6-Gingerol attenuates hepatic ischemia/reperfusion injury through regulating MKP5-mediated P38/JNK pathway.

6-Gingerol, the main bioactive compound of ginger, has antioxidant, anti-inflammatory, anti-cancer and neuroprotective effects. However, it is unclear whether 6-Gingerol has protective effects against hepatic ischemia/reperfusion (I/R) injury. In this study, the mouse liver I/R injury model and the mouse AML12 cell hypoxia/reoxygenation (H/R) model were established by pretreatment with 6-Gingerol at different concentrations to explore the potential effects of 6-Gingerol. Serum transaminase levels, liver necrotic area, cell viability, inflammatory response, and cell apoptosis were used to assess the effect of 6-Gingerol on hepatic I/R or cell H/R injury. Quantitative polymerase chain reaction (qPCR) and Western blotting were used to detect the mRNA and protein expression. The results show that 6-Gingerol decreased serum alanine aminotransferase (ALT), aspartate aminotransferase (AST) levels, liver necrosis, inflammatory cytokines IL-1ß, IL-6, MCP-1, TNF-α expression, Ly6g+ inflammatory cell infiltration, protein phosphorylation of NF-κB signaling pathway, Terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) positive cells, cell apoptosis rate, the protein expression of pro-apoptotic protein BAX and C-Caspase3, increased cell viability, and expression of anti-apoptotic protein BCL-2. Moreover, 6-Gingerol could increase the mRNA and protein expression of mitogen activated protein kinase phosphatase 5 (MKP5) and inhibit the activation of P38/JNK signaling pathway. In MKP5 knockout (KO) mice, the protective effect of 6-gingerol and the inhibition of P38/JNK pathway were significantly weakened. Therefore, our results suggest that 6-Gingerol exerts anti-inflammatory and anti-apoptotic effects to attenuate hepatic I/R injury by regulating the MKP5-mediated P38/JNK signaling pathway.

Lactobacillus fermentum WC2020 increased the longevity of Caenorhabditis elegans via JNK-mediated antioxidant pathway.

Lactobacillus fermentum can exert antiaging effects, but their roles are strain-specific, and little is known about the molecular mechanisms in some strains. This study investigated the antiaging effects of L. fermentum WC2020 (WC2020) isolated from Chinese fermented pickles and the underlying mechanism of the action in Caenorhabditis elegans. WC2020 enhanced the mean lifespan of L1-stage and L4-stage worms by 22.67% and 12.42%, respectively, compared with Escherichia coli OP50 (OP50), a standard food source for C. elegans. WC2020-induced longevity was accompanied by an increase in body length and mitochondrial transmembrane potential and a reduction in lipid accumulation and the production of reactive oxygen species and malondialdehyde. Moreover, WC2020 increased the production of glutathione, superoxide dismutases, and catalases and altered the transcripts of many phenotype-related genes. Furthermore, WC2020-fed jnk-1 rather than akt-2 or pmk-1 loss-of-function mutants showed similar lifespans to OP50-fed worms. Correspondingly, WC2020 significantly upregulated the expression of jnk-1 rather than genes involved in insulin-like, p38 MAPK, bate-catenin, or TGF-beta pathway. Moreover, the increase in body length, mitochondrial transmembrane potential, and antioxidant capability and the decrease in lipid accumulation induced by WC2020 were not observed in jnk-1 mutants. Additionally, WC2020 increased the expression of daf-16 and the proportion of daf-16::GFP in the nucleus, and increased lifespan disappeared in WC2020-fed daf-16 loss-of-function mutants. In conclusion, WC2020 activated the JNK/DAF-16 pathway to improve mitochondria function, reduce oxidative stress, and then extend the longevity of nematodes, suggesting WC2020 could be a potential probiotic targeting JNK-mediated antioxidant pathway for antiaging in food supplements and bioprocessing. PRACTICAL APPLICATION: Aging has a profound impact on the global economy and human health and could be delayed by specific diets and nutrient resources. This study demonstrated that Lactobacillus fermentum WC2020 could be a potential probiotic strain used in food to promote longevity and health via the JNK-mediated antioxidant pathway.

