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BACKGROUND: Cutaneous melanoma (CM) can be molecularly classified into four groups: BRAF mutant, NRAS mutant, NF1 mutant and triple wild-type (TWT) tumors lacking any of these three alterations. In the era of immune checkpoint inhibition (ICI) and targeted molecular therapy, the clinical significance of these groups remains unclear. Here, we integrate targeted DNA sequencing with comprehensive clinical follow-up in CM patients. METHODS: This was a retrospective cohort study that assessed clinical and molecular features from patients with localized or metastatic CM who underwent targeted next-generation sequencing as part of routine clinical care. A total of 254 patients with CM who had a CLIA-certified targeted sequencing assay performed on their tumor tissue were included. RESULTS: Of the 254 patients with cutaneous melanoma, 77 were BRAF mutant (30.3%), 77 were NRAS mutant (30.3%), 47 were NF1 mutant (18.5%), 33 were TWT (13.0%) and the remaining 20 (7.9%) carried mutations in multiple driver genes (BRAF/NRAS/NF1 co-mutated). The majority of this co-mutation group carried mutations in NF1 (n = 19 or 90%) with co-occurring mutations in BRAF or NRAS, often with a weaker oncogenic variant. Consistently, NF1 mutant tumors harbored numerous significantly co-altered genes compared to BRAF or NRAS mutant tumors. The majority of TWT tumors (n = 29, 87.9%) harbor a pathogenic mutation within a known Ras/MAPK signaling pathway component. Of the 154 cases with available TMB data, the median TMB was 20 (range 0.7-266 mutations/Mb). A total of 14 cases (9.1%) were classified as having a low TMB (≤5 mutations/Mb), 64 of 154 (41.6%) had an intermediate TMB (>5 and ≤20 mutations/Mb), 40 of 154 (26.0%) had a high TMB (>20 and ≤50 mutations/Mb) and 36 of 154 (23.4%) were classified as having a very high TMB (>50 mutations/Mb). NRAS mutant melanoma demonstrated significantly decreased overall survival on multivariable analysis (HR for death 2.95, 95% CI 1.13-7.69, p = 0.027, log-rank test) compared with other TCGA molecular subgroups. Of the 116 patients in our cohort with available treatment data, 36 received a combination of dual ICI with anti-CTLA4 and anti-PD1 inhibition as first-line therapy. Elevated TMB was associated with significantly longer progression-free survival following dual-agent ICI (HR 0.26, 95% CI 0.07-0.90, p = 0.033, log-rank test). CONCLUSIONS: NRAS mutation in CMs correlated with significantly worse overall survival. Elevated TMB was associated with increased progression-free survival for patients treated with a combination of dual ICI, supporting the potential utility of TMB as a predictive biomarker for ICI response in melanoma.

Background: The Food and Drug Administration has approved the Serine/threonine-protein kinase B-raf (BRAF) inhibitor and Mitogen-activated extracellular signal-regulated kinase (MEK) inhibitor combo as the first-line treatment for individuals with metastatic melanoma, although the majority of these patients exhibit primary or secondary drug resistance in the clinic. Dihydrotanshinone I (DHT) is a lipophilic compound extracted from the root of Salvia miltiorrhiza that has been linked to multiple antitumor activities. In this study, we investigated the effect of dihydrotanshinone I on the MAPK pathway inhibitor resistance of BRAF mutant malignant melanoma. Method: After treating A375, A375R, and A2058 cells with DHT or a combination of DHT and BRAF/MEK inhibitors, WB and Real-Time RT-qPCR were used to confirm the activation of the MAPK and STAT3/SOX2 pathways. CCK-8 was used to assess cell viability, while flow cytometry was used to identify apoptosis. In addition, mice were inoculated with A375 cells to establish a model of tumour formation, and various drug groups and treatment models were utilized. The diameter and weight of tumours in each group were then measured, and IHC and HE staining were used to assess the expression of two pathways and cytotoxicity, respectively. Results: This study found that DHT directly interacts with STAT3 protein and it can stop the feedback activation of the STAT3/SOX2 pathway caused by the use of MAPK pathway inhibitors. In addition, the combination of DHT and BRAF/MEK inhibitors can inhibit the proliferation and growth of BRAF mutant melanoma cells and primary and secondary drug-resistant cells. Finally, we proved that the combined therapy of DHT and BRAF/MEK inhibitors is reliable and effective at animal and cell levels. Conclusion: In BRAF mutant melanoma cells, DHT suppresses the STAT3/SOX2 signaling pathway. Combining DHT, BRAF inhibitors, and MEK inhibitors can help treat treatment-resistant BRAF mutant melanoma cells. Experimental results both in vitro and in vivo have shown that the combination of DHT and an inhibitor of the MAPK pathway is safer and more successful than using an inhibitor of the MAPK pathway alone when treating BRAF mutant melanoma. [ABSTRACT FROM AUTHOR]

