Lung cancer (LC) is a highly invasive malignancy and the leading cause of cancer-related deaths, with non-small cell lung cancer (NSCLC) as its most prevalent histological subtype. Despite all breakthroughs achieved in drug development, the prognosis of NSCLC remains poor. The mitogen-activated protein kinase signaling cascade (MAPKC) is a complex network of interacting molecules that can drive oncogenesis, cancer progression, and drug resistance when dysregulated. Over the past decades, MAPKC components have been used to design MAPKC inhibitors (MAPKCIs), which have shown varying efficacy in treating NSCLC. Thus, recent studies support the potential clinical use of MAPKCIs, especially in combination with other therapeutic approaches. This article provides an overview of the MAPKC and its inhibitors in the clinical management of NSCLC. It addresses the gaps in the current literature on different combinations of selective inhibitors while suggesting two particular therapy approaches to be researched in NSCLC: parallel and aggregate targeting of the MAPKC. This work also provides suggestions that could serve as a potential guideline to aid future research in MAPKCIs to optimize clinical outcomes in NSCLC.

UNASSIGNED: Dual specificity protein phosphatase 6 (DUSP6) was recently identified as a key hub gene in a causal VGF gene network that regulates late-onset Alzheimer\'s disease (AD). Importantly, decreased DUSP6 levels are correlated with an increased clinical dementia rating (CDR) in human subjects, and DUSP6 levels are additionally decreased in the 5xFAD amyloidopathy mouse model.
UNASSIGNED: To investigate the role of DUSP6 in AD, we stereotactically injected AAV5-DUSP6 or AAV5-GFP (control) into the dorsal hippocampus (dHc) of both female and male 5xFAD or wild type mice, to induce overexpression of DUSP6 or GFP.
UNASSIGNED: Barnes maze testing indicated that DUSP6 overexpression in the dHc of 5xFAD mice improved memory deficits and was associated with reduced amyloid plaque load, Aß1-40 and Aß1-42 levels, and amyloid precursor protein processing enzyme BACE1, in male but not in female mice. Microglial activation, which was increased in 5xFAD mice, was significantly reduced by dHc DUSP6 overexpression in both males and females, as was the number of \"microglial clusters,\" which correlated with reduced amyloid plaque size. Transcriptomic profiling of female 5xFAD hippocampus revealed upregulation of inflammatory and extracellular signal-regulated kinase pathways, while dHc DUSP6 overexpression in female 5xFAD mice downregulated a subset of genes in these pathways. Gene ontology analysis of DEGs (p < 0.05) identified a greater number of synaptic pathways that were regulated by DUSP6 overexpression in male compared to female 5xFAD.
UNASSIGNED: In summary, DUSP6 overexpression in dHc reduced amyloid deposition and memory deficits in male but not female 5xFAD mice, whereas reduced neuroinflammation and microglial activation were observed in both males and females, suggesting that DUSP6-induced reduction of microglial activation did not contribute to sex-dependent improvement in memory deficits. The sex-dependent regulation of synaptic pathways by DUSP6 overexpression, however, correlated with the improvement of spatial memory deficits in male but not female 5xFAD.

Mitogen-activated protein kinase (MAPK) phosphatases (MKPs) constitute members of the dual-specificity family of protein phosphatases that dephosphorylate the MAPKs. MKP-5 dephosphorylates the stress-responsive MAPKs, p38 MAPK and JNK, and has been shown to promote tissue fibrosis. Here, we provide insight into how MKP-5 regulates the transforming growth factor-β (TGF-β) pathway, a well-established driver of fibrosis. We show that MKP-5-deficient fibroblasts in response to TGF-β are impaired in SMAD2 phosphorylation at canonical and non-canonical sites, nuclear translocation, and transcriptional activation of fibrogenic genes. Consistent with this, pharmacological inhibition of MKP-5 is sufficient to block TGF-β signaling, and that this regulation occurs through a JNK-dependent pathway. By utilizing RNA sequencing and transcriptomic analysis, we identify TGF-β signaling activators regulated by MKP-5 in a JNK-dependent manner, providing mechanistic insight into how MKP-5 promotes TGF-β signaling. This study elucidates a novel mechanism whereby MKP-5-mediated JNK inactivation is required for TGF-β signaling and provides insight into the role of MKP-5 in fibrosis.