Peste des petits ruminants virus infection induces endoplasmic reticulum stress and apoptosis via IRE1-XBP1 and IRE1-JNK signaling pathways.

BACKGROUND: Peste des petits ruminants (PPR) is a contagious and fatal disease of sheep and goats. PPR virus (PPRV) infection induces endoplasmic reticulum (ER) stress-mediated unfolded protein response (UPR). The activation of UPR signaling pathways and their impact on apoptosis and virus replication remains controversial. OBJECTIVES: To investigate the role of PPRV-induced ER stress and the IRE1-XBP1 and IRE1-JNK pathways and their impact on apoptosis and virus replication. METHODS: The cell viability and virus replication were assessed by 3-(4,5-Dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide assay, immunofluorescence assay, and Western blot. The expression of ER stress biomarker GRP78, IRE1, and its downstream molecules, PPRV-N protein, and apoptosis-related proteins was detected by Western blot and quantitative reverse transcription-polymerase chain reaction, respectively. 4-Phenylbutyric acid (4-PBA) and STF-083010 were respectively used to inhibit ER stress and IRE1 signaling pathway. RESULTS: The expression of GRP78, IRE1α, p-IRE1α, XBP1s, JNK, p-JNK, caspase-3, caspase-9, Bax and PPRV-N were significantly up-regulated in PPRV-infected cells, the expression of Bcl-2 was significantly down-regulated. Due to 4-PBA treatment, the expression of GRP78, p-IRE1α, XBP1s, p-JNK, caspase-3, caspase-9, Bax, and PPRV-N were significantly down-regulated, the expression of Bcl-2 was significantly up-regulated. Moreover, in PPRV-infected cells, the expression of p-IRE1α, p-JNK, Bax, and PPRV-N was significantly decreased, and the expression of Bcl-2 was increased in the presence of STF-083010. CONCLUSIONS: PPRV infection induces ER stress and IRE1 activation, resulting in apoptosis and enhancement of virus replication through IRE1-XBP1s and IRE1-JNK pathways.

Arenobufagin induces cell apoptosis by modulating the cell cycle regulator claspin and the JNK pathway in nasopharyngeal carcinoma cells.

BACKGROUND: The high recurrence rate and incidence of distant metastasis of nasopharyngeal carcinoma (NPC) result in poor prognosis. Natural compounds that can complement combination radiation therapy need to be identified. Arenobufagin is commonly used for heart diseases and liver cancer, but its effectiveness in NPC is unclear. STUDY DESIGN AND METHODS: The effect of arenobufagin-induced apoptosis was measured by a cell viability assay, tumorigenic assay, fluorescence assay, and Western blot assay through NPC-039 and NPC-BM cell lines. The protease array, Western blot assay, and transient transfection were used to investigate the underlying mechanism of arenobufagin-induced apoptosis. A NPC xenograft model was established to explore the antitumor activity of arenobufagin in vivo. RESULTS: Our findings indicated that arenobufagin exerted cytotoxic effects on NPC cells, inhibiting proliferation through apoptosis activation. The downregulation of claspin was confirmed in arenobufagin-induced apoptosis. The combined treatment of arenobufagin and inhibitors of mitogen-activated protein kinase demonstrated that arenobufagin induced NPC apoptosis through the c-Jun N-terminal kinases (JNK) pathway inhibition. Furthermore, arenobufagin suppressed NPC tumor proliferation in vivo. CONCLUSION: Our results revealed the antitumor effect of arenobufagin in vitro and in vivo. Arenobufagin may provide clinical utility on NPC due to the suppression of claspin and the JNK pathway.

Regulation of Notch signaling by non-muscle myosin II Zipper in Drosophila.

