Modulation Of Gene Expression Research Articles

Time-restricted feeding modulates gene expression related with rhythm and inflammation in Mongolian gerbils

Time-restricted feeding (TRF) has the potential to modulate circadian rhythm and widely studied in humans and laboratory mice. However, less is known about the physiological responses to TRF in wild mammals. Here, we used Mongolian gerbils, Meriones unguiculatus, to explore the effect of 6-week TRF on gene expression related with circadian rhythm and inflammation. The TRF gerbils had higher cumulative food intake than the ad libitum (AL) group, but body mass, feeding frequency/time and metabolic rate did not differ between groups. In the hypothalamus, downregulation of rhythm-related genes Per3, Cry1 and Dbp was detected in the daytime-restricted feeding (DRF) group and Cry1 was downregulated in the nighttime-restricted feeding (NRF) group. In the liver, the expression of Per1/3, Rev-erbα/β and Dbp was lower, and Bmal1 was higher in the DRF than in AL group, while NRF gerbils showed no changes. In the colon, the expression of Bmal1 and Cry1 was higher but Per3, Rev-erbα/β and Dbp were lower in the DRF than in AL group. Further, the expression of inflammation-related genes such as NF-κB, IL-1β, IL-18 and Nlrp3 was lower in the liver of DRF gerbils, and IL-1β was lower both in the hypothalamus and liver of NRF gerbils. Moreover, the genes related with inflammation such as NF-κB, Nlrp3, IL-10/18/1β and Tnf-α were positively or negatively correlated with multiple rhythm-related genes in the central and peripheral organs. In conclusion, TRF, particularly DRF, could modulate rhythm-related genes in the central and peripheral tissues and reduce hepatic expression of inflammation-related genes in gerbils.

Single-cell transcriptomic landscape reveals the role of intermediate monocytes in aneurysmal subarachnoid hemorrhage.

Neuroinflammation is associated with brain injury and poor outcomes after aneurysmal subarachnoid hemorrhage (SAH). In this study, we performed single-cell RNA sequencing (scRNA-seq) to analyze monocytes and explore the mechanisms of neuroinflammation after SAH. We recruited two male patients with SAH and collected paired cerebrospinal fluid (CSF) and peripheral blood (PB) samples from each patient. Mononuclear cells from the CSF and PB samples were sequenced using 10x Genomics scRNA-seq. Additionally, scRNA-seq data for CSF from eight healthy individuals were obtained from the Gene Expression Omnibus database, serving as healthy controls (HC). We employed various R packages to comprehensively study the heterogeneity of transcriptome and phenotype of monocytes, including monocyte subset identification, function pathways, development and differentiation, and communication interaction. (1) A total of 17,242 cells were obtained in this study, including 7,224 cells from CSF and 10,018 cells from PB, mainly identified as monocytes, T cells, B cells, and NK cells. (2) Monocytes were divided into three subsets based on the expression of CD14 and CD16: classical monocytes (CM), intermediate monocytes (IM), and nonclassical monocytes (NCM). Differentially expressed gene modules regulated the differentiation and biological function in monocyte subsets. (3) Compared with healthy controls, both the toll-like receptor (TLR) and nod-like receptor (NLR) pathways were significantly activated and upregulated in IM from CSF after SAH. The biological processes related to neuroinflammation, such as leukocyte migration and immune response regulation, were also enriched in IM. These findings revealed that IM may play a key role in neuroinflammation by mediating the TLR and NLR pathways after SAH. In conclusion, we establish a single-cell transcriptomic landscape of immune cells and uncover the heterogeneity of monocyte subsets in SAH. These findings offer new insights into the underlying mechanisms of neuroinflammation and therapeutic targets for SAH.

Dose-dependent responses to canonical Wnt transcriptional complexes in the regulation of mammalian nephron progenitors.

In vivo and in vitro studies argue that concentration-dependent Wnt signaling regulates mammalian nephron progenitor cell (NPC) programs. Canonical Wnt signaling is regulated through the stabilization of β-catenin, a transcriptional co-activator when complexed with Lef/Tcf DNA-binding partners. Using the GSK3β inhibitor CHIR99021 (CHIR) to block GSK3β-dependent destruction of β-catenin, we examined dose-dependent responses to β-catenin in mouse NPCs, using mRNA transduction to modify gene expression. Low CHIR-dependent proliferation of NPCs was blocked on β-catenin removal, with evidence of NPCs arresting at the G2-M transition. While NPC identity was maintained following β-catenin removal, mRNA-seq identified low CHIR and β-catenin dependent genes. High CHIR activated nephrogenesis. Nephrogenic programming was dependent on Lef/Tcf factors and β-catenin transcriptional activity. Molecular and cellular features of early nephrogenesis were driven in the absence of CHIR by a mutated stabilized form of β-catenin. Chromatin association studies indicate low and high CHIR response genes are likely direct targets of canonical Wnt transcriptional complexes. Together, these studies provide evidence for concentration-dependent Wnt signaling in the regulation of NPCs and provide new insight into Wnt targets initiating mammalian nephrogenesis.