The area of wound healing presents a promising field of interest for clinicians as well as the scientific community. A major concern for physicians is the rising number of elderly people suffering from diabetes, leprosy, tuberculosis and the associated chronic wounds. While traditional therapies target basic wound care, innovative strategies that accelerate wound healing are needed. V-RAF murine sarcoma viral oncogene homolog B1 (BRAF) inhibitors are anti-cancer drugs used primarily for melanoma. They also exhibit paradoxical activity, a phenomenon characterized by unintended activation of the Mitogen-Activated Protein Kinase (MAPK) signalling pathway leading to skin hyperproliferation. Studies have demonstrated that BRAF inhibitors can be repurposed to accelerate the healing of acute and chronic wounds by exploiting their paradoxical activity. This review evaluates studies on BRAF inhibitors by employing a systematic search strategy using databases such as PubMed, Scopus, Google Scholar, and Web of Science. Articles were screened based on relevance to the paradoxical activity of BRAF inhibitors, their mechanisms, and applications in wound healing. Evidence from in vitro, in vivo, and clinical studies demonstrates that BRAF inhibitors can enhance processes such as epithelialization and angiogenesis, essential for wound repair. This review summarizes the reports on the paradoxical activity of BRAF inhibitors, the predicted mechanisms behind the paradoxical activity, and their potential use in wound healing. [ABSTRACT FROM AUTHOR]

Allergic reactions occur when the immune system overreacts to generally harmless substances, leading to both acute and chronic diseases, which can be fatal. Mast cells are critical mediators of allergic reactions as they bind allergens and trigger the release of inflammatory mediators. In this study, we investigated the anti-allergic effects of the coumarin derivative 3-bromo-4-(2-hydroxyethyl)-7-methoxy-2H-chromen-2-one in rat basophilic leukemia (RBL)-2H3 cells sensitized to dinitrophenyl (DNP)-immunoglobulin E (IgE) and human serum albumin (HSA). Our results demonstrated that 3-bromo-4-(2-hydroxyethyl)-7-methoxy-2H-chromen-2-one effectively reduces the release of β-hexosaminidase and histamine, inhibiting mast cell degranulation. Additionally, 3-bromo-4-(2-hydroxyethyl)-7-methoxy-2H-chromen-2-one suppressed the production of allergy-related pro-inflammatory cytokines (IL-4, IL-13, and TNF-α) and inhibited key signaling pathways, including MAPK, AKT, and NF-κB. Furthermore, in a passive cutaneous anaphylaxis (PCA) mouse model, 3-bromo-4-(2-hydroxyethyl)-7-methoxy-2H-chromen-2-one reduced ear edema and Evans blue infiltration, further confirming its anti-allergic effects. Collectively, these findings suggest that 3-bromo-4-(2-hydroxyethyl)-7-methoxy-2H-chromen-2-one is a promising candidate for the development of anti-allergic therapeutics. [ABSTRACT FROM AUTHOR]

As cervical cancer (CC) caused more than 300,000 deaths in the world, it is urgent to identify therapeutic targets to improve survival. Though RUNX1 is overexpressed in CC, its specific role and underlying molecular mechanisms remain incompletely understood. Here we presented that RUNX1 was upregulated in CC and associated with poor prognosis. Functional studies demonstrated that RUNX1 acts as an oncogene in CC, with overexpression accelerating cell cycle progression and promoting cell proliferation. Mechanistically, RUNX1 regulates the MAPK pathway by modulating TGFB2 expression, while TGFB2 inhibition impaired MAPK pathway activation and the proliferation driven by RUNX1 overexpression. Comprehensive analyses also suggested that RUNX1 may modulate the immune microenvironment in CC through TGFB2. These findings indicate that RUNX1 promotes CC progression by activating the MAPK pathway through upregulation of TGFB2. Our study provides new insights into the role of RUNX1 in CC proliferation and suggests RUNX1 as a potential therapeutic target in CC. [ABSTRACT FROM AUTHOR]

