Journal of advanced research最新文献

Background: Viral infectious diseases have long posed a challenge to humanity. In recent decades, transient receptor potential (TRP) channels have emerged as newly investigated cation channels. Increasing evidence suggests that TRP channel-mediated Ca²⁺ homeostasis disruptions, along with associated pathological changes, are critical factors in the onset and progression of viral infectious diseases. However, the precise roles and mechanisms of TRP channels in these diseases remain to be systematically elucidated.

Aim of review: The aim of this review is to systematically summarize recent advances in understanding TRP channels in viral infections, and based on current progress and challenges, propose future directions for research.

Key scientific concepts of review: This review summarizes the classification and biological functions of the TRP family, explores the mechanisms by which TRP channels contribute to viral infections, and highlights specific mechanisms at three levels: virus, host, and outcome. These include the direct role in viral biology and replication, the indirect role in host immunity and inflammation, and the resulting pathological changes. Additionally, we discuss the potential applications of the TRP family in the treatment of viral infectious diseases and propose future research directions.

Introduction: ABT-199 (venetoclax) is a BCL-2 suppressor with pronounced effects on acute myeloid leukemia (AML). However, its usefulness as a monotherapy or in combination with hypomethylating medicines like azacitidine is debatable due to acquired resistance. Usnic acid, a dibenzofuran extracted from lichen Usnea diffracta Vain, exhibits anticancer properties and may counteract multidrug resistance in leukemia cells.

Objective: This study investigated whether usnic acid at low-cytotoxicity level could enhance sensitivity of AML cells with acquired resistance to ABT-199 by targeting the integrated stress response pathways.

Methods: To investigate the combined effects on AML cells, we used a cell viability test, flow cytometry to quantify apoptosis, cell cycle analysis, and mitochondrial membrane potential measurement. RNA-seq and immunoblot were used to determine the potential mechanisms of ABT-199 + usnic acid combination.

Results: Usnic acid, at a low cytotoxicity level, successfully restored ABT-199 sensitivity in AML cell lines that had developed ABT-199 resistance and increased ABT-199's antileukemic activity in a xenograft model. Mechanistically, the combination of usnic acid and ABT-199 cooperated to boost the expression of the integrated stress response (ISR)-associated genes ATF4, CHOP, and NOXA through the heme-regulated inhibitor kinase (HRI), while also promoting the degradation of the anti-apoptotic protein MCL-1. ISRIB, a compound that blocks the ISR, was able to reverse the growth suppression and cell death, the increase in expression of genes related with the ISR, and the inhibition of MCL-1 protein caused by combination therapy. Additionally, the downregulation of MCL-1 was linked to an increase in MCL-1 phosphorylation at serine 159 and subsequent destruction by the proteasome.

Conclusion: In summary, usnic acid improves chemosensitivity to ABT-199 by triggering the integrated stress response, leading to decreased levels of MCL-1 protein, suggesting a potential treatment for AML cases resistant to Bcl-2 inhibitors.

Introduction: Invasive species pose a major threat to global biodiversity and agricultural productivity, yet the genomic mechanisms driving their rapid expansion into new habitats are not fully understood. The fall armyworm, Spodoptera frugiperda, originally from the Americas, has expanded its reach across the Old World, causing substantial reduction in crop yield. Although the hybridization between two genetically distinct strains has been well-documented, the role of such hybridization in enhancing the species' invasive capabilities remains largely unexplored.

Objectives: This study aims to investigate the contributions of hybridization and natural selection to the rapid invasion of the fall armyworm.

Methods: We analyzed the whole-genome resequencing data from 432 individuals spanning its global distribution. We identified the genomic signatures of selection associated with invasion and explored their linkage with the Tpi gene indicating strain differentiation. Furthermore, we detected signatures of balancing selection in native populations for candidate genes that underwent selective sweeps during the invasion process.

