Search Results (71)

Emerging evidence highlights the biological risks associated with electromagnetic fields (EMFs) generated by electronic devices. The toxic effects and mechanisms induced by exposure to EMFs on microglial cells and natural substances that inhibit them are limited to date. Here, we investigated whether exposure to 3.5 GHz EMF radiation, potentially generated by smartphones working in 5G communication or cooking using microwave ovens, affects the growth of BV2 mouse microglial cells and polydeoxyribonucleotide (PDRN), a DNA preparation derived from salmon sperm, inhibits it. Of note, exposure to 3.5 GHz EMF radiation for 2 h markedly inhibited the growth and triggered apoptosis in BV2 cells, characterized by the reduced number of surviving cells, increased genomic DNA fragmentation, increased reactive oxygen species (ROS) levels, and altered phosphorylation and expression levels of JNK-1/2, p38 MAPK, ERK-1/2, eIF-2α, and procaspase-9. Pharmacological inhibition studies revealed that JNK-1/2 and p38 MAPK activation and ROS generation were crucial for 3.5 GHz EMF-induced BV2 cytotoxicity. Of interest, PDRN effectively countered these effects by inhibiting the activation of JNK-1/2, p38 MAPK, and caspase-9, and the production of ROS, although it did not affect eIF-2 phosphorylation. In conclusion, this study is the first to report that PDRN protects against 3.5 GHz EMF-induced toxicities in BV2 microglial cells, and PDRN’s protective effects on 3.5 GHz EMF-induced BV2 cytotoxicity are mediated primarily by modulating ROS, JNK-1/2, p38 MAPK, and caspase-9. Full article

Neuropilin-1 is henceforth a relevant target in cancer treatment; however, its way of action remains partly elusive, and the development of small inhibitory molecules is therefore required for its study. Here, we report that two small-sized neuropilin antagonists (NRPa-47 and NRPa-48), VEGF-A₁₆₅/NRP-1 binding inhibitors, are able to decrease VEGF-Rs phosphorylation and to modulate their downstream cascades in the triple-negative breast cancer cell line (MDA-MB-231). Nevertheless, NRPas exert a divergent pathway regulation of MAPK phosphorylation, such as JNK-1/-2/-3, ERK-1/-2, and p38β/γ/δ-kinases, as well as their respective downstream targets. However, NRPa-47 and NRPa-48 apply a common down-regulation of the p38α-kinase phosphorylation and their downstream targets, emphasising its central regulating role. More importantly, none of the 40 selected kinases, including SAPK2a/p38α, are affected in vitro by NRPas, strengthening their specificity. Taken together, NRPas induced cell death by the down-modulation of pro-apoptotic and anti-apoptotic proteins, cell death receptors and adaptors, heat shock proteins (HSP-27/-60/-70), cell cycle proteins (p21, p27, phospho-RAD17), and transcription factors (p53, HIF-1α). In conclusion, we showed for the first time how NRPas may alter tumour cell signalling and contribute to the down-modulation of the cancer therapeutic key factor p38α-kinase phosphorylation. Thus, the efficient association of NRPas and p38α-kinase inhibitor strengthened this hypothesis. Full article

Background/Objectives: Cutibacterium acnes (C. acnes), a bacterium residing in hair follicles, triggers acne by inducing monocyte-mediated inflammatory cytokine production. Gedunin, a limonoid derived from Azadirachta indica (commonly known as neem), is renowned for its antifungal, antimalarial, anticancer, anti-inflammatory, and neuroprotective effects. However, its role in mitigating C. acnes-induced skin inflammation remains unexplored. This study investigates the anti-inflammatory effects of gedunin on C. acnes-induced skin inflammation and elucidates the underlying mechanisms. Methods: The anti-inflammatory activity of gedunin was assessed using RAW 264.7 mouse macrophage cells and mouse bone-marrow-derived macrophages (BMDMs). Key inflammatory mediators, including interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), and interleukin-6 (IL-6), were evaluated. Mechanistic studies focused on the nuclear factor-kappa B (NF-κB) and mitogen-activated protein kinase (MAPK) signaling pathways, along with the NOD-like receptor pyrin domain-containing 3 (NLRP3) inflammasome. An in vivo acne model was employed to examine gedunin’s therapeutic efficacy. Results: Gedunin significantly reduced the expression of IL-1β, TNF-α, iNOS, COX-2, and IL-6 in RAW 264.7 cells. It inhibited NF-κB activation without affecting the MAPK pathways, including JNK/SAPK, ERK, and p38 MAPK. Gedunin also suppressed the activation of the NLRP3 inflammasome in BMDMs. In the mouse acne model, gedunin effectively alleviated C. acnes-induced inflammation, primarily by targeting NF-κB signaling. Conclusions: Gedunin demonstrates potential as a therapeutic agent for acne treatment by targeting key inflammatory pathways, particularly NF-κB signaling. This study highlights gedunin’s promise as an alternative approach to managing C. acnes-induced skin inflammation. Full article

