MAPK Signaling Research Articles

Effect of Perilla frutescens polyphenols against tight junction alterations and intestinal inflammation: a Caco-2/macrophage co-culture model-based study integrated with network pharmacology

The intestinal barrier plays important roles in the uptake of nutrients and prevention of harmful pathogens. However, intestinal inflammation causes barrier dysfunction, which may contribute to inflammatory bowel disease (IBD). Polyphenols from Perilla frutescens (L.) Britt. exhibit various bioactivities, though their protective effect on the intestinal barrier remains unclear. To address this, the study investigated the effect of Perilla frutescens (L.) Britt. polyphenols (PFP) against tight junction alterations and intestinal inflammation using an intestinal-like Caco-2/macrophage co-culture model. LC-MS/MS analysis identified 15 polyphenols in the PFP extract. Furthermore, PFP were transported across the apical Caco-2 monolayer, with apigenin, genistin, syringic acid and cinnamic acid showing relatively high transport rates (> 70%). The lipopolysaccharide (LPS)-induced tight junction alterations, evaluated by trans-epithelial electrical resistance (TEER) analysis, qPCR, and immunofluorescence assay, were significantly restored by medium and high doses of PFP (P < 0.05). In addition, network pharmacology analysis demonstrated that the core targets of PFP for intestinal inflammation were mostly located in the MAPK and NF-κB signaling pathways. The expression levels of the key proteins in these pathways were further validated by qPCR and western blot analyses. Overall, PFP exhibits great potential as a novel functional food component for treating intestinal inflammation.

Reactivation of MAPK-SOX2 pathway confers ferroptosis sensitivity in KRASG12C inhibitor resistant tumors

The clinical success of KRASG12C inhibitors (G12Ci) including AMG510 and MRTX849 is limited by the eventual development of acquired resistance. A novel and effective treatment to revert or target this resistance is urgent. To this end, we established G12Ci (AMG510 and MRTX849) resistant KRASG12C mutant cancer cell lines and screened with an FDA-approved drug library. We found the ferroptosis inducers including sorafenib and lapatinib stood out with an obvious growth inhibition in the G12Ci resistant cells. Mechanistically, the G12Ci resistant cells exhibited reactivation of MAPK signaling, which repressed SOX2-mediated expression of cystine transporter SLC7A11 and iron exporter SLC40A1. Consequently, the low intracellular GSH level but high iron content engendered hypersensitivity of these resistant tumors to ferroptosis inducers. Ectopic overexpression of SOX2 or SLC7A11 and SLC40A1 conferred resistance to ferroptosis in the G12Ci resistant cells. Ferroptosis induced by sulfasalazine (SAS) achieved obvious inhibition on the tumor growth of xenografts derived from AMG510-resistant KRASG12C-mutant cells. Collectively, our results suggest a novel therapeutic strategy to treat patients bearing G12Ci resistant cancers with ferroptosis inducers.

Protective effect of Apelin-13 on D-glutamic acid-induced excitotoxicity in SH-SY5Y cell line: An in-vitro study

Excitotoxicity, resulting from excessive accumulation of glutamate in the extracellular space, leads to neuronal cell death. This study investigates the protective effects of Apelin-13 on D-Glutamic acid-induced excitotoxicity in SH-SY5Y human neuroblastoma cells, an in-vitro model for neurodegenerative diseases. Unlike the commonly studied L-glutamic acid, this research focuses on D-Glutamic acid to understand its specific impacts. SH-SY5Y cells were treated with varying concentrations of D-Glutamic acid and Apelin-13, followed by analyses at 12 and 24 h to evaluate cell viability, oxidative stress markers, and inflammatory cytokine levels. Cell viability assays revealed significant cytotoxic effects of D-Glutamic acid at doses of 10 mM and 20 mM, reducing viability by over 50 %. However, Apelin-13 treatment mitigated these effects, especially at 2 μg/mL, enhancing cell viability and reducing inflammatory cytokine levels (IL-1β and TNF-α). Apelin-13 also increased anti-inflammatory cytokine levels (IL-10 and TGF-β1) and brain-derived neurotrophic factor (BDNF), indicating its neuroprotective role. Oxidative stress markers, including ROS, AGE, AOPP, DT, T-SH, were significantly elevated by D-Glutamic acid but effectively reduced by Apelin-13. The neuroprotective mechanisms of Apelin-13 involve modulation of cAMP/PKA and MAPK signaling pathways, enhancing BDNF synthesis and suppressing oxidative stress and inflammatory responses. This study is the first to demonstrate the effects of D-Glutamic acid on SH-SY5Y cells. It highlights Apelin-13's potential as a therapeutic agent against excitotoxicity-induced neuronal damage, emphasizing its ability to modulate key molecular pathways involved in inflammation and oxidative stress. Further in-vivo studies are warranted to explore the long-term neuroprotective effects of Apelin-13 in treating neurodegenerative diseases.