Melanoma is an aggressive cancer that disregards both the MAPK and Hippo signaling pathways. This systematic review explores STK3 function in the Hippo pathway to regulate networks and its therapeutic potential in melanoma. From 1991 to 2024, we studied how STK3 interacts with the MAPK/ERK pathway to promote apoptosis and inhibit tumor growth. STK3 controls cell growth, apoptosis, and metastasis via the Hippo and MAPK pathways. It is a melanoma tumor suppressor. Some ways to target STK3 are to directly activate it, stop downstream effectors like YAP/TAZ from working, or use existing BRAF inhibitors together with other methods. Despite advancements, challenges in STK3 drug development persist, warranting further investigation. This review examined the role of STK3 in the development of melanoma and identified potential vulnerabilities for therapeutic intervention. [ABSTRACT FROM AUTHOR]

Background: Goutengsan (GTS) is a traditional Chinese medicine formula that can improve multiple nervous system diseases, such as methamphetamine (MA) dependence. However, the mechanism how GTS treats MA dependence remains unclear. This study was aimed to investigate the action mechanism of GTS on MA dependence using network pharmacology, in vivo / in vitro experimental validation, pharmacokinetics, and tissue distribution in the brain. Materials and Methods: The bioactive ingredients from GTS and possible targeted genes for treating MA dependence were predicted using network pharmacology. The binding of key components of GTS to the predicted proteins was studied using molecular docking, and the key components were verified by HPLC. The effects of GTS on an MA-induced model in rats and SH-SY5Y cells were studied. The regulatory effects of GTS on the expressions of predicted MAPK pathway-related proteins in rat brain tissues and SH-SY5Y cells were validated. Furthermore, the plasma exposure and brain tissue distribution of GTS ingredients for MA dependence treatment and MAPK pathway regulation were studied in mice. Results: Network pharmacology screened 53 active ingredients, and 287 potential targets of GTS, and showed the MAPK pathway was among the most relevant pathways. Molecular docking showed that key active ingredients (e.g., 6-gingerol, liquiritin and rhynchophylline) bound strongly with MAPK core targets, such as MAPK3, and MAPK8. Five compounds of GTS were detected by HPLC, including 6-gingerol, chlorogenic acid, liquiritin, 5-o-methylviscumaboloside and hesperidin. GTS had a therapeutic effect on MA-dependent rats, and reduced hippocampal CA1 damage and relative expressions of p-MAPK3/MAPK3, p-MAPK8/MAPK8 in brain tissues induced by MA. GTS counteracted aberrant alterations in cAMP, 5-TH and cellular morphology induced by MA induction and exerts therapeutic effects on MA-induced SH-SY5Y cell models. GTS also can antagonize the high expressions of MAPK-related proteins in MA-induced SH-SY5Y cells. Pharmacokinetic experiment revealed the four ingredients of GTS (e.g., chlorogenic acid, 5-o-methylviscumaboloside, hesperidin and rhynchophylline) were exposed in the plasma and brain, which demonstrates its pharmacological effect on MA dependence. Conclusion: GTS treats MA dependence by regulating the MAPK pathway via multiple bioactive ingredients. The network pharmacology, experimental validation and pharmacokinetics integrated strategy is efficient in discovering the key pharmacological mechanism of herbal formulae. [ABSTRACT FROM AUTHOR]

The functional role and molecular mechanisms of small‐nucleolar RNA host gene 14 (SNHG14) in triple‐negative breast cancer (TNBC) progression remain unclear. The expression levels of SNHG14 in breast cancer samples and cell lines were determined using real‐time quantitative polymerase chain reaction. Cell proliferation, migration, and invasion abilities were detected using MTS and transwell assays. By RNA sequencing, differentially expressed genes were identified between the SNHG14 siRNA and the negative control group. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway analyses were used to predict the targets and pathways regulated by SNHG14. pRAF, pMEK, and pERK expression were measured by western blot. The xenograft model was constructed to access the biological function of SNHG14 in vivo. A minimal patient‐derived xenograft model was established to evaluate the sensitivity to chemotherapy drugs. Our data indicated that SNHG14 expression was increased in TNBC tissues and cell lines. SNHG14 knockdown attenuated the proliferation, migration, and invasion abilities of TNBC cells both in vivo and in vitro. High SNHG14 expression was associated with lymph node metastasis and a high Ki67 index. The targets of SNHG14 were mainly enriched in the MAPK signaling pathway. pRAF, pMEK, and pERK expression were downregulated after being transfected with SNHG14 siRNA. Compared with the negative control group, the expression of CACNA1I, DUSP8, FGF17, FGFR4, FOS, PDGFRB, and DDIT3 was increased, and the expression of MKNK1 was decreased in the SNHG14 siRNA group. Minimal patient‐derived xenograft model demonstrated that knockdown of SNHG14 enhanced the sensitivity to Docetaxel in vivo. Compared with the DMSO group, the proliferation of Docetaxel‐resistant MDA‐MB‐231 cells was decreased in Dabrafenib, PD184352, and FR180204 treatment groups. SNHG14 knockdown inhibits TNBC progression by regulating the ERK/MAPK signaling pathway, which provides evidence for SNHG14 as a potential target for TNBC therapy. [ABSTRACT FROM AUTHOR]