During the dormant period of peach trees in winter, flower buds exhibit weak cold resistance and are susceptible to freezing at low temperatures. Understanding the physiological and molecular mechanisms underlying the response of local peach buds to low-temperature adversity is crucial for ensuring normal flowering, fruiting, and yield. In this study, the experimental materials included the conventional cultivar ‘Xia cui’ (XC) and the cold-resistant local resources ‘Ding jiaba’ (DJB) peach buds. The antioxidant enzyme activity, levels of malondialdehyde (MDA), proline (Pro), and hydrogen peroxide content (H₂O₂) were determined in peach buds at different dormancy periods. Transcriptome sequencing was performed at three dormancy stages: the dormancy entry stage (FD), deep dormancy release stage (MD), and dormancy release stage (RD). Additionally, transcriptome sequencing was conducted to analyze gene expression profiles during these stages. Our findings revealed that compared with XC cultivars, DJB peach buds exhibited decreased MDA and H₂O₂ contents but increased superoxide dismutase (SOD), peroxidase (POD), and catalase (CAT) activities as well as Pro content during the dormancy period. These findings suggest that cold-resistant cultivars possess significantly stronger antioxidant capacity than conventional cultivars under low-temperature stress. A total of 10,168 differential genes were annotated through transcriptome sequencing. Among them, 4975 were up-regulated while 5193 were down-regulated. The differentially expressed genes associated with low-temperature response in peach buds are primarily enriched in plant hormone signal transduction pathway and phenylpropane synthesis pathway. Key differentially expressed genes related to cold resistance include ARF2, GH3, and SAPK2, and differentially expressed transcription factors mainly belong to the AP2/ERF-ERF, bHLH, and C2H2 families. This study provides a theoretical foundation for understanding the key genes involved. Full article

Vulvovaginal candidiasis (VVC) is a prevalent women’s infection characterized by excessive inflammation and damage of the vaginal epithelium that, in its recurrent form (RVVC), causes more than three symptomatic episodes per year, impacting nearly 8% of women globally. Current antifungal treatments alleviate symptoms but often fail to restore the inflammatory homeostasis of mucosal tissue and prevent recurrences. α-Tocopherol (α-TOH) and garcinoic acid (GA), a vitamin E metabolite, with immunomodulatory properties, were investigated for the first time in vaginal epithelial cells exposed to C. albicans infection to assess their effects on inflammatory signaling parameters important to restore cellular homeostasis. For this purpose, the protein kinases MKK3/6, p38 stress kinase (SAPK), and ERK1/2 were studied together with c-Fos transcription factor and IL-6, IL-1α, and IL-1β secretion in A-431 vaginal epithelial cells pre-treated with GA or with α-TOH and then infected with C. albicans. GA, differently from α-TOH, significantly reduced the C. albicans-induced activation of p38-SAPK while increasing pro-survival MAPK ERK1/2 activity. This resulted in a significant reduction in the secretion levels of the inflammatory cytokines IL-6 and IL-1α, as well as IL-1β. Overall, our data indicate that GA holds potential for restoring the immuno-metabolic properties of the vaginal epithelium exposed to C. albicans infection, which may help to treat inflammatory symptoms in VVC/RVVC. Full article

