Targeting VDAC: A potential therapeutic approach for mitochondrial dysfunction in Alzheimer's disease.

Mitochondrial dysfunction has been implicated in the pathogenesis of Alzheimer's disease, a neurodegenerative disorder characterized by progressive cognitive decline. Voltage-dependent anion channel (VDAC), a protein located in the outer mitochondrial membrane, plays a critical role in regulating mitochondrial function and cellular energy metabolism. Recent studies have identified VDAC as a potential therapeutic target for Alzheimer's disease. This article aims to provide an overview of the role of VDAC in mitochondrial dysfunction, its association with Alzheimer's disease, and the potential of targeting VDAC for developing novel therapeutic interventions. Understanding the involvement of VDAC in Alzheimer's disease may pave the way for the development of effective treatments that can restore mitochondrial function and halt disease progression.

Exploring the potential of treating chronic liver disease targeting the PI3K/Akt pathway and polarization mechanism of macrophages.

Chronic liver disease is a significant public health issue that can lead to considerable morbidity and mortality, imposing an enormous burden on healthcare resources. Understanding the mechanisms underlying chronic liver disease pathogenesis and developing effective treatment strategies are urgently needed. In this regard, the activation of liver resident macrophages, namely Kupffer cells, plays a vital role in liver inflammation and fibrosis. Macrophages display remarkable plasticity and can polarize into different phenotypes according to diverse microenvironmental stimuli. The polarization of macrophages into M1 pro-inflammatory or M2 anti-inflammatory phenotypes is regulated by complex signaling pathways such as the PI3K/Akt pathway. This review focuses on investigating the potential of using plant chemicals targeting the PI3K/Akt pathway for treating chronic liver disease while elucidating the polarization mechanism of macrophages under different microenvironments. Studies have demonstrated that inhibiting M1-type macrophage polarization or promoting M2-type polarization can effectively combat chronic liver diseases such as alcoholic liver disease, non-alcoholic fatty liver disease, and liver fibrosis. The PI3K/Akt pathway acts as a pivotal modulator of macrophage survival, migration, proliferation, and their responses to metabolism and inflammatory signals. Activating the PI3K/Akt pathway induces anti-inflammatory cytokine expression, resulting in the promotion of M2-like phenotype to facilitate tissue repair and resolution of inflammation. Conversely, inhibiting PI3K/Akt signaling could enhance the M1-like phenotype, which exacerbates liver damage. Targeting the PI3K/Akt pathway has tremendous potential as a therapeutic strategy for regulating macrophage polarization and activity to treat chronic liver diseases with plant chemicals, providing new avenues for liver disease treatment.

Effects of personal growth initiative on occupational engagement of college students in the uncertain social context: A cross-lagged model and a moderated mediation model.

In recent years, the international social context has become increasingly volatile, uncertain, complex, ambiguous (VUCA), and college students need a high level of long-term occupational engagement to cope with the unpredictability of the current employment environment. In this context, this study used a longitudinal design to explore the relationship between personal growth initiative and occupational engagement among college students and, based on this, further explored the role of vocational identity and Big Five personality traits in it. This study used a questionnaire survey method and the study participants were 700 college students in Shandong, China. And the time interval between the two questionnaire measurements was 4 months, with 559 final valid participants (182 males and 377 females). The following results were found in this study: (1) The cross-lagged model found that personal growth initiative was a significant positive predictor of occupational engagement. (2) The moderated mediation model found that vocational identity mediated the relationship between personal growth initiative and occupational engagement, and that neuroticism among the Big Five personality traits played a moderating role, i.e., individuals with higher level of neuroticism personality trait had a relatively weaker positive predictive effect of vocational identity on occupational engagement. This study concludes that colleges and universities need to understand students' interests and personality traits and provide more targeted career education (e.g., intentional growth training and cognitive behavioral therapy) to promote their personal growth initiatives, reduce their neuroticism levels and in turn enhance their vocational identity in order to help college students achieve long-term sustainable occupational engagement in the uncertain social context.

Characterization of Salivary Secreted Proteins That Induce Cell Death From Riptortus pedestris (Fabricius) and Their Roles in Insect-Plant Interactions.

Riptortus pedestris (Fabricius) is a polyphagous hemipteran crop pest that mainly feeds on the leguminous plants, resulting in shriveled and dimpled seeds. With recent several outbreaks in the Huang-Huai-Hai region of China, as well as in South Korea and Japan, this species has caused enormous economic losses to soybean crops. In the present study, we found that R. pedestris feeding results in local lesions at the infestation sites. To identify the key effectors that induce plant damage during feeding, the salivary glands of R. pedestris were dissected for transcriptome sequencing, and 200 putative secreted proteins were transiently expressed in N. benthamiana. Among them, three intracellular effectors (RP191, RP246, and RP302) and one apoplastic effector (RP309) were identified as necrosis-inducing proteins (NIPs), which also triggered the reactive oxidative burst. Yeast signal sequence trap and qRT-PCR analysis suggested that these proteins might be secreted into plant tissue during R. pedestris infestation. Pathogenicity assays revealed that RP191, 246, and 302 promote Phytophthora capsici infection or induce Spodoptera litura feeding by inhibiting plant immunity. RP302 is localized to the cytoplasm and nuclei, while RP191 and 246 are endoplasmic reticulum (ER) resident proteins. RP309 stimulates the expression of PTI marker genes, and its induced cell death depends on co-receptors NbBAK1 and NbSOBIR1, indicating that it is a HAMP. Bioinformatics analysis demonstrated that four NIPs are recently evolved effectors and only conserved in the Pentatomidae. In this study, saliva-secreted proteins were used as the starting point to preliminarily analyze the harm mechanism of R. pedestris, which might provide a new idea and theoretical basis for this species control.