Decoding the role of HIF-1α in immunoregulation in Litopenaeus vannamei under hypoxic stress

Hypoxia poses a significant challenge to aquatic organisms, especially Litopenaeus vannamei (L. vannamei), which play a vital role in the global aquaculture industry. Hypoxia-inducible factor 1α (HIF-1α) is a pivotal regulator of the organism's adaptation to hypoxic conditions. To understand of how HIF-1α affects the immunity of L. vannamei under hypoxic conditions, we conducted a thorough study involving various approaches. These included observing tissue morphology, analyzing the expression of immune-related genes, assessing the activities of immune-related enzymes, and exploring immune-related pathways. Our study revealed that RNA interference (RNAi)-mediated knockdown of HIF-1α markedly reduced HIF-1α expression in the gill (75 to 95%), whereas the reduction ranged from 2 to 43% in the hepatopancreas. Knockdown of HIF-1α resulted in increased damage to both gill and hepatopancreatic tissues in hypoxic conditions. Additionally, immune-related genes, including Astakine (AST), Hemocyanin (HC), and Ferritin (FT), as well as immune-related enzymes such as Acid Phosphatase (ACP), Alkaline Phosphatase (AKP), and Phenoloxidase (PO), exhibited intricate regulatory patterns in response to hypoxia stress following the knockdown of HIF-1α. Transcriptome analysis revealed that HIF-1α knockdown significantly impacts multiple signaling pathways, including the JAK-STAT signaling pathway, Th17 cell differentiation pathways, PI3K-Akt signaling pathway, ErbB signaling pathway, MAPK signaling pathway, chemokine signaling pathway, ribosomal pathways, apoptosis, lysosomes and arachidonic acid metabolism. These alterations disrupt the organism's immune balance and interfere with normal metabolic processes, potentially leading to various immune-related diseases. We speculate that the weakened immune response resulting from HIF-1 inhibition is due to the reduced metabolic capacity, and the existence of a direct regulatory relationship between them requires further exploration. This study greatly advances our understanding of the vital role that HIF-1α plays in regulating immune responses in shrimp under hypoxic conditions, thereby deepening our comprehension of this critical biological mechanism.

Genome sequencing and functional analysis of potential Trichoderma species for controlling Pythium schmitthenneri-Induced root rot in olive trees

Root rot disease caused by Pythium schmitthenneri is a significant challenge in olive (Olea europaea L.) cultivation. Due to the limitations of chemical control, this study explores the potential of Trichoderma species as a sustainable alternative with an overview in the genetic properties involved in it. Eight Trichoderma isolates were obtained from olive roots and identified using rDNA internal transcribed spacer (ITS) sequences, revealing four species: T. harzianum, T. longibrachiatum, T. virens, and T. viride. Among these, T. harzianum T-BM6 and T. virens T-KH4, showed 81.4 and 78.77 % inhibition rates of pathogen growth, respectively, in vitro. Greenhouse trials demonstrated that these isolates reduced disease severity to 18.75 % for T-BM6 and 31.25 % for T-KH4. All isolates produced cellulase, with T-BM6 exhibiting high cellulolytic activity. Genomic analysis highlighted key genes related to the MAPK signaling pathway, sulfur metabolism, and inositol phosphate metabolism in T-BM6, and phenylalanine, tyrosine, and tryptophan metabolism in T-KH4. These results suggest that T. harzianum T-BM6 and T. virens T-KH4 are promising candidates for biological control, offering a sustainable alternative to chemical treatments for managing olive root rot.

