microRNAs (miRNAs) have been increasingly recognised to play critical roles in hepatocarcinogenesis. We and others have recently revealed that members of the microRNA-181 (miR-181) family were up-regulated in some, though not all, human cirrhotic and HCC tissues-this up-regulation induced epithelial-mesenchymal transition (EMT) in hepatocytes and tumour cells, promoting HCC progression. MiR-181s play crucial roles in governing the fate and function of various cells, such as endothelial cells, immune cells, and tumour cells. Previous reviews have extensively covered these aspects in detail. This review aims to give some insights into miR-181s, their targets and roles in modulating signal transduction pathways, factors regulating miR-181 expression and function, and their roles in HCC.

Anti-Neuroinflammatory Effects of Ginkgo biloba Extract EGb 761 in LPS-Activated BV2 Microglial Cells.

Inflammatory processes in the brain can exert important neuroprotective functions. However, in neurological and psychiatric disorders, it is often detrimental due to chronic microglial over-activation and the dysregulation of cytokines and chemokines. Growing evidence indicates the emerging yet prominent pathophysiological role of neuroinflammation in the development and progression of these disorders. Despite recent advances, there is still a pressing need for effective therapies, and targeting neuroinflammation is a promising approach. Therefore, in this study, we investigated the anti-neuroinflammatory potential of a marketed and quantified proprietary herbal extract of Ginkgo biloba leaves called EGb 761 (10-500 µg/mL) in BV2 microglial cells stimulated by LPS (10 ng/mL). Our results demonstrate significant inhibition of LPS-induced expression and release of cytokines tumor necrosis factor-α (TNF-α) and Interleukin 6 (IL-6) and chemokines C-X-C motif chemokine ligand 2 (CXCL2), CXCL10, c-c motif chemokine ligand 2 (CCL2) and CCL3 in BV2 microglial cells. The observed effects are possibly mediated by the mitogen-activated protein kinases (MAPK), p38 MAPK and ERK1/2, as well as the protein kinase C (PKC) and the nuclear factor (NF)-κB signaling cascades. The findings of this in vitro study highlight the anti-inflammatory properties of EGb 761 and its therapeutic potential, making it an emerging candidate for the treatment of neuroinflammatory diseases and warranting further research in pre-clinical and clinical settings.

Therapeutic Potential of siRNAs in Tongue Squamous Cell Carcinoma by Modulating The PI3K/AKT and ERK Signaling Pathways: A Systematic Review.

Among the various manifestations of oral cavity cancer, tongue squamous cell carcinoma (TSCC), is the most common form of this condition. TSCC represents a major challenge in the field of cancer treatment. The emergence of small interfering RNAs (siRNAs) has opened new avenues for therapeutic intervention in TSCC. This research provides an overview of siRNA-mediated mechanisms and emphasizes their complex involvement in modulating key signaling pathways associated with TSCC progression. Relevant articles from 2004 to 2023 were conducted by using different keywords, such as "Interfering RNA " and "Small Interfering ". The search was following the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines based on inclusion and exclusion criteria. The quality of the studies was assessed using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) criteria. The selected studies (n=17) were subjected to perform comprehensive analysis. We concluded that the PI3K/AKT and ERK pathways, one of oncogenic signaling cascades in TSCC is notable. siRNAs and their role in targeting specific signaling pathways help us understand the molecular mechanisms underlying TSCC that may lead to the development promising therapies for TSCC. These therapies have the advantage of personalization and precision, targeted delivery, and the potential to overcome drug resistance. Therefore, the study enhances our comprehension of siRNA-based interventions' clinical potential in TSCC.

Multinodular and vacuolating neuronal tumor in the thalamus: case report and systematic review of literature.

The authors present the first reported case of MVNT in the thalamus in a 60-year-old man with a 20-year history of epilepsy and recent progressive neurological decline presented for neurosurgical evaluation for a non-enhancing mass predominantly in the right thalamus presumed to be a low-grade glioma. The tumor was subtotally resected using a left contralateral interhemispheric transcallosal approach. Histological and molecular assessment revealed an MVNT with MAPK pathway-activating mutation. The authors also conducted a systematic review of pathology-proven cases of MVNT to provide an up-to-date overview of the literature on the localization, presenting symptoms, and recurrence of this tumor.

Mucocutaneous toxicities from MEK inhibitors: a scoping review of the literature.