Metabolic engineering of Saccharomyces cerevisiae for enhanced taxadiene production

BackgroundMetabolic engineering enables the sustainable and cost-efficient production of complex chemicals. Efficient production of terpenes in Saccharomyces cerevisiae can be achieved by recruiting an intermediate of the mevalonate pathway. The present study aimed to evaluate the engineering strategies of S. cerevisiae for the production of taxadiene, a precursor of taxol, an antineoplastic drug.ResultSCIGS22a, a previously engineered strain with modifications in the mevalonate pathway (MVA), was used as a background strain. This strain was engineered to enable a high flux towards farnesyl diphosphate (FPP) and the availability of NADPH. The strain MVA was generated from SCIGS22a by overexpressing all mevalonate pathway genes. Combining the background strains with 16 different episomal plasmids, which included the combination of 4 genes: tHMGR (3-hydroxy-3-methylglutaryl-CoA reductase), ERG20 (farnesyl pyrophosphate synthase), GGPPS (geranyl diphosphate synthase) and TS (taxadiene synthase) resulted in the highest taxadiene production in S. cerevisiae of 528 mg/L.ConclusionOur study highlights the critical role of pathway balance in metabolic engineering, mainly when dealing with toxic molecules like taxadiene. We achieved significant improvements in taxadiene production by employing a combinatorial approach and focusing on balancing the downstream and upstream pathways. These findings emphasize the importance of minor gene expression modification levels to achieve a well-balanced pathway, ultimately leading to enhanced taxadiene accumulation.

Low-Dose Metformin and Profibrotic Signature in Central Centrifugal Cicatricial Alopecia

Central centrifugal cicatricial alopecia (CCCA) is a scarring alopecia predominantly affecting Black female individuals. Current conventional treatments target inflammation but not the underlying fibrotic processes, often leading to permanent hair loss. To investigate the associations of low-dose oral metformin, an antidiabetic medication with antifibrotic properties, with clinical symptoms and scalp gene expression patterns in patients with CCCA. This retrospective clinical case series and transcriptomic analysis included patients treated at a single tertiary academic medical center between January 2023 and March 2024. All patients had biopsy-confirmed CCCA refractory to standard treatments. Transcriptomic analysis was performed on patients with previously banked, paired scalp biopsies before and after treatment with adjuvant metformin for at least 6 weeks. Extended-release metformin, 500 mg, once daily was added to participants' baseline CCCA treatment regimens. Clinical assessments included pruritus, inflammation, scalp resistance, and hair regrowth. Gene expression profiling via bulk RNA sequencing analysis evaluated differential gene expression and pathway enrichment. A total of 12 Black female participants were included in the study, and transcriptomic analysis was performed in 4 participants. After at least 6 months of metformin treatment, 9 participants experienced improvement in disease, including scalp pain, inflammation, and/or pruritus, and 6 demonstrated clinical evidence of hair regrowth. The addition of metformin led to reversal of many prominent gene pathways previously identified in CCCA. Transcriptomic analysis revealed upregulation of pathways and genes (keratin-associated proteins [KRTAPs]) involved in keratinization, epidermis development, and the hair cycle (absolute log2-fold change > 4), with concomitant downregulation of fibrosis-related pathways and genes (eg, MMP7, COL6A1) (fold change >1.5; all false discovery rate <.05). Gene set analysis showed reduced expression of helper T cell 17 and epithelial-mesenchymal transition pathways and elevated adenosine monophosphate kinase signaling and KRTAPs after metformin treatment. In this case series of patients with treatment-refractory CCCA, low-dose oral metformin was associated with symptomatic improvement and dual modulation of gene expression, stimulating hair growth pathways while suppressing fibrosis and inflammation markers. These findings provide a rationale for future clinical trials studying metformin as a targeted therapy for CCCA and other cicatricial alopecias.

Therapeutic applications of RNA nanostructures.