Introduction: Breast cancer (BC) is the most prevalent malignancy among women worldwide. Lectin, mannose‐binding 2 (LMAN2) is a cargo receptor engaged in the transport and sorting of glycoproteins. Despite its ubiquity, the function and underlying mechanisms of LMAN2 in BC continue to elude understanding. Methods: Multiple databases were employed to examine the expression of LMAN2 in breast cancer. Immunohistochemistry(IHC), qRT‐PCR, and Western blot were performed to quantify LMAN2 expression in BC cell lines and clinical samples. Heat map analysis and Kaplan–Meier analysis were used to analyze the correlation between LMAN2 and clinicopathological features. SiRNAs and overexpression plasmids were transfected into two BC cells to assess the effect of LMAN2 on malignant phenotypes. Coimmunoprecipitation and immunofluorescence were used to screen for potential interacting proteins. Additionally, tumor subcutaneous xenograft mode was constructed to explore tumor chemoresistance. Result: LMAN2 expression was significantly higher in BC compared to that in matched, adjacent normal tissues, and its higher expression level was correlated with worse patient prognosis. In vitro, we found that LMAN2 functions as an oncogene, promoting BC cell proliferation, cell cycle progression, invasion, and chemoresistance while preventing apoptosis. Coimmunoprecipitation and colocalization experiments confirmed the direct binding of LMAN2 to MAPK9 in BC cells. Our investigation of signaling pathways suggested that LMAN2 is involved in the regulation of the MAPK signaling pathway, utilizing this pathway to confer cisplatin resistance. Furthermore, knockdown of LMAN2 improves the sensitivity of drug‐resistant BC cells to cisplatin (DDP) in vivo. Conclusion: LMAN2 was a novel diagnostic and prognostic biomarker for BC that promotes chemoresistance via interaction with MAPK9 and activation of the MAPK pathway. [ABSTRACT FROM AUTHOR]

Sarcocystosis is an emerging disease in yaks, and Sarcocystis infection creates a health threat to humans and animals. During a recent study, Sarcocystis infection was detected in yaks by means of morphological observation using hematoxylin and eosin, Giemsa, and acridine orange staining. The species of Sarcocystis isolated from yaks were analyzed and identified phylogenetically. To establish the best model for culturing sarcocystosis isolated from yaks in vitro, four different cell lines—PAMs, Pk15, HeLa, and Vero cells—were used. The effects of sarcocystosis isolated from yaks on the MAPK signaling pathway in Vero cells were detected using Wes automatic Western blot and RT-qPCR. The results from the phylogenetic tree indicate that the sequences of Sarcocystis obtained from yaks in this study were grouped within the Sarcocystis cruzi clade. Results also have shown that S. cruzi had a higher proliferation rate in Vero cells, suggesting that Vero cells are more suitable for the long-term culturing of S. cruzi in vitro. Results also indicate that S. cruzi infecting Vero cells could cause the activation of ERK1/2 pathway, while inhibiting the ERK1/2 pathway could suppress S. cruzi infection in Vero cells. Therefore, the study and exploration of Sarcocystis-host relationships can effectively provide certain theoretical knowledge and the basis for the treatment of clinical diseases and the development of Sarcocystis drugs. [ABSTRACT FROM AUTHOR]

BRAF V600E mutations are frequently found in histiocytic/dendritic cell neoplasms such as Erdheim-Chester disease (ECD) and Langerhans cell histiocytosis (LCH), but few reports have also described BRAF mutations in Rosai-Dorfman disease (RDD), and even these cases may predominantly represent mixed histiocytosis. BRAF mutations have been studied in histiocytic/dendritic cell neoplasms and described to be associated with increased risk of relapse and long-term consequences, but few studies have examined BRAF V600E mutation in RDD, which is recognized as a neoplasm given the high frequency of MAPK pathway alterations. Here, we report a case of BRAF V600E-mutated RDD in a patient who presented with generalized lymphadenopathy. During our evaluation of this patient, we also found expression of PD-L1 in neoplastic histiocytes. During our review period, only few cases of RDD reported to harbor BRAF mutation or were evaluated for the expression of PDL1 by neoplastic cells. Given the potential challenges in distinguishing RDD from other histiocytic/dendritic cell neoplasms, including mixed histiocytosis with similar clinicopathological manifestations, we will discuss the current state of knowledge regarding the frequency and clinical impact of BRAF V600E in RDD, as well as the role of BRAF mutations in RDD pathogenesis. Distinction of BRAF V600E mutated histiocytic/dendritic cell neoplasms requires consideration of distinctive histopathological and immunophenotypic findings in appropriate clinical and radiologic setting. Given the increasing use of BRAF inhibitors as well as checkpoint blockade inhibitors to treat a number of cancers, we will discuss the clinical implications of the presence of BRAF V600E mutation and PD-L1 expression in RDD. [ABSTRACT FROM AUTHOR]