In this study, a mixture of Platycodon grandiflorum, Pyrus serotina, Chaenomeles sinensis, and Raphanus sativus (PPCRE) was investigated for their immuno-enhancing effects, as well as the molecular mechanism of PPCRE in RAW264.7 cells. PPCRE dramatically increased nitric oxide (NO) and prostaglandin E₂ (PGE₂) generation depending on the concentration while exhibiting no cytotoxicity. PPCRE markedly upregulated the mRNA and protein expression of immune-related cytotoxic factors such as cyclooxygenase (COX)-1, COX-2, and inducible nitric oxide synthase (iNOS) and pro-inflammatory cytokines such as interleukin (IL)-1β, IL-6, and tumor necrosis factor alpha (TNF-α), as well as the mRNA level of IL-4. PPCRE increased the mitogen-activated protein kinase (MAPK) signaling pathway by upregulating the phosphorylation of extracellular signal-regulated kinase (ERK), stress-activated protein kinase/Jun N-terminal-kinase (SAPK/JNK), and p38. Furthermore, PPCRE considerably activated the nuclear factor kappa B (NF-κB) signaling pathway by increasing phosphorylation of NF-κB-p65. PPCRE-stimulated RAW264.7 cells increased macrophage phagocytic capacity. In conclusion, our study found that PPCRE improved immune function by modulating inflammatory mediators and regulating the MAPK and NF-κB pathway of signaling in macrophages. Full article

Proteasomes play an important role in the physiology of cancer cells, and inhibition of their activity may be used as a promising therapeutic strategy against glioblastoma (GBM). Although certain proteasome inhibitors (PIs) have been approved for the treatment of other malignancies, they have limited effectiveness against GBM due to low brain bioavailability. Marizomib (MZB) is an irreversible, second-generation proteasome inhibitor, which unlike other PIs can penetrate through the blood–brain barrier, making it a promising therapeutic tool in brain malignancies. The antitumor activity of MZB was investigated in LN229 and U118 cells. The MTT test and the ATP-based assay were performed to evaluate cytotoxicity. Flow cytometry analysis was used to determine the apoptotic death of GBM cells. Luminescent assays were used to assess levels of reactive oxygen species (ROS) and the activity of caspase 3/7. RT-qPCR and Western blot analyses were used to determine gene and protein expressions. Marizomib decreased the viability and caused apoptotic death of GBM cells. The proapoptotic effect was accompanied by activation of caspase 3 and overexpression of cl-PARP, Noxa, Cyt C, and DR5. Moreover, treatment with MZB triggered endoplasmic reticulum (ER) stress, as shown by increased expressions of GRP78, IRE1α, p-EIF2α, p-SAPK/JNK, CHOP, ATF6α, and ATF4. On the contrary, overproduction of ROS or increased expressions of ERO1α, LC3 II, Beclin 1, and ATG5 were not detected, suggesting that neither oxidative stress nor autophagy were involved in the process of MZB-induced cell death. Thus, marizomib represents a potentially promising compound for facilitating further progress in brain cancer therapy. Full article

Rotenone (ROT), the most significant rotenoid, which has shown anticancer activity, has also been reported to be toxic to normal cells, inducing Parkinson’s disease (PD)-like neuronal loss with aggregation of α-synuclein (α-syn). To reduce the adverse effects of ROT, its derivative, rotenoisin A (ROA), is obtained by directly irradiating a ROT solution in methanol using γ-rays, which has been reported for potential anticancer properties. However, its PD-inducing effects have not yet been researched or reported. This study sought to compare the activities of ROA and ROT on the aggregation of α-syn, apoptosis, and autophagy in SH-SY5Y cells. ROA decreased cell survival less when compared with ROT on SH-SY5Y cells at 48 h in a dose-dependent manner. ROT (0.5 and 1 μM) and ROA (4 and 5 μM) decreased the expression of tyrosine hydroxylase. Western blot analysis of the Triton X-100 insoluble fraction revealed that both ROT and ROA significantly increased the levels of oligomeric, dimeric, and monomeric phosphorylated Serine129 α-syn and total monomeric α-syn. Moreover, both compounds decreased the proportion of neuronal nuclei, the neurofilament-heavy chain, and β3-tubulin. The phosphorylation of ERK and SAPK were reduced, whereas ROA did not act on Akt. Additionally, the increased Bax/Bcl-2 ratio further activated the downstream caspases cascade. ROT promoted the LC3BII/I ratio and p62 levels; however, different ROA doses resulted in different effects on autophagy while inducing PD-like impairments in SH-SY5Y cells. Full article