Integrative network pharmacology and multi-omics to study the potential mechanism of Niuhuang Shangqing Pill on acute pharyngitis.

Niuhuang Shangqing Pill (NSP) is a renowned Chinese medicine prescription listed in the Chinese Pharmacopoeia (Edition 2020, volume 1) and is utilized in clinical practice for treating headaches and acute pharyngitis (AP) associated with "Shanghuo". Despite its widespread use, the pharmacological mechanism and bioactive components underlying NSP in treating AP remain unclear. This study delved into evaluate the alleviation effect of NSP on AP and explore the mechanisms by analyzing multi-omics. UHPLC-Q Exactive Orbitrap HRMS was employed for the chemical ingredients of NSP. Multiple compositions, targets and pathways involved in the treatment of AP with NSP were predicted by network pharmacology. Additionally, wistar rat model of AP induced by capsaicin was established to evaluate the anti-AP activity of NSP in vivo. The potential mechanism of NSP to improve AP was investigated by real-time PCR, pharyngeal transcriptome analysis, non-targeted metabolomics, immunofluorescence and western blot. 119 compounds were identified by UHPLC-Q Exactive Orbitrap HRMS. Both clinical data of Gene Expression Omnibus (GEO) and network pharmacology demonstrated that MAPK signaling pathway and TNF signaling pathway were the critical pathway for AP treatment. In rat model of AP induced by capsaicin, NSP demonstrated the ability to reduce the levels of IL-1β, TNF-α, IL-6, CGRP, SP, PGE2, COX-2 in serum. Moreover, Transcriptomics analysis comprehensively indicated that NSP regulated the MAPK signaling pathway, TNF signaling pathway, biosynthesis of phenylalanine, tyrosine and tryptophan, arachidonic acid metabolism in AP rats. Metabolomics analysis verified that NSP could rebalance arachidonic acid metabolism, biosynthesis of phenylalanine, tyrosine and tryptophan and regulate metabolic profiles. Multi-omics Correlation analysis exhibited that the relative expression of Tnfrsf1b was significantly negatively correlated with 12(S)-HPETE. Immunofluorescence, real-time PCR and western blot of pharyngeal tissue revealed that NSP inhibited the TNF/p38-MAPK/NF-κB signaling pathway. Additionally, in vitro study on RAW264.7 cells confirmed that NSP counteract LPS-induced inflammatory by inhibiting the TNF/p38-MAPK/NF-κB signaling pathway. Overall, NSP effectively ameliorated capsaicin-induced AP by modulating the arachidonic acid metabolism and TNF/p38-MAPK/NF-κB signaling pathway. NSP effectively ameliorated capsaicin-induced AP by modulating the arachidonic acid metabolism, biosynthesis of phenylalanine, tyrosine and tryptophan, as well as the TNF/p38-MAPK/NF-κB signaling pathway.

MAPK signaling pathway induced LOX-1+ polymorphonuclear myeloid-derived suppressor cells in biliary atresia

Biliary atresia (BA) is a severe pediatric liver disease characterized by progressive bile duct destruction and fibrosis, leading to significant liver damage and frequently necessitating liver transplantation. This study elucidates the role of LOX-1+ polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) in BA pathogenesis and assesses their potential as non-invasive early diagnostic biomarkers. Using flow cytometry, immunofluorescence, and molecular profiling, we analyzed the expression and activity of these cells in peripheral blood and liver tissues from BA patients and controls. Our findings reveal a significant increase in the frequencies and function of LOX-1+PMN-MDSCs in BA patients, along with MAPK signaling pathway upregulation, indicating their involvement in disease mechanisms. Additionally, the frequencies of LOX-1+PMN-MDSC in peripheral blood significantly positively correlate with liver function parameters in BA patients, demonstrating diagnostic performance comparable to traditional serum markers. These findings suggest that LOX-1+PMN-MDSCs contribute to the immunosuppressive environment in BA and could serve as potential diagnostic targets.