Abstract Allergic reactions occur when the immune system overreacts to generally harmless substances, leading to both acute and chronic diseases, which can be fatal. Mast cells are critical mediators of allergic reactions as they bind allergens and trigger the release of inflammatory mediators. In this study, we investigated the anti-allergic effects of the coumarin derivative 3-bromo-4-(2-hydroxyethyl)-7-methoxy-2H-chromen-2-one in rat basophilic leukemia (RBL)-2H3 cells sensitized to dinitrophenyl (DNP)-immunoglobulin E (IgE) and human serum albumin (HSA). Our results demonstrated that 3-bromo-4-(2-hydroxyethyl)-7-methoxy-2H-chromen-2-one effectively reduces the release of β-hexosaminidase and histamine, inhibiting mast cell degranulation. Additionally, 3-bromo-4-(2-hydroxyethyl)-7-methoxy-2H-chromen-2-one suppressed the production of allergy-related pro-inflammatory cytokines (IL-4, IL-13, and TNF-α) and inhibited key signaling pathways, including MAPK, AKT, and NF-κB. Furthermore, in a passive cutaneous anaphylaxis (PCA) mouse model, 3-bromo-4-(2-hydroxyethyl)-7-methoxy-2H-chromen-2-one reduced ear edema and Evans blue infiltration, further confirming its anti-allergic effects. Collectively, these findings suggest that 3-bromo-4-(2-hydroxyethyl)-7-methoxy-2H-chromen-2-one is a promising candidate for the development of anti-allergic therapeutics.

Abstract Phosphorylation of Ser32 and Ser36 controls the degradation of IκBα is the conserved cascade mechanisms of immune core signaling pathway, NF-κB pathway in metazoans, but it’s response to abiotic stress and the presence of novel phosphorylation mechanisms in other species remain unclear. Herein, we reported a novel heat-induced phosphorylation site (Ser74) at oysters’ major IκBα, which independently regulated ubiquitination-proteasome degradation without the requirement of phosphorylation at S32 and S36. And this site was phosphorylated by ERK/MAPK pathway, which then promoted REL nuclear translocation to activate cell survival related genes to defend heat-stress. The MAPK-NF-κB cascade exhibited divergent thermal responses and adaptation patterns between two congeneric oyster species with differential habitat temperatures, indicating its involvement in shaping temperature adaptation. This study demonstrated that the existence of complex and unique phosphorylation-mediated signaling transduction mechanism in marine invertebrates, and expanded our understanding of the evolution and function of established classical pathway crosstalk mechanisms.

Abstract 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.

To observe the effects of electroacupuncture at "ST36" and "BL20" on water metabolism and intestinal mucosal permeability in colon tissue of rats with spleen deficiency and dampness-containing type ulcerative colitis (SDDR-UC) and to investigate its mechanism of action. 60 SD rats were randomly divided into 4 groups: normal group, model group, non-meridian non- acupuncture group and non-meridian non-acupuncture group, electroacupuncture group and non-meridian and non-acupoint group. The normal group was fed normally, and the other three groups were replicated the SDDR-UC model using the method of combining disease and evidence. In the electroacupuncture group, the "ST36" and "BL20" were selected, and in the non-meridian and non-acupoint group, the non-meridian and non-acupoint points were selected, and the intervention process lasted 20 min for 14 d. The general conditions of the rats were observed, and the body weights, grasping strengths, changes in the lengths of the colon, and the scores of the colonic mucous membrane damage index (CMDI) scores were measured. Hematoxylin-eosin staining (HE) method was used to observe the histopathological morphology of colon. Western blot (WB) method was used to detect the phosphorylation of mitogen- activated protein kinase (p38MAPK), extracellular signal-regulated kinase ½ (ERK½ MAPK), and aquaporin protein 4 (AQP4), immunohistochemistry (IHC) for ZO-1 and Occludin. Quantitative real-time PCR (RT-qPCR) for AQP4. Quantitative real-time PCR (RT-qPCR) method was used to detect AQP4 mRNA expression. The results show that compared with the normal group, rats in the model group and the non-transthoracic non-cavity group show decreased body weight, grasping power, colon length and increased CMDI score (P<0.01). Colon tissues show pathological morphological manifestations such as inflammatory cell infiltration and crypt abscess, with decreased expression of AQP4, ZO-1 and Occludin (P<0.01), and phosphorylation of p38MAPK, ERK½ MAPK elevated (P<0.05). Compared with the model group, rats in the electroacupuncture group show elevated body weight, grip strength, colon length, decreased CMDI score (P<0.01), reduced inflammatory infiltration of colon tissue, relatively regular crypt margins, significantly higher expression levels of AQP4, ZO-1, Occludin (P<0.01), and phosphorylation of p38MAPK, ERK½ MAPK proteins significantly decrease (P<0.05). Electroacupuncture of "ST36" and "BL20" may play an important role in improving water metabolism and intestinal mucosal permeability in SDDR-UC rats by inhibiting the phosphorylation of p38MAPK, ERK½ MAPK and up-regulating the expression of AQP4, ZO-1 and Occludin. [ABSTRACT FROM AUTHOR]