Results: Our analysis revealed pronounced genomic differentiation between native and invasive populations. Invasive populations displayed a uniform genomic structure distinctly different from that of native populations, indicating hybridization between the strains during invasion. This hybridization likely contributes to maintaining high genetic diversity in invasive regions, which is crucial for survival and adaptation. Additionally, polymorphisms on genes under selection during invasion were possibly preserved through balancing selection in their native environments.

Conclusion: Our findings reveal the genomic basis of the fall armyworm's successful invasion and rapid adaptation to new environments, highlighting the important role of hybridization in the dynamics of invasive species.

Introduction: Myocardial ischemia-reperfusion injury (MIRI) remains a prevalent clinical challenge globally, lacking an ideal therapeutic strategy. Macrophages play a pivotal role in MIRI pathophysiology, exhibiting dynamic inflammatory and resolutive functions. Macrophage polarization and metabolism are intricately linked to MIRI, presenting potential therapeutic targets. Pubescenoside C (PBC) from Ilex pubescens showed significantly anti-inflammatory effects, however, the effect of PBC on MIRI is unknown.

Objectives: This study aimed to assess the cardioprotective effects of PBC against MIRI and elucidate the underlying mechanisms.

Methods: Sprague-Dawley rats, H9c2 and RAW264.7 macrophages were used to establish the in vitro and in vivo models of MIRI. TTC/Evans blue staining, immunohistochemical staining, metabonomics analysis, chemical probe, surface plasmon resonance (SPR), co-immunoprecipitation (CO-IP) assays were used for pharmacodynamic and mechanism study.

Results: PBC administration effectively reduced myocardial infarct size, decreased ST-segment elevation, and lowered CK-MB levels, concurrently promoting macrophage M2 polarization in MIRI. Furthermore, PBC-treated macrophages and their conditioned culture medium attenuated the apoptosis of H9c2 cells induced by oxygen-glucose deprivation/reoxygenation (OGD/R). Metabonomics analysis revealed that PBC increased the production of itaconic acid (ITA) and malic acid (MA) in macrophages, which conferred protection against OGD/R injury in H9c2 cells. Mechanistic investigations indicated that ITA exerted its effects by covalently modifying pyruvate kinase M2 (PKM2) at Cys474, Cys424, and Lys151, thereby facilitating PKM2's mitochondrial translocation and enhancing the PKM2/Bcl2 interaction, subsequently leading to decreased degradation of Bcl2. SPR assays further revealed that PBC bound to HSP90, facilitating the interaction between HSP90 and GSK3β and resulting in the inactivation of GSK3β activity and upregulation of key metabolic enzymes for ITA and MA production (Acod1 and Mdh2).

Conclusion: PBC alleviates MIRI-induced cardiomyocyte apoptosis by modulating the HSP90/ITA/PKM2 axis. Furthermore, pharmacological upregulation of ITA emerges as a promising therapeutic approach for MIRI, hinting at PBC's potential as a candidate drug for MIRI therapy.

Introduction: High fructose intake has been implicated as a risk factor for behavioral disorders, potentially through cell ferroptosis induction in the central nervous system. Neural stem cells (NSCs) are crucial for maintaining hippocampal neurogenesis to resist behavioral alterations. Gastrodin, derived from the traditional Chinese herb Gastrodia elata, has neuroprotective effect.

Objectives: This study aimed to elucidate the underlying mechanism by which high fructose induces sweet taste preference and assesses the impact of gastrodin on hippocampal NSC ferroptosis.

Methods: Mice and cultured NSCs were treated with high fructose and/or gastrodin, respectively. NSC ferroptosis was evaluated by assay of lipid peroxidation and DNA double-strand breaks. Transcriptome sequencing (RNA-seq), Western blotting, and chromatin immunoprecipitation (ChIP) were employed to explore the potential mechanism underlying high fructose-induced NSC ferroptosis and the modulation of gastrodin. Simultaneously, specific gene expression was regulated by lentivirus injection into the hippocampus of mice.