Pharmacokinetic profiling and network pharmacology of honey-fried Licorice: An Integrative workflow to study traditional Chinese medicines (TCMs)

Licorice, known as the “elder statesman,” is commonly used in traditional Chinese medicine (TCM) formulations. This study aims to establish a workflow combining animal and in silico experiments to elucidate the mechanisms of TCMs at both qualitative and quantitative levels. UPLC-Q-TOF-MS/MS was employed to qualitatively characterize the total components of honey-fried licorice and the plasma components after oral administration in Beagle dogs. A UPLC-Q-Trap-MS/MS method was developed for the pharmacokinetic study of honey-fried licorice components in Beagle dog plasma. Network pharmacology and molecular docking were utilized to explore the primary functional targets and pathways. In total, we identified 68 constituents in honey-fried licorice, with 28 detected in Beagle dog plasma, and 18 of them, mainly belong to flavonoids and terpenoids, showing significant exposure. The plasma pharmacokinetic study of these 18 constituents revealed that compounds like liquiritin, glycyrrhizic acid, licoricesaponin G2, and glycyrrhetic acid-3-o-glucuronide had significant exposure. Network pharmacology and molecular docking analyses identified MAPK3, PIK3CB, PIK3CA, RAF1, and EGFR as the main targets of the active constituents of honey-fried licorice, involved in pathways such as the Ras signaling pathway, human cytomegalovirus infection, and the MAPK signaling pathway. This study provides a comprehensive profile and pharmacokinetic characteristics of honey-fried licorice, offering insights into its pharmacological, toxicological, and clinical aspects. The established workflow can serve as a standard for investigating other TCMs.

Eudesmane-guaiane sesquiterpenoid dimers from Aucklandia costus trigger paraptosis-like cell death via ROS accumulation and MAPK hyperactivation

Three novel sesquiterpenoid heterodimers, designated as auckcostusolides A–C (1–3), were isolated from Aucklandia costus leaves. The structures of compounds 1–3 were elucidated through comprehensive spectroscopic analysis, with their absolute configurations established using a combination of X-ray single-crystal diffraction and electronic circular dichroism (ECD) calculations. Notably, compounds 1 and 2, despite sharing identical planar structures derived from two identical sesquiterpenoids, exhibited opposite configurations at C-11 and C-8′. This configurational difference can be attributed to distinct Diels−Alder cycloaddition processes between the sesquiterpenoid monomers. Additionally, the cytotoxic effects of compounds 1–3 were evaluated against colorectal cancer HCT116 cells, fibrosarcoma HT1080 cells, and hepatocellular carcinoma HepG2 cells. Compounds 1–3 induced cell death was characterized by endoplasmic reticulum (ER) swelling and cytoplasmic vacuolization, typical morphological changes associated with paraptosis. Mechanistic studies revealed that compounds 1 and 3 triggered paraptosis-like cell death through the accumulation of reactive oxygen species (ROS), activation of ER stress, and stimulation of the MAPK signaling pathway.

Transcription factor Pofst3 regulates Pleurotus ostreatus development by targeting multiple biological pathways

Pleurotus ostreatus is a popular edible mushroom cultivated worldwide. However, the mechanism of P. ostreatus primordia formation is unclear. Pofst3 is a MHR superfamily transcription factor, which has the function of regulating primordia formation. In this study, the target genes of Pofst3 in P. ostreatus were identified by DAP-Seq approach at the genome level, 1481 peaks were obtained and the Pofst3 binding motif sequence was GARGRVGARGAR. The interaction between transcription factor Pofst3 and this motif was confirmed in vitro and in vivo through electrophoretic mobility shift (EMSA) and yeast one-hybrid screening (Y1H) assays. Among the top 20 GO enrichment results, most were related to transcriptional regulation, and some transcription factor encoding genes, such as HMG-box (gene_5346), MADS-box (gene_86), FOG (gene_6211) and RFX (gene_3496) were obtained. Besides basic metabolism, MAPK signaling pathway, Inositol phosphate metabolism, Glycosylphosphatidylinositol (GPI)-anchor biosynthesis and Pentose phosphate pathway were significantly enriched in the KEGG pathway analysis. The expression levels of randomly selected 11 genes, some transcription factor genes, and genes involved in metabolic pathways in wild and Pofst3 transgenic P. ostreatus strains indicated that target genes likely involved in the development of the P. ostreatus primordia. These results indicated that transcription factor Pofst3 ultimately negatively regulated the development of P. ostreatus primordia very likely through regulating a series of biological pathways.