Introduction: Verticillium dahliae causes a serious decline in cotton yield and quality, posing a serious threat to the cotton industry. However, the mechanism of resistance to V. dahliae in cotton is still unclear, which limits the breeding of resistant cultivars. Methods: To analyze the defense mechanisms of cotton in response to V. dahliae infection, we compared the defense responses of two upland cotton cultivars from Xinjiang (JK1775, resistant; Z8,susceptible) using transcriptome sequencing at different infection stages. Results: The results revealed a significant differential expression of genes in the two cotton cultivars post V. dahliae infection, with the number of DEGs in JK1775 being higher than that in Z8 at different infection stages of V. dahliae. Interestingly, the DEGs of both JK1775 and Z8 were enriched in the MAPK signaling pathway in the early and late stages of infection. Importantly, the upregulated DEGs in both cultivars were significantly enriched in all stages of the phenylpropanoid metabolic pathway. Some of these DEGs were involved in the regulation of lignin and coumarin biosynthesis, which may be one of the key factors contributing to the resistance of upland cotton cultivars to V. dahliae in Xinjiang. Lignin staining experiments further showed that the lignin content increased in both resistant and susceptible varieties after inoculation with V. dahliae. Discussion: This study not only provides insights into the molecular mechanisms of resistance to Verticillium wilt in Xinjiang upland cotton but also offers important candidate gene resources for molecular breeding of resistance to Verticillium wilt in cotton. [ABSTRACT FROM AUTHOR]

Phosphorylation of Ser32 and Ser36 controls the degradation of IκBα is the conserved cascade mechanisms of immune core signaling pathway, NF-κB pathway in metazoans, but it's response to abiotic stress and the presence of novel phosphorylation mechanisms in other species remain unclear. Herein, we reported a novel heat-induced phosphorylation site (Ser74) at oysters' major IκBα, which independently regulated ubiquitination-proteasome degradation without the requirement of phosphorylation at S32 and S36. And this site was phosphorylated by ERK/MAPK pathway, which then promoted REL nuclear translocation to activate cell survival related genes to defend heat-stress. The MAPK-NF-κB cascade exhibited divergent thermal responses and adaptation patterns between two congeneric oyster species with differential habitat temperatures, indicating its involvement in shaping temperature adaptation. This study demonstrated that the existence of complex and unique phosphorylation-mediated signaling transduction mechanism in marine invertebrates, and expanded our understanding of the evolution and function of established classical pathway crosstalk mechanisms. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is characterized by cognitive decline and the accumulation of amyloid-beta plaques and hyperphosphorylated tau protein. The role of tau lactylation at the K677 site in AD progression is not well understood. This study explores how tau K677 lactylation affects ferritinophagy, ferroptosis, and their functions in an AD mouse model. Results show that mutating the K677 site to R reduces tau lactylation and inhibits ferroptosis by regulating iron metabolism factors like NCOA4 and FTH1.Tau-mutant mice showed improved memory and learning skills compared to wild-type mice. The mutation also reduced neuronal damage and was associated with decreased tau lactylation at the K677 site, regardless of phosphorylated tau levels. Gene set enrichment analysis showed that lactylation at this site was linked to the MAPK pathway, which was important for ferritinophagy in AD mice. In summary, our research indicates that the K677 mutation in tau protein may protect against AD by influencing ferritinophagy and ferroptosis through MAPK signaling pathways. Understanding these modifications in tau could lead to new treatments for AD. [Display omitted] • The K677 mutation in the tau protein may confer a protective effect against Alzheimer's disease. • The results show that replacing the K677 residue with arginine reduces tau lactylation and inhibits ferroptosis. • Decreased neuronal damage was linked to reduced tau lactylation at K677, independent of phosphorylated tau levels. [ABSTRACT FROM AUTHOR]