BACKGROUND: MEK inhibitors cause a wide spectrum of mucocutaneous toxicities which can delay or interrupt life-saving therapy. PURPOSE: To summarize the morphology, incidence, and clinical presentation of mucocutaneous toxicities from MEK inhibitors via a scoping review of the literature. METHODS: We conducted a scoping review of the published literature, including clinical trials, retrospective and prospective studies, reviews, and case reports and series. All included literature was analyzed by a panel of pediatric and adult oncodermatologists. RESULTS: Of 1626 initial citations, 227 articles met final inclusion criteria. Our review identified follicular reactions, ocular toxicities, xerosis, eczematous dermatitis, edema, and paronychia as the most common mucocutaneous side effects from MEK inhibitor therapy. Grade 1 and 2 reactions were the most prevalent and were typically managed while continuing treatment; however, grade 3 toxicities requiring dose reductions or treatment interruptions were also reported. CONCLUSION: Mucocutaneous toxicities to MEK inhibitor therapy are common and most often mild in severity. Early recognition and treatment can mitigate disruptions in oncologic therapy.

Silibinin Mitigates Vanadium-induced Lung Injury via the TLR4/MAPK/NF-κB Pathway in Mice.

BACKGROUND/AIM: Silibinin, has been investigated for its potential benefits and mechanisms in addressing vanadium pentoxide (V2O5)-induced pulmonary inflammation. This study explored the anti-inflammatory activity of silibinin and elucidate the mechanisms by which it operates in a mouse model of vanadium-induced lung injury. MATERIALS AND METHODS: Eight-week-old male BALB/c mice were exposed to V2O5 to induce lung injury. Mice were pretreated with silibinin at doses of 50 mg/kg and 100 mg/kg. Histological analyses were performed to assess cell viability and infiltration of inflammatory cells. The expression of pro-inflammatory cytokines (TNF-α, IL-6, IL-1ß) and activation of the MAPK and NF-[Formula: see text]B signaling pathways, as well as the NLRP3 inflammasome, were evaluated using real-time PCR, western blot analysis, and immunohistochemistry. Whole blood analysis was conducted to measure white blood cell counts. RESULTS: Silibinin treatment significantly improved cell viability, reduced inflammatory cell infiltration, and decreased the expression of pro-inflammatory cytokines in V2O5-induced lung injury. It also notably suppressed the activation of the MAPK and NF-[Formula: see text]B signaling pathways, along with a marked reduction in NLRP3 inflammasome expression levels in lung tissues. Additionally, silibinin-treated groups exhibited a significant decrease in white blood cell counts, including neutrophils, lymphocytes, and eosinophils. CONCLUSION: These findings underscore the potent anti-inflammatory effects of silibinin in mice with V2O5-induced lung inflammation, highlighting its therapeutic potential. The study not only confirms the efficacy of silibinin in mitigating inflammatory responses but also provides a foundational understanding of its role in modulating key inflammatory pathways, paving the way for future therapeutic strategies against pulmonary inflammation induced by environmental pollutants.

Advances in Melanoma: From Genetic Insights to Therapeutic Innovations.

Advances in melanoma research have unveiled critical insights into its genetic and molecular landscape, leading to significant therapeutic innovations. This review explores the intricate interplay between genetic alterations, such as mutations in BRAF, NRAS, and KIT, and melanoma pathogenesis. The MAPK and PI3K/Akt/mTOR signaling pathways are highlighted for their roles in tumor growth and resistance mechanisms. Additionally, this review delves into the impact of epigenetic modifications, including DNA methylation and histone changes, on melanoma progression. The tumor microenvironment, characterized by immune cells, stromal cells, and soluble factors, plays a pivotal role in modulating tumor behavior and treatment responses. Emerging technologies like single-cell sequencing, CRISPR-Cas9, and AI-driven diagnostics are transforming melanoma research, offering precise and personalized approaches to treatment. Immunotherapy, particularly immune checkpoint inhibitors and personalized mRNA vaccines, has revolutionized melanoma therapy by enhancing the body's immune response. Despite these advances, resistance mechanisms remain a challenge, underscoring the need for combined therapies and ongoing research to achieve durable therapeutic responses. This comprehensive overview aims to highlight the current state of melanoma research and the transformative impacts of these advancements on clinical practice.