Esophageal squamous cell carcinoma (ESCC) is a deadly consequence of radiation exposure to the esophagus. ESCC arises from esophageal epithelial cells that undergo malignant transformation and features a perturbed squamous cell differentiation program. Understanding the dose- and radiation quality-dependence of the esophageal epithelium response to radiation may provide insights into the ability of radiation to promote ESCC. We have explored factors that may play a role in esophageal epithelial radiosensitivity and their potential relationship to ESCC risk. We have utilized a murine three-dimensional (3D) organoid model that recapitulates the morphology and functions of the stratified squamous epithelium of the esophagus to study persistent dose- and radiation quality-dependent changes. Interestingly, although high-linear energy transfer (LET) Fe ion exposure induced a more intense and persistent alteration of squamous differentiation and 53BP1 DNA damage foci levels as compared to Cs, the MAPK/SAPK stress pathway signaling showed similar altered levels for most phospho-proteins with both radiation qualities. In addition, the lower dose of high-LET exposure also revealed nearly the same degree of morphological changes, even though only ~36% of the cells were predicted to be hit at the lower 0.1 Gy dose, suggesting that a bystander effect may be induced. Although p38 and ERK/MAPK revealed the highest levels following high-LET exposure, the findings reveal that even a low dose (0.1 Gy) of both radiation qualities can elicit a persistent stress signaling response that may critically impact the differentiation gradient of the esophageal epithelium, providing novel insights into the pathogenesis of radiation-induced esophageal injury and early stage esophageal carcinogenesis. Full article

Plant acyl-CoA-binding proteins (ACBPs) function in plant development and stress responses, with some ACBPs interacting with protein partners. This study tested the interaction between two Class II GmACBPs (Glycine max ACBPs) and seven kinases, using yeast two-hybrid (Y2H) assays and bimolecular fluorescence complementation (BiFC). The results revealed that both GmACBP3.1 and GmACBP4.1 interact with two soybean kinases, a mitogen-activated protein kinase MPK2, and a serine/threonine-protein kinase SAPK2, highlighting the significance of the ankyrin-repeat (ANK) domain in facilitating protein–protein interactions. Moreover, an in vitro kinase assay and subsequent Phos-tag SDS-PAGE determined that GmMPK2 and GmSAPK2 possess the ability to phosphorylate Class II GmACBPs. Additionally, the kinase-specific phosphosites for Class II GmACBPs were predicted using databases. The HDOCK server was also utilized to predict the binding models of Class II GmACBPs with these two kinases, and the results indicated that the affected residues were located in the ANK region of Class II GmACBPs in both docking models, aligning with the findings of the Y2H and BiFC experiments. This is the first report describing the interaction between Class II GmACBPs and kinases, suggesting that Class II GmACBPs have potential as phospho-proteins that impact signaling pathways. Full article

Intervertebral disc degeneration (IDD) is a major cause of lower back pain. The pathophysiological development of IDD is closely related to the stimulation of various stressors, including proinflammatory cytokines, abnormal mechanical stress, oxidative stress, metabolic abnormalities, and DNA damage, among others. These factors prevent normal intervertebral disc (IVD) development, reduce the number of IVD cells, and induce senescence and apoptosis. Stress-activated protein kinases (SAPKs), particularly, c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (p38 MAPK), control cell signaling in response to cellular stress. Previous studies have shown that these proteins are highly expressed in degenerated IVD tissues and are involved in complex biological signal-regulated processes. Therefore, we summarize the research reports on IDD related to JNK and p38 MAPK. Their structure, function, and signal regulation mechanisms are comprehensively and systematically described and potential therapeutic targets are proposed. This work could provide a reference for future research and help improve molecular therapeutic strategies for IDD. Full article

JNK is named after c-Jun N-terminal kinase, as it is responsible for phosphorylating c-Jun. As a member of the mitogen-activated protein kinase (MAPK) family, JNK is also known as stress-activated kinase (SAPK) because it can be activated by extracellular stresses including growth factor, UV irradiation, and virus infection. Functionally, JNK regulates various cell behaviors such as cell differentiation, proliferation, survival, and metabolic reprogramming. Dysregulated JNK signaling contributes to several types of human diseases. Although the role of the JNK pathway in a single disease has been summarized in several previous publications, a comprehensive review of its role in multiple kinds of human diseases is missing. In this review, we begin by introducing the landmark discoveries, structures, tissue expression, and activation mechanisms of the JNK pathway. Next, we come to the focus of this work: a comprehensive summary of the role of the deregulated JNK pathway in multiple kinds of diseases. Beyond that, we also discuss the current strategies for targeting the JNK pathway for therapeutic intervention and summarize the application of JNK inhibitors as well as several challenges now faced. We expect that this review can provide a more comprehensive insight into the critical role of the JNK pathway in the pathogenesis of human diseases and hope that it also provides important clues for ameliorating disease conditions. Full article