Background: Activating BRAF gene alterations are central to melanocytic tumor pathogenesis. A small, emerging subset of melanocytic tumors driven by BRAF fusions has distinct therapeutic implications and has been described to have Spitzoid morphology patterns. However, such morphological patterns do not encompass all cases, and little is known about the functional molecular events. Materials and Methods: We conducted a retrospective search through our molecular archives to identify melanocytic tumors with BRAF fusions. We reviewed clinical, histopathological, and genomic features. We further explored transcriptomic and protein‐level findings. Results: Histopathologic patterns varied, with many cases without a distinctive pattern. We identified novel and diverse BRAF gene fusion partners. Differential transcriptomic analysis between low‐risk BRAF fusion tumors and reference BRAF V600E tumors showed no differentially expressed genes. However, quantitatively stronger MAPK pathway activation of BRAF fusion tumors over BRAF V600E tumors was demonstrated by statistically significant stronger staining of p‐ERK immunohistochemistry. Gene‐specific RNA analysis shows comparable BRAF transcript levels between the two groups. Discussion and Conclusion: The quantitatively stronger activation of the MAPK pathway of BRAF fusion tumors, instead of qualitatively different transcriptomes, may account for the morphology difference from conventional BRAF V600E tumors. BRAF fusions likely act through dysregulated protein function rather than RNA upregulation related to the characteristics of the fusion partners. [ABSTRACT FROM AUTHOR]

The active ingredients of plants were screened by molecular docking technology and the result were verified. According to the verification results of molecular docking, the five active ingredients were combined in equal proportions to form a compound drug. In the HaCaT photoaging model, the effects of the compound drug on antioxidant and senescence-associated secretory phenotype (SASP) factors of the NF-κB and MAPK pathways were studied via SOD and MDA kits, DCFH-DA fluorescent probes and ELISA. In the skin photoaging model, the effects of the compound drug on antioxidants and the SASP factors of the NF-κB and MAPK pathways were studied via SOD, MDA, and CAT kits and ELISA. The results revealed that the compound drug increased SOD activity, decreased the MDA content and intracellular ROS, inhibited IL-6 in the NF-κB pathway, and inhibited MMP-1 and collagen I in the MAPK pathway. The results of HE, Masson and Victoria blue skin staining revealed that the compound drug inhibited abnormal thickening of the epidermis, abnormal breaking and accumulation of collagen fibers and elastic fibers, and maintained their orderly arrangement. Moreover, the results revealed that the compound drug increased SOD, CAT and collagen I, and reduced the MDA content, the SASP factors IL-6 and TNF-α of the NF-κB pathway, and the SASP factors MMP-1 of the MAPK pathway. The above results indicate that the active ingredients of the compound drug screened by molecular docking have the potential to reduce skin photoaging. [ABSTRACT FROM AUTHOR]

Introduction: Zhachong Shisanwei Pill (ZSP) is a classical Mongolian formula that combines 13 types of Chinese medicinal materials and has been used for treating ischemic stroke (IS) for centuries. However, the underlying molecular mechanisms have yet to be fully elucidated. The aim of this study is to explore potential mechanism of ZSP on nerve cells in cerebral ischemic injury. Methods: To simulate the pathological process of oxidative stress following IS, an injury model using PC12 cells was induced with hydrogen peroxide (H2O2). Afterward, PC12 cells were treated with ZSP medicated serum at low, medium, and high doses. Various assays were conducted to assess cell viability and oxidative stress indicators, including lactate dehydrogenase (LDH), malondialdehyde (MDA), superoxide dismutase (SOD), catalase (CAT), reactive oxygen species (ROS), and mitochondrial membrane potential (MMP). Cell apoptosis was evaluated through morphological assessment and flow cytometry. Additionally, the expression levels of apoptosis-related proteins (Bcl-2, Bax, Caspase-9, Caspase-3, PARP) and signaling pathway proteins (JNK, phosphorylated JNK, ERK, phosphorylated ERK, p38, and phosphorylated p38) were measured using automated Western blotting. Results: Our findings indicate that ZSP medicated serum preconditioning improves the condition of PC12 cells injured by H2O2. Specifically, it increased cell survival rates and reduced LDH release. Additionally, ZSP treatment decreased ROS levels and MDA content, while enhancing the activity of SOD and CAT in the injured PC12 cells. ZSP also reversed the depolarization of mitochondrial membrane potential and protected cells from apoptosis by modulating the expression of apoptosis-related proteins, including Bcl-2, Bax, Caspase-9, Caspase-3, and PARP. Furthermore, the overactivation of the MAPK signaling pathway due to H2O2-induced injury was inhibited, as evidenced by the downregulation of phosphorylated JNK, ERK, and p38 levels. Discussion: Mongolian medicine ZSP demonstrates protective effects against H2O2-induced oxidative stress and apoptosis in PC12 cells. The underlying mechanism may involve the inhibition of the MAPK signaling pathway, enhancement of antioxidant enzyme activity, reduction of intracellular peroxidation levels, and suppression of intrinsic apoptosis pathways. [ABSTRACT FROM AUTHOR]