HucMSCs can alleviate abnormal vasculogenesis induced by high glucose through the MAPK signaling pathway

HucMSCs can alleviate abnormal vasculogenesis induced by high glucose through the MAPK signaling pathway

NXP031 restores memory function by dual effects degrading Aβ accumulation and facilitating antioxidant pathway in Alzheimer's disease models

Alzheimer’s disease (AD) is a representative neurodegenerative disease that is characterized by the overaccumulation of amyloid beta (Aβ) proteins. Since AD is accompanied by excessive oxidative stress, which aggravates neurological pathologies, the use of antioxidants has been considered to prevent disease development. NXP031, a combination of vitamin C (VitC) and an optimized aptamer that binds to VitC and stabilizes the reactivity of VitC, was designed. This study aimed to evaluate the effects of NXP031 on AD pathology, including Aβ accumulation, Aβ-induced oxidative stress, neuronal damage, and neuroinflammation. When NXP031 was administered to 5xFAD transgenic mice, NXP031 exerted a strong inhibitory action on Aβ accumulation, superior to that of VitC, by inducing an increase in Aβ-degrading endopeptidase expression. NXP031 diminished lipid peroxidation levels, activated Nrf2-mediated antioxidant pathways, and suppressed overactivated neuroinflammation. An in vitro study using Neuro2a cells revealed that NXP031 protects the cells against oxidative stress by regulating the MAPK signaling pathway-mediated apoptosis. Additionally, the neuroprotective effects of NXP031 were confirmed in a dose-dependent manner when administered to intrahippocampal Aβ-injected mice, as NXP031 attenuated memory decline, neuronal apoptosis, synaptic degeneration, and excessive glial activation, and reduced NOX-2 expression in the hippocampus. Taken together, NXP031 reduced the Aβ burden by regulating Aβ-degeneration and attenuated memory impairment, neuronal death, synaptic degeneration, and neuroinflammation induced by Aβ toxicity. These results suggest the potential of NXP031 as a therapeutic agent for AD.

Traditional Chinese herbal formula, Fuzi-Lizhong pill, produces antidepressant-like effects in chronic restraint stress mice through systemic pharmacology