OBJECTIVE: To detect the expression of autophagy components, p38 MAPK (p38) and phosphorylated forkhead box transcription factor O-1 (pFoxO1) in pulmonary vascular endothelial cells of chronic thromboembolic pulmonary hypertension (CTEPH) rats and to investigate the possible mechanism through which tissue factor (TF) regulates autophagy.
METHODS: Pulmonary artery endothelial cells (PAECs) were isolated from CTEPH (CTEPH group) and healthy rats (control group (ctrl group)) which were cocultured with TF at different time points including 12 h, 24 h, 48 h and doses including 0 nM,10 nM, 100 nM, 1µM, 10µM, 100µM and cocultured with TFPI at 48 h including 0 nM, 2.5 nM, 5 nM. The expression of forkhead box transcription factor O-1 (FoxO1), pFoxO1, p38, Beclin-1 and LC3B in PAECs was measured. Coimmunoprecipitation (co-IP) assays were used to detect the interaction between FoxO1 and LC3.
RESULTS: The protein expression of p-FoxO1/FoxO1 was significantly lower in the CTEPH groups (cocultured with TF from 0 nM to 100 µM) than in the ctrl group at 12 h, 24 h, and 48 h (P < 0.05) and was significantly lower in the CTEPH groups (cocultured with TFPI from 0 nM to 5 nM) than in the ctrl group at 48 h (P < 0.05). The protein expression of p38 in the CTEPH groups treated with 0 nM, 10 nM, 100 nM or 1 µM TF for 48 h significantly increased than ctrl groups (P < 0.05) and was significantly increased in the CTEPH groups (cocultured with TFPI concentration from 0 nM to 5 nM) than in the ctrl group at 48 h (P < 0.05). The protein expression of Beclin1 at the same concentration (cocultured with TF from 0 nM to 100 µM) was significantly lower in the CTEPH groups than ctrl groups after 24 h and 48 h (P < 0.05) and was significantly decreased in the CTEPH groups (cocultured with TFPI concentration from 2.5 nM to 5 nM) than in the ctrl group at 48 h (P < 0.05). The protein expression of LC3-II/LC3-I at the same concentration (cocultured with TF 0 nM, 1 µM, 10 µM, and 100 µM) was significantly lower in the CTEPH than in the ctrl groups after 12 h (P < 0.05) and was significantly lower in the CTEPH groups (cocultured with TFPI concentration from 0 nM to 5 nM) than in the ctrl group at 48 h (P < 0.05). There were close interactions between FoxO1 and LC3 in the control and CTEPH groups at different doses and time points.
CONCLUSIONS: The autophagic activity of PAECs from CTEPH rats was disrupted. TF, FoxO1 and p38 MAPK play key roles in the autophagic activity of PAECs. TF may regulate autophagic activity through the p38 MAPK-FoxO1 pathway.

Chronic inflammation contributes to a number of diseases. Therefore, control of the inflammatory response is an important therapeutic goal. To identify novel anti-inflammatory compounds, we synthesized and screened a library of 80 pyrazolo[1,5-a]quinazoline compounds and related derivatives. Screening of these compounds for their ability to inhibit lipopolysaccharide (LPS)-induced nuclear factor κB (NF-κB) transcriptional activity in human THP-1Blue monocytic cells identified 13 compounds with anti-inflammatory activity (IC50 < 50 µM) in a cell-based test system, with two of the most potent being compounds 13i (5-[(4-sulfamoylbenzyl)oxy]pyrazolo[1,5-a]quinazoline-3-carboxamide) and 16 (5-[(4-(methylsulfinyl)benzyloxy]pyrazolo[1,5-a]quinazoline-3-carboxamide). Pharmacophore mapping of potential targets predicted that 13i and 16 may be ligands for three mitogen-activated protein kinases (MAPKs), including extracellular signal-regulated kinase 2 (ERK2), p38α, and c-Jun N-terminal kinase 3 (JNK3). Indeed, molecular modeling supported that these compounds could effectively bind to ERK2, p38α, and JNK3, with the highest complementarity to JNK3. The key residues of JNK3 important for this binding were identified. Moreover, compounds 13i and 16 exhibited micromolar binding affinities for JNK1, JNK2, and JNK3. Thus, our results demonstrate the potential for developing lead anti-inflammatory drugs based on the pyrazolo[1,5-a]quinazoline and related scaffolds that are targeted toward MAPKs.

BACKGROUND: Neurotrophins are essential factors for neural growth and function; they play a crucial role in neurodegenerative diseases where their expression levels are altered. Our previous research has demonstrated changes in synaptic plasticity and neurotrophin expression levels in a pharmacological model of Huntington\'s disease induced by 3-nitropropionic acid (3-NP). In the 3- NP-induced HD model, corticostriatal Long Term Depression (LTD) was impaired, but neurotrophin-3 (NT-3) restored striatal LTD. This study delves into the NT-3-induced signaling pathways involved in modulating and restoring striatal synaptic plasticity in cerebral slices from 3-NPinduced striatal degeneration in mice in vivo.
METHODS: Phospholipase C (PLC), phosphatidylinositol-3-kinase (PI3K), and mitogen-activated protein kinase (MEK)/extracellular signal-regulated kinase (ERK) pathways activated by NT-3 were analyzed by means of field electrophysiological recordings in brain slices from control and 3-NP treated in the presence of specific inhibitors of the signaling pathways.
RESULTS: Using specific inhibitors, PLC, PI3K, and MEK/ERK signaling pathways contribute to NT3-mediated plasticity modulation in striatal tissue slices recorded from control animals. However, in the neurodegeneration model induced by 3-NP, the recovery of striatal LTD induced by NT-3 was prevented only by the PLC inhibitor. Moreover, the PLC signaling pathway appeared to trigger downstream activation of the endocannabinoid system, evidenced by AM 251, an inhibitor of the CB1 receptor, also hindered NT-3 plasticity recovery.
CONCLUSIONS: Our finding highlights the specific involvement of the PLC pathway in the neuroprotective effects of NT-3 in mitigating synaptic dysfunction under neurodegenerative conditions.