The Notch pathway is an evolutionarily conserved signaling system that is intricately regulated at multiple levels and it influences different aspects of development. In an effort to identify novel components involved in Notch signaling and its regulation, we carried out protein interaction screens which identified non-muscle myosin II Zipper (Zip) as an interacting partner of Notch. Physical interaction between Notch and Zip was further validated by co-immunoprecipitation studies. Immunocytochemical analyses revealed that Notch and Zip co-localize within same cytoplasmic compartment. Different alleles of zip also showed strong genetic interactions with Notch pathway components. Downregulation of Zip resulted in wing phenotypes that were reminiscent of Notch loss-of-function phenotypes and a perturbed expression of Notch downstream targets, Cut and Deadpan. Further, synergistic interaction between Notch and Zip resulted in highly ectopic expression of these Notch targets. Activated Notch-induced tumorous phenotype of larval tissues was enhanced by over-expression of Zip. Notch-Zip synergy resulted in the activation of JNK pathway that consequently lead to MMP activation and proliferation. Taken together, our results suggest that Zip may play an important role in regulation of Notch signaling.

Targeting MAPK-ERK/JNK pathway: A potential intervention mechanism of myocardial fibrosis in heart failure.

Myocardial fibrosis is a significant pathological basis of heart failure. Overactivation of the ERK1/2 and JNK1/2 signaling pathways of MAPK family members synergistically promotes the proliferation of myocardial fibroblasts and accelerates the development of myocardial fibrosis. In addition to some small molecule inhibitors and Western drugs, many Chinese medicines can also inhibit the activity of ERK1/2 and JNK1/2, thus slowing down the development of myocardial fibrosis, and are generally safe and effective. However, the specific biological mechanisms of ERK1/2 and JNK1/2 signaling pathways in myocardial fibrosis still need to be fully understood, and there is no systematic review of existing drugs and methods to inhibit them from improving myocardial fibrosis. This study aims to summarize the roles and cross-linking mechanisms of ERK1/2 and JNK1/2 signaling pathways in myocardial fibrosis and to systematically sort out the small-molecule inhibitors, Western drugs, traditional Chinese medicines, and non-pharmacological therapies that inhibit ERK1/2 and JNK1/2 to alleviate myocardial fibrosis. In the future, we hope to conduct more in-depth research from the perspective of precision-targeted therapy, using this as a basis for developing new drugs that provide new perspectives on the prevention and treatment of heart failure.

Curcumin-Piperlongumine Hybrid Molecule Increases Cell Cycle Arrest and Apoptosis in Lung Cancer through JNK/c-Jun Signaling Pathway.

The instability of curcumin's structure and the toxic side effects of piperlongumine have limited their potential applications in cancer treatment. To overcome these challenges, we designed and synthesized a novel curcumin-piperlongumine hybrid molecule, 3-[(E)-4-hydroxy-3-methoxybenzylidene]-1-[(E)-3-(3,4,5-trimethoxyphenyl)acryloyl]piperidin-2-one (CP), using a molecular hybridization strategy. CP exhibited enhanced structural stability and safety compared with its parent compounds. Through in vitro and in vivo biological activity screenings, CP effectively inhibited cell proliferation, caused cell cycle arrest in the G2/M phase, and induced apoptosis. Mechanistically, CP-induced apoptosis was partially mediated by cell cycle arrest. Furthermore, we discovered that CP induces cell cycle arrest and apoptosis through the regulation of JNK signaling. These findings highlight the potential of CP as a promising therapeutic agent for lung cancer treatment.

The zinc finger protein CG12744 regulates intestinal stem cells in aged Drosophila through the EGFR and BMP pathways.