RNA-based therapeutics have gained wide public interest in recent years. RNA is a versatile molecule that exists in many forms including mRNA, siRNA, miRNA, ribozymes, and other non-coding RNAs and is primarily applied for gene therapy. RNA is also used as a modular building block to construct RNA nanostructures. The programmable nature of RNA nanostructures enables the generation of simple, modulable, and multi-functional RNA-based therapeutics. Although the therapeutic application of RNA may be limited due to its structural instability, advances in RNA nanotechnology have improved the stability of RNA nanostructures for greater application. Various strategies have been developed to enhance the stability of RNA nanostructures enabling their application in vivo. In this review, we examine the therapeutic applications of RNA nanostructures. Non-immunogenic RNA nanostructures can be rationally designed with functional RNA molecules to modulate gene expression for gene therapy. On the other hand, nucleic acids can be sensed by cellular receptors to elicit an innate immune response, for which certain DNA and RNA motifs can function as adjuvants. Taking advantage of this adjuvant potential, RNA nanostructures can be used for immunotherapy and be designed for cancer vaccines. Thus, we examine the therapeutic application of immunogenic RNA nanostructures for cancer immunotherapy. RNA nanostructures represent promising platforms to design new nanodrugs, gene therapeutics, immunotherapeutic adjuvants, and cancer vaccines. Ongoing research in the field of RNA nanotechnology will continue to empower the development of RNA nanostructure-based therapeutics with high efficacy and limited toxicity.

Design, Synthesis, and In Vitro Cytotoxic Studies of Some Novel Arylidene-Hydrazinyl-Thiazoles as Anticancer and Apoptosis-Inducing Agents.

Cancer, defined by uncontrolled cell growth, poses a significant global health challenge, necessitating the development of new anticancer drugs crucial to address drug resistance, side effects, and the need for combination therapies. The study presents the design, synthesis, and anticancer screening of a series of novel functionalized arylidene-hydrazinyl-thiazoles against various human cancer cell lines. The environmentally benign synthetic protocol involves the visible-light prompted, NBS-mediated domino reaction of thiosemicarbazide, heteroaryl aldehydes, and unsymmetrical 1,3-diketones. The regioselective organic transformation delivered the single regioisomeric product, characterized unambiguously through detailed 2D NMR spectral studies. In vitro cytotoxic studies revealed that the synthesized derivatives exhibited excellent cytotoxic potential against BxPC-3, MOLT-4, and MCF-7 cancer cell lines. Notably, compounds 4m, 4n, and 4r showed significant cytotoxicity, reducing cell survival to 23.85-26.45% for BxPC-3, 30.08-33.30% for MOLT-4, and 44.40-47.63% for MCF-7 at a concentration of 10 μM. These compounds profoundly induced apoptosis, evidenced by increased caspase-3/7 activity, loss of mitochondrial membrane potential, and modulation of Bcl2 and Bax gene expression. Additionally, these compounds caused robust cell cycle arrest at the G2/M phase by inhibiting tubulin polymerization, indicating their multifaceted impact on cancer cells.

Epigenetic Regulation of DNA Methylation and RNA Interference in Gastric Cancer: A 2024 Update.

Gastric cancer (GC) remains a significant public health concern because of its lethality, underscoring the need for deeper insights into its molecular mechanisms. Recent studies have increasingly highlighted the role of epigenetic modifications as critical players in cancer progression. Despite their importance, research specifically addressing epigenetic factors in GC is relatively scarce. This paper seeks to bridge that gap by examining recent literature that elucidates the epigenetic landscape associated with GC. The investigation of long noncoding RNAs (lncRNAs) has revealed their substantial involvement in gene dysregulation and epigenetic alterations within GC tumors. Notably, lncRNAs such as LINC00853 and LINC01266 have been identified as significant contributors to the epigenetic modulation of gene expression. Furthermore, the overexpression of KAT5 and GPX4 has been shown to mitigate the antiproliferative effects resulting from the depletion of circRHOT1, suggesting a complex interplay between these molecules in GC pathophysiology. Another pivotal aspect of epigenetic regulation in GC involves modifications in N6-methyladenosine (m6A), which play crucial roles in mRNA maturation processes such as splicing, export, degradation, and translation. m6A modifications are known for their influence on various cancer-related pathways, thus presenting a potential avenue for targeted interventions. Our findings indicate that the most pronounced instances of epigenetic dysregulation in GC can be traced back to the effects of long lncRNAs and alterations in m6A modification patterns. This underscores the urgent need for comprehensive investigations into these epigenetic factors, as a deeper understanding could lead to enhanced diagnostic markers and innovative therapeutic strategies. The integration of genetic and epigenetic considerations is essential for advancing the field of GC research. This synthesis of recent findings concerning epigenetic regulation offers valuable insights that could inform future studies and therapeutic developments. There is a critical need for ongoing research to elucidate the complexities of epigenetic modifications in GC, ultimately improving patient outcomes through tailored interventions.