Ethnopharmacological relevanceFuzi-Lizhong pill (FLP) is a well-validated traditional Chinese medicine (TCM) formula that has long been used in China for gastrointestinal disease and adjunctive therapy for depression. In our previous study, we reported that the principal herb of FLP, Aconitum carmichaelii Debx. (Fuzi), exhibits antidepressant-like effects. However, there have been no reports on whether FLP produces antidepressant-like effects and its potential molecular mechanisms. Aim of the studyWe aim to demonstrate the antidepressant-like effects of FLP in chronic restraint stress (CRS) mice and to explore the associated molecular mechanisms. Materials and methodsThe active components and probable molecular targets of FLP, as well as the targets related to depression, were identified through network pharmacology. A protein-protein interaction (PPI) network was generated using the overlapping targets, followed by the visualization as well as identification of the core targets associated with the antidepressant-like action of FLP. Subsequently, KEGG and GO enrichment analyses were conducted. UHPLC-MS/MS was employed to further detect the active compounds in FLP. Molecular docking was applied to assess the connections between the active components as well as the core targets. The efficacy of FLP in treating depression and its molecular mechanisms were examined using western blotting, ELISA, 16S rRNA sequencing, HE staining, Nissl staining, and Golgi-Cox staining in a CRS-induced mouse model. ResultsNetwork pharmacology and UHPLC-MS/MS analyses indicated that the active compounds of FLP comprised taraxerol, songorine, neokadsuranic acid B, ginkgetin, hispaglabridin B, quercetin, benzoylmesaconine and liquiritin. KEGG pathway analysis implicated that the PI3K/Akt/mTOR as well as MAPK signaling pathways are closely related to the therapeutic effects of FLP on depression. Molecular docking analysis demonstrated that the main components of FLP bind to PI3K, AKT, mTOR, BDNF and MAPK. FLP significantly decreased immobility in mice that were elevated by CRS in the FST and the TST. FLP also significantly increased sucrose preference in mice after CRS in the SPT. FLP upregulated proteins associated with BDNF-TrkB and PI3K/Akt/mTOR signaling and downregulated proteins associated with MAPK signaling. Serum levels of CORT, IL-6, IL-1β, and TNF-α in CRS mice were significantly decreased following treatment with FLP. In addition, FLP ameliorated CRS-induced gut microbiota dysbiosis as demonstrated by 16S rRNA sequencing analysis. FLP ameliorated CRS-induced intestinal inflammation and neuronal damage. Finally, antidepressant-like effects and concomitant increases in dendritic spine density induced by FLP administration were also reduced after rapamycin treatment. ConclusionThese results demonstrate that FLP has antidepressant-like effects in mice exposed to CRS that involve activation of the PI3K/Akt/mTOR signaling pathway, increase in spinogenesis, inhibition of the MAPK signaling pathway, decrease in inflammation, and amelioration of gut microbiota dysbiosis. These findings provide novel evidence for the clinical application of FLP on depression.

Lysimachia mauritiana Lam. Extract Alleviates Airway Inflammation Induced by Particulate Matter Plus Diesel Exhaust Particles in Mice.

The respiratory-protective effects of Lysimachia mauritiana (LM) against airway inflammation were evaluated in a mouse model exposed to a fine dust mixture of diesel exhaust particles and particulate matter with a diameter of less than 10 µm (PM10D). To induce airway inflammation, PM10D was intranasally injected into BALB/c mice three times a day for 12 days, and LM extracts were given orally once per day. The immune cell subtypes, histopathology, and expression of inflammatory mediators were analyzed from the bronchoalveolar lavage fluid (BALF) and lungs. LM alleviated the accumulation of neutrophils and the number of inflammatory cells in the lungs and the BALF of the PM10D-exposed mice. LM also reduced the release of inflammatory mediators (MIP-2, IL-17, IL-1α, CXCL1, TNF-α, MUC5AC, and TRP receptor channels) in the BALF and lungs. Lung histopathology was used to examine airway inflammation and the accumulation of collagen fibers and inflammatory cells after PM10D exposure and showed that LM administration improved this inflammation. Furthermore, LM extract inhibited the MAPK and NF-κB signaling pathway in the lungs and improved expectoration activity through an increase in phenol red release from the trachea. LM alleviated PM10D-exposed neutrophilic airway inflammation by suppressing MAPK/NF-κB activation. This study indicates that LM extract may be an effective therapeutic agent against inflammatory respiratory diseases.

Ononin delays the development of osteoarthritis by down-regulating MAPK and NF-κB pathways in rat models.