Epigallocatechin gallate improves oleic acid-induced hepatic steatosis in laying hen hepatocytes via the MAPK pathway.

Fatty liver disease in laying hens, characterized by excessive lipid accumulation in hepatocytes, poses significant challenges to poultry health and production efficiency. In this study, we investigated the therapeutic potential of epigallocatechin gallate (EGCG), a bioactive compound found in green tea, in mitigating oleic acid (OA)-induced hepatic steatosis in primary chicken hepatocytes. Treatment with EGCG effectively attenuated lipid deposition by downregulating lipid synthesis-related genes. Moreover, EGCG mitigated oxidative stress, inflammation, DNA damage, and apoptosis induced by OA, thereby preserving hepatocyte viability. Mechanistically, EGCG exerted its protective effects by modulating the p38 MAPK signaling pathway. Our findings suggest that EGCG holds promise as a therapeutic agent for managing fatty liver disease in poultry, offering insights into novel strategies for improving poultry health and production outcomes.

Canine Histiocytic and Hemophagocytic Histiocytic Sarcomas Display KRAS and Extensive PTPN11/SHP2 Mutations and Respond In Vitro to MEK Inhibition by Cobimetinib.

Histiocytic sarcoma (HS) is a rare and highly aggressive cancer in humans and dogs. In dogs, it has a high prevalence in certain breeds, such as Bernese mountain dogs (BMDs) and flat-coated retrievers. Hemophagocytic histiocytic sarcoma (HHS) is a unique form of HS that presents with erythrophagocytosis. Due to its rareness, the study of HHS is very limited, and mutations in canine HHS patients have not been studied to date. In previous work, our research group identified two major PTPN11/SHP2 driver mutations, E76K and G503V, in HS in dogs. Here, we report additional mutations located in exon 3 of PTPN11/SHP2 in both HS and HHS cases, further supporting that this area is a mutational hotspot in dogs and that mutations in tumors and liquid biopsies should be evaluated utilizing comprehensive methods such as Sanger and NextGen sequencing. The overall prevalence of PTPN11/SHP2 mutations was 55.8% in HS and 46.2% in HHS. In addition, we identified mutations in KRAS, in about 3% of HS and 4% of HHS cases. These findings point to the shared molecular pathology of activation of the MAPK pathway in HS and HHS cases. We evaluated the efficacy of the highly specific MEK inhibitor, cobimetinib, in canine HS and HHS cell lines. We found that the IC50 values ranged from 74 to 372 nM, which are within the achievable and tolerable ranges for cobimetinib. This finding positions cobimetinib as a promising potential candidate for future canine clinical trials and enhances our understanding of the molecular defects in these challenging cancers.

Comparative transcriptome reveals EphA2 and c-Fos as key factors driving enhanced replication in high-passage porcine deltacoronavirus strain.

Porcine deltacoronavirus (PDCoV), a cross-species transmissible enterovirus, frequently induces severe diarrhea and vomiting symptoms in piglets, which not only pose a significant menace to the global pig industry but also a potential public safety risk. In a previous study, we isolated a vaccine candidate, PDCoV CZ2020-P100, by passaging a parental PDCoV strain in vitro, exhibiting attenuated virulence and enhanced replication. However, the factors underlying these differences between primary and passaged strains remain unknown. In this study, we present the transcriptional landscapes of porcine kidney epithelial cells (LLC-PK1) cells infected with PDCoV CZ2020-P1 strain and P100 strain using the RNA-sequencing. We identified 105 differentially expressed genes (DEGs) in P1-infected cells and 295 DEGs in P100-infected cells. Enrichment analyses indicated that many DEGs showed enrichment in immune and inflammatory responses, with a more and higher upregulation of DEGs enriched in the P100-infected group. Notably, the DEGs were concentrated in the MAPK pathway within the P100-infected group, with significant upregulation in EphA2 and c-Fos. Knockdown of EphA2 and c-Fos reduced PDCoV infection and significantly impaired P100 replication compared to P1, suggesting a novel mechanism in which EphA2 and c-Fos are highly involved in passaged virus replication. Our findings illuminate the resemblances and distinctions in the gene expression patterns of host cells infected with P1 and P100, confirming that EphA2 and c-Fos play key roles in high-passage PDCoV replication. These results enhance our understanding of the changes in virulence and replication capacity during the process of passaging.