Digoxin and exercise effects on skeletal muscle Na+,K+-ATPase isoform gene expression in healthy humans.

In muscle, digoxin inhibits Na+,K+-ATPase (NKA) whereas acute exercise can increase NKA gene expression, consistent with training-induced increased NKA content. We investigated whether oral digoxin increased NKA isoform mRNA expression (qPCR) in muscle at rest, during and post-exercise in 10 healthy adults, who received digoxin (DIG, 0.25mg per day) or placebo (CON) for 14 days, in a randomised, double-blind and cross-over design. Muscle was biopsied at rest, after cycling 20min (10min each at 33%, then 67% ), then to fatigue at 90% and 3h post-exercise. No differences were found between DIG and CON for NKA α1-3 or β1-3 isoform mRNA. Both α1 (354%, P=0.001) and β3 mRNA (P=0.008) were increased 3h post-exercise, with α2 and β1-2 mRNA unchanged, whilst α3 mRNA declined at fatigue (-43%, P=0.045). In resting muscle, total β mRNA (∑(β1+β2+β3)) increased in DIG (60%, P=0.025) and also when transcripts for each isoform were normalised to CON then either summed (P=0.030) or pooled (n=30, P=0.034). In contrast, total α mRNA (∑(α1+α2+α3), P=0.348), normalised then summed (P=0.332), or pooled transcripts (n=30, P=0.717) did not differ with DIG. At rest, NKA α1-2 and β1-2 protein abundances were unchanged by DIG. Post-exercise, α1 and β1-2 proteins were unchanged, but α2 declined at 3h (19%, P=0.020). In conclusion, digoxin did not modify gene expression of individual NKA isoforms at rest or with exercise, indicating NKA gene expression was maintained consistent with protein abundances. However, elevated resting muscle total β mRNA with digoxin suggests a possible underlying β gene-stimulatory effect. HIGHLIGHTS: What is the central question of this study? Na+,K+-ATPase (NKA) in muscle is important for Na+/K+ homeostasis. We investigated whether the NKA-inhibitor digoxin stimulates increased NKA gene expression in muscle and exacerbates NKA gene responses to exercise in healthy adults. What is the main finding and its importance? Digoxin did not modify exercise effects on muscle NKA α1-3 and β1-3 gene transcripts, which comprised increased post-exercise α1 and β3 mRNA and reduced α3 mRNA during exercise. However, in resting muscle, digoxin increased NKA total β isoform mRNA expression. Despite inhibitory-digoxin or acute exercise stressors, NKA gene regulation in muscle is consistent with the maintenance of NKA protein contents.

Relationship between COVID-19 and orofacial clefts.

MicroRNAs (miRNAs) are essential modulators of gene expression and are associated with various pathological processes, including spinal cord injury (SCI). This investigation aimed to elucidate miR-10a activity in SCI and its potential interaction with sirtuin 1 (SIRT1). The SCI rat model was established to assess hind limb movement, measure levels of miR-10a, SIRT1, neuronal survival, and inflammatory factors. An in-vitro SCI cell model was also developed to evaluate cell viability and inflammatory factor levels. The interaction between miR10a and SIRT1 was verified. Upregulated miR-10a and downregulated SIRT1 expression were found in the tissues of SCI rats. miR-10a knockdown in SCI rats enhanced the recovery of motor function, increased neuronal survival, and reduced the levels of inflammatory cytokines. Luciferase reporter assays confirmed that miR-10a targeted SIRT1 directly. In PC12 cells, downregulation of miR-10a increased SIRT1 expression, enhanced cell viability, and reduced inflammatory factor levels after LPS stimulation. Conversely, SIRT1 knockdown inhibited the protective effects of downregulated miR-10a on cell viability and inflammatory responses. The results suggest that miR-10a downregulation protects against SCI by upregulating SIRT1 expression, improving functional recovery, and reducing inflammation. Targeting the miR-10a/SIRT1 axis is a promising strategy for SCI treatment.