Osteoarthritis (OA) is featured as cartilage loss, joint pain and loss of labor, which the inflammatory reaction may play critical roles. Ononin is an isoflavone isolating from medicinal plants and has anti-inflammatory effects. Our study investigated the anti-inflammation response of ononin on OA. Anterior cruciate ligament transection (ACLT)-induced OA operation was used to establish research model, then treated with ononin for 8 weeks. The condition of joint injury was assessed using pathological staining. The concentration of tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β) and interleukin-6 (IL-6) in serum were measured by Elisa kit. The expression of collagen II and matrix metalloproteinase 13 (MMP-13) proteins to assess cartilage metabolism level by immunohistochemistry and Western blot. We detected the expression of proteins involved in the MAPK and NF-κB signaling pathways. Finally, we used molecular docking to assess the affinity of ononin for the target proteins ERK1/2, JNK1/2, p38 and p65. Our results confirmed that ononin ameliorated cartilage impairment through histopathological analysis by improving the morphological structures and cartilage tidal lines and decreasing Osteoarthritis Research Society International (OARSI) scores in OA rats. Moreover, ononin inhibited the secretion of above factors in OA rats. Furthermore, ononin has been shown to improve cartilage content levels in OA rats. In addition, ononin inhibited the reactivity of MAPK and NF-κB pathways in OA rats. And molecular docking indicated the ligand molecules could stably bind to the proteins of above receptors. Our results demonstrated that ononin may ameliorate cartilage damage and inflammatory response in OA rats by downgrading MAPK and NF-κB pathways, thus identifying ononin as a potential novel drug to treat OA.

Retraction Note: The proto-oncogene c-src is involved in primordial follicle activation through the PI3K, PKC and MAPK signaling pathways

Retraction Note: The proto-oncogene c-src is involved in primordial follicle activation through the PI3K, PKC and MAPK signaling pathways

In silico identification and verification of Tanshinone IIA-related prognostic genes in hepatocellular carcinoma.

Currently, adequate treatment and prognostic prediction means for Hepatocellular Carcinoma (HCC) haven't entered into medical vision. Tanshinone IIA (TanIIA) is a natural product, which can be utilized as a potential treatment of HCC due to its high anti-tumor activity. However, the effect on HCC prognosis, as well as the potential targets and molecular mechanism of TanIIA still remain ambiguous. Herein, we investigated them via network pharmacology, explored TanIIA-related prognostic genes by machine learning methods, and verified using molecular docking and cell experiments. Potential TanIIA-targeted genes and HCC-related genes were obtained from the corresponding database. The Protein-Protein Interaction (PPI) network and enrichment analyses of the intersection targets were conducted. Furthermore, a TanIIA-related prognostic model was built and verified. We attempted to explore the expression of the TanIIA-related prognostic genes and evaluate its chemotherapeutic sensitivities and the immune infiltrations. Followed by exploration of anti-tumor activity on the human HCC cells Hep3B and HepG2 cell lines in vitro (CCK-8, flow cytometry and transwell assay), the docking molecular was performed. Ultimately, the corresponding protein expressions were determined by western blotting. A total of 64 intersecting targets were collected. Similarly, GO/KEGG enrichment analysis showed that TanIIA can inhibit HCC by affecting multiple pathways, especially the MAPK signaling pathway. A five-gene signature related to TanIIA was constructed on account of Least Absolute Shrinkage and Selection Operator (LASSO) Cox regression model. Among five genes, ALB, ESR1 and SRC tend to be core genes because of probable status as potential targets for sorafenib. Molecular docking results demonstrated the potential for active interaction between the core genes relevant proteins and TanIIA. Studies in vitro had shown that TanIIA regulated the expressions of Bcl-2, Bax and MMP9 in HCC cells, inhibiting their growth, inducing apoptosis and preventing cell invasion. Additionally, we are able to detect an up-regulated trend in the expression of ALB and ESR1, while a down-regulated in the expression of SRC by TanIIA. Regulating the expression of TanIIA-related gene signatures (ALB, SRC and ESR1), and inhibiting the SRC/MAPK/ERK signaling axis might potentially contribute to the TanIIA treatment of HCC. And the three gene signatures could be identified for predicting the prognosis of HCC, which may provide novel biomarkers for HCC treatment.

TAT-PPA1 protects against oxidative stress-induced loss of dopaminergic neurons.