AIM: Aging is a process characterized by a time-dependent decline in the functionality of adult stem cells and is closely associated with age-related diseases. However, understanding how aging promotes disease and its underlying causes is critical for combating aging. MAIN METHODS: The offspring of UAS-Gal4 and CG12744RNAiDrosophila were cultured for 33 days to evaluate the role of CG12744 in the aging intestine. Immunofluorescence was performed to detect specific cell type markers for assessing proliferation and differentiation. qRT-PCR was used to observe the changes in signaling regulating intestinal homeostasis in the aging intestine after CG12744 knockdown. 16S rRNA-seq analysis was also conducted to elucidate the role of gut microbes in CG12744-mediated intestinal dysfunction. KEY FINDINGS: The mRNA levels of CG12744 were significantly increased in the aged midguts. Knockdown of CG12744 in progenitor cells further exacerbates the age-related intestinal hyperplasia and dysfunction. In particular, upon depletion of CG12744 in progenitors, enteroblasts (EBs) exhibited an increased propensity to differentiate along the enteroendocrine cell (EE) lineage. In contrast, the overexpression of CG12744 in progenitor cells restrained age-related gut hyperplasia in Drosophila. Moreover, CG12744 prevented age-related intestinal stem cell (ISC) overproliferation and differentiation by modulating the EGFR, JNK, and BMP pathways. In addition, the inhibition of CG12744 resulted in a significant increase in the gut microbial composition in aging flies. SIGNIFICANCE: This study established a role for the CG12744 in regulating the proliferation and differentiation of adult stem cells, thereby identifying a potential therapeutic target for diseases caused by age-related dysfunction stem cell dysfunction.

ß-Lapachone induces ferroptosis of colorectal cancer cells via NCOA4-mediated ferritinophagy by activating JNK pathway.

ß-Lapachone is a natural product that can promote ROS generation and ultimately triggers tumor cells death by inducing DNA damage. Recent studies have indicated that the targeting of ferroptosis or iron metabolism is a feasible strategy for treating cancer. In this study, bulk RNA-seq analysis suggested that ß-Lapachone might induce ferroptosis in CRC cells. We further tested this hypothesis using a xenograft model of human colorectal cancer as an animal model and in SW620 and DLD-1 of CRC cell lines. Western blot was used to determine the key proteins of ferroptosis (SLC7A11, GPX4), autophagy (LC3B, P62, ATG7), ferritinophagy (NCOA4, FTH1, TFRC), and JNK pathway (p-JNK, JNK, p-c-Jun, c-Jun). The levels of MDA, GSH/GSSG, lipid ROS, and intracellular ferrous iron were determined after ß-Lapachone treatment, and inhibitors of various pathways, including NAC, Ferrostatin-1, DFO, 3-MA, and SP600125 were utilized to explore the molecular mechanism underlying ß-Lapachone-mediated ferroptosis. As the result, we identified that ß-Lapachone inhibited cell proliferation and induced apoptosis, autophagy, and ROS generation. In addition, ß-Lapachone induced ferroptosis as demonstrated by intra-cellular iron overload, increased levels of lipid ROS and MDA. Mechanistically, JNK signaling pathway was involved in ß-Lapachone-induced xCT/GPX4-mediated ferroptosis and NCOA4-mediated ferritinophagy in CRC cells. In vivo experiments in nude mice demonstrated that ß-Lapachone significantly inhibited CRC growth and induced ferroptosis and NCOA4-mediated ferritinophagy. These findings not only identify a novel role for ß-Lapachone in ferroptosis but also indicate that ß-Lapachone may be a valuable candidate for the research and development of anti-cancer therapeutic agents.

Exploring dual effects of dinutuximab beta on cell death and proliferation of insulinoma.