Abstract P126: Exercise-Induced Changes in Skeletal Muscle of Patients with Chronic Kidney Disease on Maintenance Hemodialysis

Background: Chronic kidney disease (CKD) patients on maintenance hemodialysis (MHD) often experience sarcopenia and functional decline. The impact of exercise and inactivity on sarcopenia in CKD is poorly understood. We aimed to identify exercise-responsive genes that are differentially expressed between controls and patients on MHD. We also aim to investigate the changes in gene expression in skeletal muscle following a resistance exercise program in patients on MHD. Methods: In a cross-sectional study, we performed RNA sequencing analysis in skeletal muscle biopsies from two groups (matched for age, gender, body mass index, and history of diabetes): controls (n=13) and patients on maintenance hemodialysis (MHD, n=10). In a separate cohort, we conducted a 12-week intradialytic resistance training in seven patients on MHD. Skeletal muscle biopsies were collected pre- and post-intervention to assess the acute (before and after a single bout of exercise) and chronic (after 12 weeks) effects of exercise. Total RNA was extracted and used to construct libraries for RNA sequencing using the Illumina NovaSeq 6000 system. Differentially expressed genes (DEGs) were identified based on a false discovery rate (FDR) of less than 0.05 and a fold change greater than 1.5. Exercise and inactivity-responsive genes in non-CKD populations identified in the MetaMEx (www.metamex.eu) were used as reference. Results: We found significant DEGs between the control and MHD that were affected by exercise or inactivity according to MetaMEx. These genes and fold changes between control and MHD groups are depicted in Table 1. In the exercise intervention cohort, we observed no significant differences in the expression of these genes either acutely (Figure 1A) or 12 weeks after the exercise intervention (Figure 1B). Conclusion: We found many DEGs related to exercise and inactivity between patients on MHD and controls; however, resistance training does not significantly alter skeletal muscle gene expression. Future studies should explore alternative exercise interventions, such as HIIT exercise, aerobic training, combined aerobic and resistance training, or longer duration programs, to determine if these approaches can effectively modulate gene expression and improve sarcopenia and frailty in this population.

Platelet-derived factors modify gene expression profile of human trophoblasts

Platelet-derived factors modify gene expression profile of human trophoblasts

Eccentric contraction increases hydrogen peroxide levels and alters gene expression through Nox2 in skeletal muscle of male mice.

Hydrogen peroxide (H2O2) is one of the key signaling factors regulating skeletal muscle adaptation to muscle contractions. Eccentric (ECC) and concentric (CONC) contractions drive different muscle adaptations with ECC resulting in greater changes. The present investigation tested the hypothesis that ECC produces higher cytosolic and mitochondrial H2O2 concentrations [H2O2] and alters gene expression more than CONC. Cytosolic and mitochondrial H2O2-sensitive fluorescent proteins, HyPer7 and MLS-HyPer7, were expressed in the anterior tibialis muscle of C57BL6J male mice. Before and for 60 min after either CONC or ECC (100 Hz, 50 contractions), [H2O2]cyto and [H2O2]mito were measured by in vivo fluorescence microscopy. RNA sequencing was performed in control (noncontracted), CONC, and ECC muscles to identify genes impacted by the contractions. [H2O2]cyto immediately after ECC was greater than after CONC (CONC: +6%, ECC: +11% vs. rest, P < 0.05) and remained higher for at least 60 min into recovery. In contrast, the elevation of [H2O2]mito was independent of the contraction modes (time; P < 0.0042, contraction mode; P = 0.4965). The impact of ECC on [H2O2]cyto was abolished by NADPH oxidase 2 (Nox2) inhibition (GSK2795039). Differentially expressed genes were not present after CONC or ECC + GSK but were found after ECC and were enriched for vascular development and apoptosis-related genes, among others. In conclusion, in mouse anterior tibialis, ECC, but not CONC, evokes a pronounced cytosolic H2O2 response, caused by Nox2, that is mechanistically linked to gene expression modifications.NEW & NOTEWORTHY This in vivo model successfully characterized the effects of eccentric (ECC) and concentric (CONC) contractions on cytosolic and mitochondrial [H2O2] in mouse skeletal muscle. Compared with CONC, ECC induced higher and more sustained [H2O2]cyto-an effect that was abolished by Nox2 inhibition. ECC-induced [H2O2]cyto elevations were requisite for altered gene expression.

Anticancer potential of hydroxycinnamic acids: mechanisms, bioavailability, and therapeutic applications.