Repurposing of niclosamide, an anthelmintic, by targeting ERK/MAPK signaling pathway in the experimental paradigm of autism spectrum disorders.

AIM: The current study explores niclosamide's neuroprotective potential in an animal model of autism spectrum disorder (ASD) and goes further to understand how the ERK/MAPK signaling pathway is thought to contribute to this activity. METHODS: In order to create an autism-like phenotype in rats, 4 µl of 1 M PPA was infused intracerebroventricularly. The oral treatment with niclosamide (50 and 100 mg/kg) and risperidone (1 mg/kg) (used as standard) was given from 3rd to 30th day. Between the 14th and 28th day, behavioral assessments were made for sociability, stereotypy, anxiety, depression, novelty preference, repetitive behavior, and perseverative behavior. The animals were euthanized on the 29th day, and oxidative stress markers were assessed in the brain homogenate. The levels of neuroinflammatory cytokines such as TNF-α, IL-6, NF-κB, IFN-γ and glutamate were estimated using ELISA kits. To assess the involvement of the ERK/MAPK signaling pathway, levels of Nrf2 and ERK2 were also measured. KEY FINDINGS: Niclosamide therapy significantly restored behavioral, biochemical, neurological, and molecular impairments. Hence, niclosamide could be a potential neurotherapeutic candidate for further studies for use in ASD.

Antioxidative and immunity-enhancing effects of heat-killed probiotic Enterococcus faecium KU22001 without toxin or antibiotic resistance.

This study evaluated the probiotic properties, safety profile, and antioxidative and immune system-enhancing effects of Enterococcus faecium strains isolated from human infant feces. E. faecium KU22001, E. faecium KU22002, and E. faecium KU22005 exhibited potential probiotic properties; however, to eliminate concerns about toxin production and antibiotic resistance, the E. faecium strains were heat-treated prior to experimental usage. E. faecium KU22001 showed the highest antioxidant activity and lowest reactive oxygen species production among the three strains. The immune system-enhancing effects of heat-killed E. faecium strains were evaluated using a nitric oxide assay. E. faecium KU22001 induced an increase in the mRNA expression of inducible nitric oxide synthase, cyclooxygenase-2, and proinflammatory cytokines, including tumor necrosis factor-α, interleukin-1ß, and interleukin-6 in RAW 264.7 cells. Furthermore, E. faecium KU22001 activated the mitogen-activated protein kinase pathway, which was a key regulator of the immune system. These results demonstrate the potential use of E. faecium KU22001 as a multifunctional food material.

Nano-TiO2 regulates the MAPK (ERK, P38) pathway to promote apoptosis and inhibit proliferation of human colon cells.

BACKGROUND: Nano titanium dioxides (TiO2) are widely used in drug development, food additives and packaging materials. Although several studies have demonstrated the poisonousness of TiO2 in vivo and in vitro, the underlying molecular mechanisms have not been fully revealed. METHODS: Characterization of TiO2 by FTIR, XRD, TEM and DLS. The NCM460 cell line, representing normal colon epithelial cells, was utilized as a model to assess the impact of TiO2 nanoparticles (TiO2-NPs) on cell proliferation and apoptosis. The potential molecular mechanisms underlying its toxic effects were investigated through transcriptome analysis, RT-qPCR, and western blot experiments. RESULTS: The particle size of the TiO2-NPs used is about 25 nm, which has typical characteristics of anatase. TiO2-NPs at a concentration of 30-60 µg/mL will cause changes in colon cell morphology, decreased proliferation ability, and increased number of apoptotic cells. TiO2-NPs at a concentration of 6 µg/mL did not significantly modify the transcriptome expression profile of colon cells; while 30 µg/mL had a significant effect, leading to up-regulation of gene expression. The differentially expressed genes predominantly modulate the MAPK signaling pathway, TNF signaling pathway, cytokine-cytokine receptor interaction, and other related pathways. Further, western blot analysis revealed that higher concentrations of TiO2-NPs (30-60 µg/mL) could up-regulate the expression of P53, P21 and Bax, while down-regulating the expression of Bcl2 by regulating the MAPK (ERK, P38) signaling pathway. Simultaneously, it also promoted the decreased in Fos protein expression and inhibited the phosphorylation of Jun and Fos. CONCLUSION: This study demonstrates that TiO2-NPs may exert potential toxic effects on colon cells, and therefore the intake of TiO2-NPs should be strictly regulated in practical applications.