Results: Our data showed that gastrodin mitigated sweet taste preference decline and hippocampal NSC ferroptosis in high fructose-fed mice, being consistent with reduction of reactive oxygen species (ROS) and iron accumulation in hippocampal NSC mitochondria. Mechanistically, we identified CDGSH iron-sulfur domain 1 (CISD1) as a mediator of NSC ferroptosis, with its expression being augmented by high fructose. Overexpression of Zic family member 2 (ZIC2) increased the transcription of Cisd1 gene. Additionally, overexpression of Zic2 with lentiviral vectors in hippocampus showed the decreased sweet taste preference in mice, consistently up-regulated CISD1 protein expression and reduced hippocampal NSC number. Gastrodin downregulated ZIC2 expression to inhibit CISD1 transcription in its attenuation of high fructose-induced NSC ferroptosis and sweet taste preference decrease.

Conclusion: Collectively, high fructose can drive hippocampal NSC ferroptosis by upregulating ZIC2 and CISD1 expression, thereby contributing to the decline in sweet taste preference. Gastrodin emerges as a promising agent for mitigating NSC ferroptosis and improving sweet taste preference.

Introduction: Triple-negative breast cancer (TNBC) is the primary cause of breast cancer-induced death in women. Literature has confirmed the benefits of Salidroside (Sal) in treating TNBC. However, the study about potential therapeutic targets and mechanisms of Sal-anchored TNBC remains limited.

Objective: This study was designed to explore the main targets and potential mechanisms of Sal against TNBC.

Methods: Network pharmacology, bioinformatics, and machine learning algorithm strategies were integrated to examine the role, potential targets, and mechanisms of the Sal act in TNBC. MDA-MB-231 cells and tumor-bearing nude mice were chosen for in vitro and in vivo experimentation. Cell viability and cytotoxicity were determined using CCK-8, LDH test, and Calcein-AM/PI staining. Antioxidant defense, lipid peroxidation, and iron metabolism were explored using glutathione, glutathione peroxidase, malondialdehyde (MDA), C11-BODIPY 581/591 probe, and FerroOrange dye. Glutathione peroxidase 4 (GPX4) or stearoyl-CoA desaturase 1 (SCD1) overexpression or nuclear receptor co-activator 4 (NCOA4) deficiency was performed to demonstrate the mechanism of Sal on TNBC.

Results: The prediction results confirmed that 22 ferroptosis-related genes were identified in Sal and TNBC, revealing that the potential mechanism of the Sal act on TNBC was linked with ferroptosis. Besides, these genes were mainly involved in the mTOR, PI3K/AKT, and autophagy signaling pathway by functional enrichment analysis. The in vitro validation results confirmed that Sal inhibited TNBC cell proliferation by modulating ferroptosis via elevation of intracellular Fe²⁺ and lipid peroxidation. Mechanistically, Sal sensitized TNBC cells to ferroptosis by inhibiting the PI3K/AKT/mTOR axis, thereby suppressing SCD1-mediated lipogenesis of monounsaturated fatty acids to induce lipid peroxidation, additionally facilitating NCOA4-mediated ferritinophagy to increase intracellular Fe²⁺ content. The GPX4 or SCD1 overexpression or NCOA4 deficiency results further supported our mechanistic studies. In vivo experimentation confirmed that Sal is vital for slowing down tumor growth by inducing ferroptosis.

Conclusions: Overall, this study elucidates TNBC pathogenesis closely linked to ferroptosis and identifies potential biomarkers in TNBC. Meanwhile, the study elucidates that Sal sensitizes TNBC to ferroptosis by SCD1-mediated lipogenesis and NCOA4-mediated ferritinophagy, regulated by PI3K/AKT/mTOR signaling pathways. Our findings provide a theoretical basis for applying Sal to treat TNBC.