The mirid bug Apolygus lucorum deploys a glutathione peroxidase as a candidate effector to enhance plant susceptibility.

The mirid bug Apolygus lucorum has become a major agricultural pest since the large-scale cultivation of Bt-cotton. It was assumed that A. lucorum, similarly to other phloem sap insects, could secrete saliva that contains effector proteins into plant interfaces to perturb host cellular processes during feeding. However, the secreted effectors of A. lucorum are still uncharacterized and unstudied. In this study, 1878 putative secreted proteins were identified from the transcriptome of A. lucorum, which either had homology with published aphid effectors or shared common features with plant pathogens and insect effectors. One hundred and seventy-two candidate effectors were used for cell death-inducing/suppressing assays, and a putative salivary gland effector, Apolygus lucorum cell death inhibitor 6 (Al6), was characterized. The mRNAs of Al6 were enriched at feeding stages (nymph and adult) and, in particular, in salivary glands. Moreover, we revealed that the secreted Al6 encoded an active glutathione peroxidase that reduced reactive oxygen species (ROS) accumulation induced by INF1 or Flg22. Expression of the Al6 gene in planta altered insect feeding behavior and promoted plant pathogen infections. Inhibition of cell death and enhanced plant susceptibility to insect and pathogens are dependent on glutathione peroxidase activity of Al6. Thus, this study shows that a candidate salivary gland effector, Al6, functions as a glutathione peroxidase and suppresses ROS induced by pathogen-associated molecular pattern to inhibit pattern-triggered immunity (PTI)-induced cell death. The identification and molecular mechanism analysis of the Al6 candidate effector in A. lucorum will provide new insight into the molecular mechanisms of insect-plant interactions.

The glycoside hydrolase 18 family chitinases are associated with development and virulence in the mosquito pathogen Pythium guiyangense.

Chitinases, the enzymes responsible for the biological degradation of chitin, participate in numerous physiological processes such as nutrition, parasitism, morphogenesis and immunity in various organisms. However, the genome-wide distribution, evolution and biological functions of chitinases are rarely reported in oomycetes. This study systematically investigated the glycoside hydrolase 18 (GH18) family of chitinases from the mosquito pathogenic oomycete, Pythium guiyangense using bioinformatics and experimental assays. A total of 3 pairs of GH18 chitinase genes distributed in three distinct phylogenic clusters were identified from P. guiyangense genome, which is consistent with the ones in plant pathogenic oomycetes. Further transcriptional analysis revealed that Pgchi1/2 was highly expressed at the development stages, while Pgchi3/4 and Pgchi5/6 were up-regulated at the infection stages. The biological function analysis of chitinase genes using genetic transformation silencing method showed that silencing of Pgchi1/2 resulted in reduced zoospore production, without affecting the virulence. However, attenuation of Pgchi3/4 and Pgchi5/6 genes regulated not only oxidative stress responses, but also led to decreased infection rates to mosquito larvae. Taken together, this study provides a comprehensive overview of P. guiyangense chitinase family and reveals their diverse roles in the development, stress response, and virulence, which would elucidate insightful information on the molecular mechanism of chitinase in entomopathogenic pathogens.

Genome-wide and functional analyses of tyrosine kinase-like family genes reveal potential roles in development and virulence in mosquito pathogen Pythium guiyangense.

The tyrosine kinase-like (TKL) gene family is widely existed in most eukaryotes and participates in many biological processes, however, has been rarely studied in oomycetes. In this study we performed bioinformatic and experimental analyses to characterize TKLs in Pythium guiyangense, a promising mosquito biological control agent. Our results revealed that TKLs were widely distributed in all the detected oomycetes, but were largely expanded in P. guiyangense in a species-specific expansion manner. The expansion was mostly driven by whole-genome duplication and tandem duplication. Domain distributions and exon-intron structures were highly conserved in the same group while diverse in different groups, suggesting of functional divergence. Transcriptional analysis revealed that over one fourth of TKLs were differentially expressed after infection of mosquito larvae, implying that these genes might participate in the infection process. Furthermore, subgroup A TKLs were functionally investigated using genetic transformation silencing method. Our findings demonstrated that subgroup A TKLs were up-regulated at the early infection stages and silencing of subgroup A TKLs led to reduced mycelia growth, zoospore production and alteration of stress responses. Pathogenicity assays also revealed that silencing of subgroup A TKLs reduced P. guiyangense virulence to mosquito larvae. Taken together, this study provides a comprehensive overview of P. guiyangense TKL family and reveals their potential roles in growth, development, stress response, and especially virulence.