Insulinoma INS-1 cells are pancreatic beta cell tumors. Dinutuximab beta (DB) is a monoclonal antibody used in the treatment of neuroblastoma. The aim of this study is to investigate the effects of DB on pancreatic beta cell tumors at the molecular level. DB (Qarziba®) was available from EUSA Pharma. Streptozotocin (STZ) was used induce to cell cytotoxicity. DB was applied to the cells before or after the STZ application. KCND3, KCNN4, KCNK1, and PTHrP gene expression levels were analyzed by q-RT-PCR, and protein levels were analyzed by Western blotting. Analysis of glucose-stimulated insulin secretion was performed. Ca+2 and CA19-9 levels were determined by the ELISA kit. PERK, CHOP, HSP90, p-c-Jun, p-Atf2, and p-Elk1 protein levels were analyzed by simple WES. Decreased KCND3, KCNK1, and PTHrP protein levels and increased KCND3, KCNN4, KCNK1, and PTHrP gene expression levels were observed with DB applied after STZ application. Cell dysfunction was detected with DB applied before and after STZ application. Ca19-9 and Ca+2 levels were increased with DB applied after STZ application. PERK, CHOP, and p-Elk1 levels decreased, while HSP90 levels increased with DB applied after STZ application. CHOP, p-Akt-2, and p-c-Jun levels increased in the DB group. As a result, INS-1 cells go to cell death via the ERK signaling pathway without ER stress and release insulin with the decrease of K+ channels and an increase in Ca+2 levels with DB applied after STZ application. Moreover, the cells proliferate via JNK signaling with DB application. DB holds promise for the treatment of insulinoma. The study should be supported by in vivo studies.

Stanniocalcin-1 Promotes PARP1-Dependent Cell Death via JNK Activation in Colitis.

Stanniocalcin-1 (STC1) is upregulated by inflammation and modulates oxidative stress-induced cell death. Herein, the function of STC1 in colitis and stress-induced parthanatos, a newly identified type of programmed necrotic cell death dependent on the activation of poly-ADP ribose polymerase-1 (PARP1) is investigated. Results show that STC1 expression is markedly increased in the inflamed colonic mucosa of Crohn's disease (CD) patients and chemically-induced mice colitis models. Evaluation of parthanatos severity and pro-inflammatory cytokine expression shows that intestinal-specific Stc1 knockout (Stc1INT-KO ) mice are resistant to dextran sulfate sodium (DSS)-induced colitis and exhibit lower disease severity. STC1-overexpressing cells show an increased degree of parthanatos and proinflammatory cytokine expression, whereas STC1-knockout cells show a decreased degree of parthanatos. Co-immunoprecipitation, mass spectrometry, and proteomic analyses indicate that STC1 interacts with PARP1, which activates the JNK pathway via PARP1-JNK interactions. Moreover, inhibition of PARP1 and JNK alleviates parthanatos and inflammatory injuries triggered by STC1 overexpression. Finally, following restoration of Stc1 and Parp1 expression by adeno-associated viruses, and overexpression of Stc1 and Parp1 aggravated DSS-induced colitis in Stc1INT-KO mice. In conclusion, STC1 mediates oxidative stress-associated parthanatos and aggravates inflammation via the STC1-PARP1-JNK interactions and subsequent JNK pathway activation in CD pathogenesis.

Ubiquitin signalling in Drosophila innate immune responses.

Cells respond to invading pathogens and danger signals from the environment by adapting gene expression to meet the need for protective effector molecules. While this innate immune response is required for the cell and the organism to recover, excess immune activation may lead to loss of homeostasis, thereby promoting chronic inflammation and cancer progression. The molecular basis of innate immune defence is comprised of factors promoting survival and proliferation, such as cytokines, antimicrobial peptides and anti-apoptotic proteins. As the molecular mechanisms regulating innate immune responses are conserved through evolution, the fruit fly Drosophila melanogaster serves as a convenient, affordable and ethical model organism to enhance understanding of immune signalling. Fly immunity against bacterial infection is built up by both cellular and humoral responses, where the latter is regulated by the Imd and Toll pathways activating NF-κB transcription factors Relish, Dorsal and Dif, as well as JNK activation and JAK/STAT signalling. As in mammals, the Drosophila innate immune signalling pathways are characterised by ubiquitination of signalling molecules followed by ubiquitin receptors binding to the ubiquitin chains, as well as by rapid changes in protein levels by ubiquitin-mediated targeted proteasomal and lysosomal degradation. In this review, we summarise the molecular signalling pathways regulating immune responses to pathogen infection in Drosophila, with a focus on ubiquitin-dependent control of innate immunity and inflammatory signalling.