Drought stress significantly restricts the growth, yield, and quality of peppers. Strigolactone (SL), a relatively new plant hormone, has shown promise in alleviating drought-related symptoms in pepper plants. However, there is limited knowledge on how SL affects the gene expression in peppers when exposed to drought stress (DS) after the foliar application of SL. To explore this, we conducted a thorough physiological and transcriptome analysis investigation to uncover the mechanisms through which SL mitigates the effects of DS on pepper seedlings. DS inhibited the growth of pepper seedlings, altered antioxidant enzyme activity, reduced relative water content (RWC), and caused oxidative damage. On the contrary, the application of SL significantly enhanced RWC, promoted root morphology, and increased leaf pigment content. SL also protected pepper seedlings from drought-induced oxidative damage by reducing MDA and H₂O₂ levels and maintaining POD, CAT, and SOD activity. Moreover, transcriptomic analysis revealed that differentially expressed genes were enriched in ribosomes, ABC transporters, phenylpropanoid biosynthesis, and Auxin/MAPK signaling pathways in DS and DS + SL treatment. Furthermore, the results of qRT-PCR showed the up-regulation of AGR7, ABI5, BRI1, and PDR4 and down-regulation of SAPK6, NTF4, PYL6, and GPX4 in SL treatment compared with drought-only treatment. In particular, the key gene for SL signal transduction, SMXL6, was down-regulated under drought. These results elucidate the molecular aspects underlying SL-mediated plant DS tolerance, and provide pivotal strategies for effectively achieving pepper drought resilience. Full article

The three major mitogen-activated protein kinase (MAPK) pathways (ERK1/2, p38, and JNK/SAPK) are upstream regulators of the nuclear receptor superfamily (NRSF). These ligand-activated transcription factors are divided into subclasses comprising receptors for endocrine hormones, metabolic compounds (e.g., vitamins, diet), xenobiotics, and mediators released from host immune reactions such as tissue injury and inflammation. These internal and external cues place the NRSF at the frontline as sensors and translators of information from the environment towards the genome. For most of the former “orphan” receptors, physiological and synthetic ligands have been identified, opening intriguing opportunities for combination therapies with existing cancer medications. Hitherto, only preclinical data are available, warranting further validation in clinical trials in patients. The current review summarized the existing literature covering the expression and function of NRSF subclasses in human solid tumors and hematopoietic malignancies and their modulatory effects on innate (e.g., macrophages, dendritic cells) and adaptive (i.e., T cell subsets) immune cells, encouraging mechanistic and pharmacological studies in combination with current clinically approved therapeutics against immune checkpoint molecules (e.g., PD1). Full article

Tauopathies are a group of neurodegenerative diseases characterized by the pathological aggregation of hyperphosphorylated tau in neurons and glia. Primary tauopathies are not uncommon in humans but exceptional in other species. We evaluate the clinical, neuropathological, and genetic alterations related to tau pathology in 16 cats aged from 1 to 21 years with different clinical backgrounds. Interestingly, a 10-year-old female cat presented a six-year progressive history of mental status and gait abnormalities. The imaging study revealed generalized cortical atrophy. Due to the poor prognosis, the cat was euthanatized at the age of ten. Neuropathological lesions were characterized by massive neuronal loss with marked spongiosis and associated moderate reactive gliosis in the parietal cortex, being less severe in other areas of the cerebral cortex, and the loss of Purkinje cells of the cerebellum. Immunohistochemical methods revealed a 4R-tauopathy with granular pre-tangles in neurons and coiled bodies in oligodendrocytes. Deposits were recognized with several phospho-site antibodies (4Rtau, tau5, AT8, PFH, tau-P Thr181, tau-P-Ser 262, tau-P Ser 422) and associated with increased granular expression of active tau kinases (p38-P Thr180/Tyr182 and SAPK/JNK-P Thr138/Thr185). The genetic study revealed well-preserved coding regions of MAPT. No similar alterations related to tau pathology were found in the other 15 cats processed in parallel. To our knowledge, this is the first case reporting a primary 4R-tauopathy with severe cerebral and Purkinje cell degeneration in an adult cat with neurological signs starting at a young age. Full article