Iron deficiency is a common nutritional issue that seriously affects male reproductive health. Lotus root polysaccharide iron (LRPF), a novel nutritional supplement, may ameliorate the damage caused by iron deficiency, however, the mechanism is unclear. In this study, we comprehensively determined the benefits of LRPF on reproduction in iron-deficient mice by integrating transcriptomics, microbiomics and serum metabolomics. Microbiomics showed that LRPF could restore changes to the intestinal microbiota caused by iron deficiency. Metabolomics results showed that LRPF stabilised steroid hormone and fatty acid metabolism in iron-deficient mice, reduced the content of ethyl chrysanthemumate (EC) and ameliorated the reproductive impairment. The transcriptomic analysis showed that LRPF regulated steroid hormone synthesis and the peroxisome proliferator-activated receptor (PPAR) signalling pathway in iron-deficient mice. In vitro experiments showed that LRPF could promote steroid hormone synthesis in Leydig cells by activating PPARγ. In conclusion, this study highlights the advantage of LRPF to improve testicular development.

Introduction: Granulosa cells (GCs) is essential for maintaining follicular development. Follicle-stimulating Hormone (FSH) has been demonstrated to effectively promote GCs proliferation, driving the establishment of various superovulation techniques for animal husbandry. However, these techniques face challenges, such as high costs, hormonal imbalances, and an increased risk of early ovarian dysfunction. Therefore, it is important to investigate new methods to improve GCs proliferation.

Objectives: This study aimed to investigate the effect of sulforaphane (SFN) on ovarian GCs proliferation and the underlying mechanisms.

Methods: A comparative transcriptomic analysis of ovaries from the control, SFN, and FSH groups was conducted to identify the primary factors contributing to high proliferative capacity. The role of SFN in the regulation of cell proliferation has been examined in mouse ovarian GCs. Gene interference, overexpression, CUT&TAG technology, and transcriptome analyses were performed to elucidate the underlying mechanisms of the nuclear factor E2-related factor 2 (NRF2)-transketolase (TKT) axis in mediating GCs proliferation.

Results: Our research revealed a previously unknown function of SFN, an isothiocyanate of plant origin that is prevalent in cruciferous vegetables, in facilitating the proliferation of mouse ovarian GCs. The efficacy of SFN in enhancing GCs proliferation is similar to that of FSH. At the mechanistic level, SFN promotes NRF2 to transport to the nucleus, which subsequently activates the key enzyme of the non-oxidative pentose phosphate pathway TKT. This activation is instrumental in generating ribose 5-phosphate, a critical precursor for amino acid and nucleotide biosynthesis that underpins the proliferation of GCs.

Conclusion: Collectively, our findings delineate a novel pathway by which SFN, through the NRF2-TKT axis, enhances the nucleotide pool and thereby supports the proliferation of mouse GCs, presenting novel avenues for exploration in reproductive biology and agricultural sciences.

Introduction: Diabetic kidney disease (DKD) has become the primary cause of chronic renal failure in China, and renal tubulointerstitial fibrosis plays a central role in DKD progression. Urinary exosomes, which reflect kidney changes, are largely influenced by RNA-binding proteins (RBPs) in their miRNA content.

Objectives: Our research aimed to determine the effect of the RNA-binding protein RBMX on exosomal miRNA in DKD.

Methods: We introduced a higher level of Rbmx into diabetic mice using an adenoassociated virus and isolated exosomes from their kidney tissue through advanced centrifugation techniques and specialized kits. We then conducted a series of tests, including qRT-PCR, Western blot, MitoSOX, ATP luminescence, coimmunoprecipitation, SUMOylation assays, RNA immunoprecipitation, and confocal microscopy.

Results: RBMX is found in higher levels in DKD and contributes to worsening kidney fibrosis, mitochondrial damage, and miRNA mismanagement in exosomes. It specifically binds with miR-26a, miR-23c, and miR-874 within the exosomes. This dysfunction may be linked to changes in RBMX SUMOylation. These miRNAs seem to protect against mitochondrial damage in kidney cells by targeting CERS6.

Conclusion: DeSUMOylation of RBMX plays a crucial role in determining the makeup of miRNAs in kidney cell exosomes, impacting the protective miRNAs which regulate mitochondrial damage through their interaction with CERS6 mRNA, ultimately affecting mitochondrial health in DKD.