Lipocalin 2 (LCN2) Knockdown Regulates Treg/Th17 Balance to Improve Asthma in Mice.

Purpose: Asthma substantially affects the quality of life and health of children. Lipocalin 2 (LCN2) is an immune-related protein, which is predicted to be highly expressed in asthma. Here, we investigated the role of LCN2 in ovalbumin (OVA)-induced asthma mouse model. Methods: We knocked down LCN2 in an asthma mouse model and performed histopathological analysis using hematoxylin and eosin (H&E) staining assay. Differentiated cells were assessed using Diff-Quick staining assay. We investigated the regulatory T (Treg) cell/ T helper 17 (Th17) cell balance using flow cytometry and enzyme-linked immunosorbent assay (ELISA). Inflammatory factors were measured using quantitative real-time reverse transcription PCR (qRT-PCR). The involved pathways were assessed using Western blotting. Results: LCN2 was upregulated in patients with asthma. OVA promoted pathological deterioration in the lungs, increased IgE levels in the plasma, and elevated the number of differentiated inflammatory cells, whereas LCN2 knockdown abrogated the OVA-induced effects. Additionally, the Treg/Th17 imbalance and increased inflammatory cytokine levels were improved by LCN2 knockdown in OVA-treated mice. Moreover, LCN2 knockdown reversed the activation of the janus kinase (JNK) pathway. Conclusion: LCN2 knockdown improved the Treg/Th17 balance, alleviated inflammation, and inactivated the JNK pathway in OVA-induced asthma mouse model, suggesting that LCN2 may be a novel therapeutic target for asthma in children.

Necroptosis and NLPR3 inflammasome activation mediated by ROS/JNK pathway participate in AlCl3-induced kidney damage.

Aluminum (Al) is a common environmental pollutant that can induce kidney damage. However, the mechanism is not clear. In the present study, to explored the exact mechanism of AlCl3-induced nephrotoxicity, C57BL/6 N male mice and HK-2 cells were used as experimental subjects. Our results showed that Al induced reactive oxygen species (ROS) overproduction, c-Jun N-terminal kinase (JNK) signaling activation, RIPK3-dependent necroptosis, NLRP3 inflammasome activation, and kidney damage. In addition, inhibiting JNK signaling could downregulate the protein expressions of necroptosis and NLRP3 inflammasome, thereby alleviating kidney damage. Meanwhile, clearing ROS effectively inhibited JNK signaling activation, which in turn inhibited necroptosis and NLRP3 inflammasome activation, ultimately alleviating kidney damage. In conclusion, these findings suggest that necroptosis and NLPR3 inflammasome activation mediated by ROS/JNK pathway participate in AlCl3-induced kidney damage.

Resveratrol inhibits autophagy against myocardial ischemia-reperfusion injury through the DJ-1/MEKK1/JNK pathway.

Resveratrol (RES), a natural polyphenolic compound found in red wine and grape skins, has attracted significant attention due to its cardioprotective properties. DJ-1, a multifunctional protein that participated in transcription regulation and antioxidant defense, was shown to provide a significant protective impact in cardiac cells treated with ischemia-reperfusion. We created a myocardial ischemia-reperfusion (I/R) model in vivo and in vitro by ligating the left anterior descending branch of rats and subjecting H9c2 cells to anoxia/reoxygenation (A/R) to investigate whether RES reduces myocardial ischemia-reperfusion injury by upregulating DJ-1. We discovered that RES dramatically enhanced cardiac function in rats with I/R. Subsequently, we found that RES prevented the rise in autophagy (P62 degradation and LC3-II/LC3-I increase) induced by cardiac ischemia-reperfusion in vitro and in vivo. Notably, the autophagic agonist rapamycin (RAPA) eliminated RES-induced cardioprotective effects. In addition, Further data showed that RES significantly increased the expression of DJ-1 in the myocardium with the treatment of I/R. At the same time, pretreatment with RES reduced phosphorylation of MAPK/ERK kinase kinase 1 (MEKK1) and Jun N-terminal Kinase (JNK) stimulated by cardiac ischemia-reperfusion, and Beclin-1 mRNA and protein levels while decreasing lactate dehydrogenase (LDH) and improving cell viability. However, the lentiviral shDJ-1 and JNK agonist anisomycin disrupted the effects of RES. In summary, RES could inhibit autophagy against myocardial ischemia-reperfusion injury through DJ-1 modulation of the MEKK1/JNK pathway, providing a novel therapeutic strategy for cardiac homeostasis.