Introduction: The MAPK genes are critical for gonadal differentiation in eutherian mammals, but their role in marsupial mammals is unknown. Characterisation and phylogenetic analyses of the tammar wallaby MAPK genes show these genes are highly conserved with their orthologues in mammalian and non-mammalian species. Methods: We cultured sexually indifferent tammar gonads in the presence of p38α and -β MAPK inhibitor, SB202190. Results: SB202190 downregulated SOX9 and AMH levels in XY-treated gonads when compared to controls, similar to the effects of oestrogen on the MAPK pathway in males. In contrast, XX gonads treated with the SB202190 inhibitor showed no change in mRNA expression between the control and treated gonads for any of the markers tested. Conclusions: This study confirms that components of the MAPK pathway drive testis differentiation via the key downstream genes SOX9 and AMH in marsupials as is observed in eutherian mammals. [ABSTRACT FROM AUTHOR]

Introduction: Verticillium dahliae causes a serious decline in cotton yield and quality, posing a serious threat to the cotton industry. However, the mechanism of resistance to V. dahliae in cotton is still unclear, which limits the breeding of resistant cultivars. Methods: To analyze the defense mechanisms of cotton in response to V. dahliae infection, we compared the defense responses of two upland cotton cultivars from Xinjiang (JK1775, resistant; Z8,susceptible) using transcriptome sequencing at different infection stages. Results: The results revealed a significant differential expression of genes in the two cotton cultivars post V. dahliae infection, with the number of DEGs in JK1775 being higher than that in Z8 at different infection stages of V. dahliae. Interestingly, the DEGs of both JK1775 and Z8 were enriched in the MAPK signaling pathway in the early and late stages of infection. Importantly, the upregulated DEGs in both cultivars were significantly enriched in all stages of the phenylpropanoid metabolic pathway. Some of these DEGs were involved in the regulation of lignin and coumarin biosynthesis, which may be one of the key factors contributing to the resistance of upland cotton cultivars to V. dahliae in Xinjiang. Lignin staining experiments further showed that the lignin content increased in both resistant and susceptible varieties after inoculation with V. dahliae. Discussion: This study not only provides insights into the molecular mechanisms of resistance to Verticillium wilt in Xinjiang upland cotton but also offers important candidate gene resources for molecular breeding of resistance to Verticillium wilt in cotton. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

The World Health Organization's 5th edition classification of Central Nervous System (CNS) tumors differentiates diffuse gliomas into adult and pediatric variants. Pediatric-type diffuse low-grade gliomas (pDLGGs) are distinct from adult gliomas in their molecular characteristics, biological behavior, clinical progression, and prognosis. Various molecular alterations identified in pDLGGs are crucial for treatment. There are four distinct entities of pDLGGs. All four of these tumor subtypes exhibit diffuse growth and share overlapping histopathological and imaging characteristics. Molecular analysis is essential for differentiating these lesions. [ABSTRACT FROM AUTHOR]

Understanding the molecular and cellular mechanisms driving pediatric low-grade glioma (pLGG)—the most prevalent brain tumor in children—is essential for the identification and evaluation of novel effective treatments. This review explores the intricate relationship between the mitogen-activated protein kinase (MAPK) pathway, oncogene-induced senescence (OIS), the senescence-associated secretory phenotype (SASP), and the tumor microenvironment (TME), integrating these elements into a unified framework termed the MAPK/OIS/SASP/TME (MOST) axis. This integrated approach seeks to deepen our understanding of pLGG and improve therapeutic interventions by examining the MOST axis' critical influence on tumor biology and response to treatment. In this review, we assess the axis' capacity to integrate various biological processes, highlighting new targets for pLGG treatment, and the need for characterized in vitro and in vivo preclinical models recapitulating pLGG's complexity to test targets. The review underscores the need for a comprehensive strategy in pLGG research, positioning the MOST axis as a pivotal approach in understanding pLGG. This comprehensive framework will open promising avenues for patient care and guide future research towards inventive treatment options. [ABSTRACT FROM AUTHOR]