Parkinson's disease (PD) is a neurodegenerative disorder characterized by the progressive loss of dopaminergic neurons in the substantia nigra (SN) of the midbrain, resulting in severe motor impairments. Inorganic pyrophosphatase 1 (PPA1) plays a key role in various biological processes, and this study introduces a cell-penetrating PPA1 fusion protein (TAT-PPA1) to explore its transduction into cells and brain tissues. TAT-PPA1 effectively penetrates SH-SY5Y cells and the SN region of PD animal models without toxicity, exhibiting protective effects against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP-)-induced cell death. TAT-PPA1 revealed an inhibitory influence on the MAPK signaling pathway and MPTP-induced reactive oxygen species (ROS) production. TAT-PPA1 suppresses JNK, AKT, p53, ERK, and p38 phosphorylation, showcasing its multifaceted role in cell survival pathways. In the MPTP-induced PD animal model, TAT-PPA1 prevents dopaminergic cell death and enhances motor function. This study shows that TAT-PPA1 protects against oxidative stress and cell death in neurodegenerative diseases, suggesting potential as a PD treatment.

Characterization of the regulatory network and pathways in duodenum affecting chicken abdominal fat deposition

The excessive accumulation of abdominal fat in chickens has resulted in a reduction in both the feed conversion efficiency and the slaughter yield. To elucidate the regulatory mechanisms and metabolic pathways affecting abdominal fat deposition in the context of broiler breeding, a cohort of 400 Qingyuan partridge chickens with varying abdominal fat deposition was established. Whole transcriptome sequencing analyses were conducted on the duodenum of 20 representative chickens to ascertain the regulatory networks at this vital digestive and absorptive organ. Consequently, 116 differentially expressed genes were identified, exhibiting a trend of increasing or decreasing expression in correlation with the accumulation of abdominal fat. A total of 36 DEmRNAs, 170 DElncRNAs, 92 DEcircRNAs and 88 DEmiRNAs were identified as differentially expressed between chickens with extremely high and low abdominal fat deposition. The functional enrichment analyses demonstrated that the differentially expressed RNA in the duodenum were involved in the regulation of chicken abdominal fat deposition by mediating a series of metabolic pathways, including the Wnt signaling pathway, the PPAR signaling pathway, the Hippo signaling pathway, the FoxO signaling pathway, the MAPK signaling pathway and other signaling pathways that are involved in fatty acid metabolism and degradation. The construction of putative interaction pairs led to the suggestion of two lncRNA-miRNA-mRNA ceRNA networks comprising two mRNAs, two miRNAs, and 29 lncRNAs, as well as two circRNA-lncRNA-miRNA-mRNA ceRNA networks comprising 26 mRNAs, 12 miRNAs, 17 lncRNAs, and nine circRNAs, as core regulatory networks in the duodenum affecting chicken abdominal fat deposition. The aforementioned genes including TMEM150C, REXO1, PIK3C2G, ppp1cb, PARP12, SERPINE2, LRAT, CYP1A1, INSR and APOA4, were proposed as candidate genes, while the miRNAs, including miR-107-y, miR-22-y, miR-25-y, miR-2404-x and miR-16-x, as well as lncRNAs such as ENSGALT00000100291, TCONS_00063508, TCONS_00061201 and TCONS_00079402 were the candidate regulators associated with chicken abdominal fat deposition. The findings of this study provide a theoretical foundation for the molecular mechanisms of mRNAs and non-coding RNAs in duodenal tissues on abdominal fat deposition in chickens.

Early Transcriptional Changes in Feline Herpesvirus-1-Infected Crandell-Rees Feline Kidney Cells

FHV-1 is a highly contagious pathogen that significantly threatens feline health and contributes to rising pet healthcare costs. The mechanisms underlying FHV-1 and host interactions remain poorly understood. For the first time, we conducted a systematic analysis of transcriptomic changes in CRFK cells following FHV-1 infection using RNA-seq. The differentially expressed genes (DEGs) displayed significant associations with cellular components, particularly the chromatin structure. Pathway analysis of the DEGs highlighted key host immune responses, including Toll-like receptors (TLRs), IL-17, TNF, MAPK, and Rap1 signaling pathways. By integrating the RNA-seq and RT-qPCR results, we identified CXCL8, CXCL10, MMP1, MMP9, CSF2, CSF3, CCL20, TLR2, TLR3, TLR4, TNF, and FOS as potentially important genes in the host’s immune response to FHV-1. These findings provide valuable insights into the mechanisms underlying FHV-1 and host interactions.