The complement system is an evolutionarily conserved arm of innate immunity, which forms one of the first lines of host response to pathogens and assists in the clearance of debris. A deficiency in key activators/amplifiers of the cascade results in recurrent infection, whereas a deficiency in regulating the cascade predisposes to accelerated organ failure, as observed in colitis and transplant rejection. Given that there are over 60 proteins in this system, it has become an attractive target for immunotherapeutics, many of which are United States Food and Drug Administration-approved or in multiple phase 2/3 clinical trials. Moreover, there have been key advances in the last few years in the understanding of how the complement system operates locally in tissues, independent of its activities in circulation. In this review, we will put into perspective the abovementioned discoveries to optimally modulate the spatiotemporal nature of complement activation and regulation at mucosal surfaces.

The maintenance of normal vascular function and homeostasis is largely dependent on the signaling mechanisms that occur within and between cells of the vasculature. TGF-β-activated kinase 1 (TAK1), a multifaceted signaling molecule, has been shown to play critical roles in various tissue types. Although the precise function of TAK1 in the vasculature remains largely unknown, emerging evidence suggests its potential involvement in both physiological and pathological processes. A comprehensive search strategy was employed to identify relevant studies, PubMed, Web of Science, and other relevant databases were systematically searched using keywords related to TAK1, TABs and MAP3K7.In this review, we discussed the role of TAK1 in vascular signaling, with a focus on its function, activation, and related signaling pathways. Specifically, we highlight the TA1-TABs complex is a key factor, regulating vascular smooth muscle cells (VSMCs) and endothelial cells (ECs) involved in the processes of inflammation, vascular proliferation and angiogenesis. This mini review aims to elucidate the evidence supporting TAK1 signaling in the vasculature, in order to better comprehend its beneficial and potential harmful effects upon TAK1 activation in vascular tissue.

This study investigated the anti-inflammatory effects of Pediococcus acidilactici strains isolated from fermented vegetables on lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophages. In addition, the probiotic characteristics and safety were evaluated. Our results show that Ped. acidilactici strains possess high survivability in simulated gastrointestinal environments and strong attachment to HT-29 cells. All Ped. acidilactici strains exhibited γ-hemolysis and resistance to gentamicin, kanamycin, and streptomycin, a characteristic commonly observed in lactic acid bacteria. Treatment with Ped. acidilactici inhibited the expression of inducible nitric oxide synthase and cyclooxygenase-2, leading to a subsequent reduction in nitric oxide and prostaglandin E2 production. Furthermore, the strains downregulated interleukin (IL)-1β and IL-6 mRNA levels, ultimately suppressing their production. We demonstrated that Ped. acidilactici strains could modulate the activation of nuclear factor-κB, mitogen-activated protein kinase, and activator protein-1, which are known to regulate inflammatory responses. Consequently, the anti-inflammatory properties of Ped. acidilactici strains in this study support their potential application as therapeutic agents for inflammatory diseases, providing molecular insights into next-generation functional probiotic products.

Cadmium (Cd), as a non-essential and toxic heavy metal in plants, has deleterious effects on plant physiological and biochemical processes. Nitric oxide (NO) is one of the most important signaling molecules for plants to response diverse stresses. Here, we found that Cd-induced programmed cell death (PCD) was accompanied by NO bursts, which exacerbated cell death when NO was removed and vice versa. Proteomic analysis of S-nitrosylated proteins showed that the differential proteins in Cd-induced PCD and in NO-alleviated PCD mainly exist together in carbohydrate metabolism and amino acid metabolism, while some of the differential proteins exist alone in metabolism of cofactors and vitamins and lipid metabolism. Meanwhile, S-nitrosylation of proteins in porphyrin and chlorophyll metabolism and starch and sucrose metabolism could explain the leaf chlorosis induced by PCD. Moreover, protein transport protein SEC23, ubiquitinyl hydrolase 1 and pathogenesis-related protein 1 were identified to be S-nitrosylated in vivo, and their expressions were increased in Cd-induced PCD while decreased in NO treatment. Similar results were obtained in tomato seedlings with higher S-nitrosylation. Taken together, our results indicate that NO might be involved in the regulation of Cd-induced PCD through protein S-nitrosylation, especially proteins involved in PCD response.