Plasmodium parasitophorous vacuole membrane protein Pfs16 promotes malaria transmission by silencing mosquito immunity.

With rising cases for the first time in years, malaria remains a significant public health burden. The sexual stage of the malaria parasite infects mosquitoes to transmit malaria from host to host. Hence, an infected mosquito plays an essential role in malaria transmission. Plasmodium falciparum is the most dominant and dangerous malaria pathogen. Previous studies identified a sexual stage-specific protein 16 (Pfs16) localized to the parasitophorous vacuole membrane. Here, we elucidate the function of Pfs16 during malaria transmission. Our structural analysis identified Pfs16 as an alpha-helical integral membrane protein with one transmembrane domain connecting to two regions across parasitophorous vacuole membrane. ELISA assays showed that insect cell-expressed recombinant Pfs16 (rPfs16) interacted with Anopheles gambiae midguts, and microscopy found that rPfs16 was bound to midgut epithelial cells. Transmission-blocking assays demonstrated that polyclonal antibodies against Pfs16 significantly reduced the number of oocysts in mosquito midguts. However, on the contrary, feeding rPfs16 increased the number of oocysts. Further analysis revealed that Pfs16 reduced the activity of mosquito midgut caspase 3/7, a key enzyme in the mosquito Jun-N-terminal kinase immune pathway. We conclude that Pfs16 facilitates parasites to invade mosquito midguts by actively silencing the mosquito's innate immunity through its interaction with the midgut epithelial cells. Therefore, Pfs16 is a potential target to control malaria transmission.

Physiological and Psychological Stress of Microwave Radiation-Induced Cardiac Injury in Rats.

Electromagnetic waves are widely used in both military and civilian fields, which could cause long-term and high-power exposure to certain populations and may pose a health hazard. The aim of this study was to simulate the long-term and high-power working environment of workers using special electromagnetic radiation occupations to clarify the radiation-induced stress response and cardiac damage and thus gain insights into the mechanisms of injuries caused by electromagnetic radiation. In this study, the combination of microwave and stress was an innovative point, aiming to broaden the research direction with regard to the effect and mechanism of cardiac injury caused by radiation. The myocardial structure was observed by optical and transmission electron microscope, mitochondrial function was detected by flow cytometry, oxidative-stress markers were detected by microplate reader, serum stress hormone was detected by radioimmunoassay, and heart rate variability (HRV) was analyzed by multichannel-physiological recorder. The rats were weighed and subjected to an open field experiment. Western blot (WB) and immunofluorescence (IF) were used to detect the expressions and distributions of JNK (c-Jun N-terminal kinase), p-JNK (phosphorylated c-Jun N-terminal kinase), HSF1 (heat shock factor), and NFATc4 (nuclear factor of activated T-cell 4). This study found that radiation could lead to the disorganization, fragmentation, and dissolution of myocardial fibers, severe mitochondrial cavitation, mitochondrial dysfunction, oxidative-stress injury in myocardium, increase to stress hormone in serum, significant changes in HRV, and a slow gain in weight. The open field experiment indicated that the rats experienced anxiety and depression and had decreased exercise capacity after radiation. The expressions of JNK, p-JNK, HSF1, and NFATc4 in myocardial tissue were all increased. The above results suggested that 30 mW/cm2 of S-band microwave radiation for 35 min could cause both physiological and psychological stress damage in rats; the damage was related to the activation of the JNK pathway, which provided new ideas for research on protection from radiation.