Infection mechanisms and putative effector repertoire of the mosquito pathogenic oomycete Pythium guiyangense uncovered by genomic analysis.

Pythium guiyangense, an oomycete from a genus of mostly plant pathogens, is an effective biological control agent that has wide potential to manage diverse mosquitoes. However, its mosquito-killing mechanisms are almost unknown. In this study, we observed that P. guiyangense could utilize cuticle penetration and ingestion of mycelia into the digestive system to infect mosquito larvae. To explore pathogenic mechanisms, a high-quality genome sequence with 239 contigs and an N50 contig length of 1,009 kb was generated. The genome assembly is approximately 110 Mb, which is almost twice the size of other sequenced Pythium genomes. Further genome analysis suggests that P. guiyangense may arise from a hybridization of two related but distinct parental species. Phylogenetic analysis demonstrated that P. guiyangense likely evolved from common ancestors shared with plant pathogens. Comparative genome analysis coupled with transcriptome sequencing data suggested that P. guiyangense may employ multiple virulence mechanisms to infect mosquitoes, including secreted proteases and kazal-type protease inhibitors. It also shares intracellular Crinkler (CRN) effectors used by plant pathogenic oomycetes to facilitate the colonization of plant hosts. Our experimental evidence demonstrates that CRN effectors of P. guiyangense can be toxic to insect cells. The infection mechanisms and putative virulence effectors of P. guiyangense uncovered by this study provide the basis to develop improved mosquito control strategies. These data also provide useful knowledge on host adaptation and evolution of the entomopathogenic lifestyle within the oomycete lineage. A deeper understanding of the biology of P. guiyangense effectors might also be useful for management of other important agricultural pests.

Xenobiotic pregnane X receptor promotes neointimal formation in balloon-injured rat carotid arteries.

Pregnane X receptor (PXR) is a member of nuclear receptor superfamily and responsible for the detoxification of xenobiotics. Recent studies demonstrated that PXR was also expressed in the vasculature and protected the vessels from endogenous and exogenous insults, thus representing a novel gatekeeper in vascular defense. In this study, we examined the potential function of PXR in the neointimal formation following vascular injury. In the rat carotid artery after balloon injury, overexpression of a constitutively active PXR increased the intima-to-media ratio in the injured region. PXR increased cell proliferation and migration in cultured rat aortic smooth muscle cells (SMCs) by inducing the expressions of cyclins (cyclin A, D1, and E) and cyclin-dependent kinase 2. In addition, PXR increased the phosphorylation and activation of extracellular-signal-regulated kinase 1/2 (ERK1/2) and p38 mitogen-activated protein kinase (MAPK). Inactivation of ERK1/2 and p38 MAPK pathways using selective inhibitors (U0126 and SB203580) abrogated PXR-induced SMC proliferation and migration. Furthermore, cigarette smoke particles (CSP) activated PXR in SMCs. Knockdown of PXR by small interfering RNA suppressed the cell proliferation, migration, and activation of the MAPK pathways by CSP. These findings suggested a novel role for PXR in promoting SMC proliferation and migration, and neointimal hyperplasia. Therefore, PXR may be a potential therapeutic target for vascular disease related to xenobiotics such as cigarette smoking and other environmental pollutants.

Nuciferine relaxes rat mesenteric arteries through endothelium-dependent and -independent mechanisms.

BACKGROUND AND PURPOSE: Nuciferine, a constituent of lotus leaf, is an aromatic ring-containing alkaloid, with antioxidative properties. We hypothesize nuciferine might affect vascular reactivity. This study aimed at determining the effects of nuciferine on vasomotor tone and the underlying mechanism EXPERIMENTAL APPROACH: Nuciferine-induced relaxations in rings of rat main mesenteric arteries were measured by wire myographs. Endothelial NOS (eNOS) was determined by immunoblotting. Intracellular NO production in HUVECs and Ca(2+) level in both HUVECs and vascular smooth muscle cells (VSMCs) from rat mesenteric arteries were assessed by fluorescence imaging. KEY RESULTS: Nuciferine induced relaxations in arterial segments pre-contracted by KCl or phenylephrine. Nuciferine-elicited arterial relaxations were reduced by removal of endothelium or by pretreatment with the eNOS inhibitor L-NAME or the NO-sensitive guanylyl cyclase inhibitor ODQ. In HUVECs, the phosphorylation of eNOS at Ser(1177) and increase in cytosolic NO level induced by nuciferine were mediated by extracellular Ca(2+) influx. Under endothelium-free conditions, nuciferine attenuated CaCl2-induced contraction in Ca(2+)-free depolarizing medium. In the absence of extracellular calcium, nuciferine relieved the vasoconstriction induced by phenylephrine and the addition of CaCl2. Nuciferine also suppressed Ca(2+) influx in Ca(2+)-free K(+)-containing solution in VSMCs. CONCLUSIONS AND IMPLICATIONS: Nuciferine has a vasorelaxant effect via both endothelium-dependent and -independent mechanisms. These results suggest that nuciferine may have a therapeutic effect on vascular diseases associated with aberrant vasoconstriction.