Corrigendum: Bushen huoxue decoction inhibits RANKL-stimulated osteoclastogenesis and glucocorticoid-induced bone loss by modulating the NF-κB, ERK, and JNK signaling pathways.

[This corrects the article DOI: 10.3389/fphar.2022.1007839.].

p20BAP31 induces cell apoptosis via both AIF caspase-independent and the ROS/JNK mitochondrial pathway in colorectal cancer.

BACKGROUND: During cell apoptosis, the C-terminus of BAP31 is cleaved by caspase-8 and generates p20BAP31, which has been shown to induce an apoptotic pathway between the endoplasmic reticulum (ER) and mitochondria. However, the underlying mechanisms of p20BAP31 in cell apoptosis remains unclear. METHODS: We compared the effects of p20BAP31 on cell apoptosis in six cell lines and selected the most sensitive cells. Functional experiments were conducted, including Cell Counting Kit 8 (CCK-8), reactive oxygen species (ROS), and mitochondrial membrane potential (MMP) assay. Then, cell cycle and apoptosis were investigated by flow cytometry and verified by immunoblotting. Next, NOX inhibitors (ML171 and apocynin), ROS scavenger (NAC), JNK inhibitor (SP600125), and caspase inhibitor (Z-VAD-FMK) were used to further investigate the underlying mechanisms of p20BAP31 on cell apoptosis. Finally, apoptosis-inducing factor (AIF) translocation from the mitochondria to the nuclei was verified by immunoblotting and immunofluorescence assay. RESULTS: We found that overexpression of p20BAP31 indeed induced apoptosis and had a much greater sensitivity in HCT116 cells. Furthermore, the overexpression of p20BAP31 inhibited cell proliferation by causing S phase arrest. Further study revealed that p20BAP31 reduced MMP, with a significant increase in ROS levels, accompanied by the activation of the MAPK signaling pathway. Importantly, the mechanistic investigation indicated that p20BAP31 induces mitochondrial-dependent apoptosis by activating the ROS/JNK signaling pathway and induces caspase-independent apoptosis by promoting the nuclear translocation of AIF. CONCLUSIONS: p20BAP31 induced cell apoptosis via both the ROS/JNK mitochondrial pathway and AIF caspase-independent pathway. Compared with antitumor drugs that are susceptible to drug resistance, p20BAP31 has unique advantages for tumor therapy.

Spinocerebellar Ataxia in a Hungarian Female Patient with a Novel Variant of Unknown Significance in the CCDC88C Gene.

Spinocerebellar ataxia (SCA) 40 is an extremely rare subtype of the phenotypically and genetically diverse autosomal dominant ataxias caused by mutations of the CCDC88C gene. Most reported cases of SCA40 are characterized by late-onset cerebellar ataxia and variable extrapyramidal features; however, there is a report of a patient with early-onset spastic paraparesis as well. Here, we describe a novel missense CCDC88C mutation (p.R203W) in the hook domain of the DAPLE protein encoded by the CCDC88C gene that was identified in a female patient who developed late-onset ataxia, dysmetria and intention tremor. To explore the molecular consequences of the newly identified and previously described CCDC88C mutations, we carried out in vitro functional tests. The CCDC88C alleles were expressed in HEK293 cells, and the impact of the mutant DAPLE protein variants on JNK pathway activation and apoptosis was assessed. Our results revealed only a small-scale activation of the JNK pathway by mutant DAPLE proteins; however, increased JNK1 phosphorylation could not be detected. Additionally, none of the examined mutations triggered proapoptotic effect. In conclusion, we identified a novel mutation of the CCDC88C gene from a patient with spinocerebellar ataxia. Our results are not in accord with previous observations and do not support the primary role of the CCDC88C mutations in induction of JNK pathway activation in ataxia. Therefore, we propose that CCDC88C mutations may exert their effects through different and possibly in much broader, yet unexplored, biological processes.