Hydroxycinnamic acids (HCAs) are plant compounds with anticancer potential due to their antioxidant, anti-inflammatory, apoptosis-inducing, and proliferation-inhibiting effects. This review aims to consolidate and analyze current knowledge on the anticancer effects of HCAs, exploring their mechanisms of action, bioavailability challenges, and potential therapeutic applications. A comprehensive literature search on PubMed/MedLine, Scopus, Web of Science, and Google Scholar focused on the anticancer properties, mechanisms, bioavailability, and safety profiles of HCAs. Studies have shown that HCAs, such as caffeic acid, ferulic acid, and sinapic acid, inhibit the growth of cancer cells in vitro and in vivo and sensitize cancer cells to chemotherapy and radiation therapy. These effects are mediated by mechanisms including the inhibition of cell survival pathways, modulation of gene expression, and induction of oxidative stress and DNA damage. Additionally, several studies have demonstrated that HCAs exhibit selective toxicity, with a higher propensity to induce cell death in cancerous cells compared to normal cells. However, the toxicity profile of HCAs can vary depending on the specific compound, dosage, and experimental conditions. The anticancer properties of HCAs suggest potential applications in cancer prevention and treatment. However, it is essential to distinguish between their use as dietary supplements and therapeutic agents, as the dosage and formulation suitable for dietary supplements may be insufficient for therapeutic purposes. The regulatory and practical implications of using HCAs in these different contexts require careful consideration. Further research is needed to determine appropriate dosages, formulations, long-term effects, and regulatory frameworks for HCAs as both dietary supplements and therapeutic agents.

Kynurenic Acid Modulates the Expression of Genes and the Activity of Cellular Antioxidant Enzymes in the Hypothalamus and Hippocampus in Sheep.

Kynurenic acid (KYNA), a tryptophan metabolite, is believed to exert neuromodulatory and neuroprotective effects in the brain. This study aimed to examine KYNA's capacity to modify gene expression and the activity of cellular antioxidant enzymes in specific structures of the sheep brain. Anestrous sheep were infused intracerebroventricularly with two KYNA doses-lower (4 × 5 μg/60 μL/30 min, KYNA20) and higher (4 × 25 μg/60 μL/30 min, KYNA100)-at 30 min intervals. The abundance of superoxide dismutase 2 (SOD2), catalase (CAT), and glutathione peroxidase 1 (GPx1) mRNA, as well as enzyme activities, were determined in the medial-basal hypothalamus (MBH), the preoptic (POA) area of the hypothalamus, and in the hippocampal CA1 field. Both doses of KYNA caused a decrease (p < 0.01) in the expression of SOD2 and CAT mRNA in all structures examined compared to the control group (except for CAT in the POA at the KYNA100 dose). Furthermore, lower levels of SOD2 mRNA (p < 0.05) and CAT mRNA (p < 0.01) were found in the MBH and POA and in the POA and CA, respectively, in sheep administered with the KYNA20 dose. Different stimulatory effects on GPx1 mRNA expression were observed for both doses (p < 0.05-p < 0.01). KYNA exerted stimulatory but dose-dependent effects on SOD2, CAT, and GPx1 activities (p < 0.05-p < 0.001) in all brain tissues examined. The results indicate that KYNA may influence the level of oxidative stress in individual brain structures in sheep by modulating the expression of genes and the activity of at least SOD2, CAT, and GPx1. The present findings also expand the general knowledge about the potential neuroprotective properties of KYNA in the central nervous system.

Differential gene expression in the kidneys of SHR and WKY rats after intravenous administration of Akkermansia muciniphila-derived extracellular vesicles

Although Akkermansia muciniphila (Am) plays a beneficial role as a probiotic in the treatment of metabolic syndrome, the mechanisms remain elusive. We tested the hypothesis that Am extracellular vesicles (AmEVs) protect against hypertension through modulation of gene expression in the kidneys of spontaneously hypertensive rats (SHRs). Extracellular vesicles purified from anaerobically cultured Am (1.0 × 108 or 1.0 × 109 particles/kg) or vehicles were injected into the tail veins of Wistar-Kyoto rats (WKYs) and SHRs weekly for 4 weeks. Renal cortical tissues isolated from both rat strains were analyzed by trichrome stain and RT-qPCR. AmEVs protect against the development of hypertension in SHRs without a serious adverse reaction. AmEVs increased the expression of vasocontracting Agt and At1ar as well as vasodilating At2r, Mas1 and Nos2 in the kidneys of both strains. These results indicate that AmEVs have a protective effect against hypertension without a serious adverse reaction. Therefore, it is foreseen that AmEVs may be utilized as a novel therapeutic for the treatment of hypertension.

Regulatory Dynamics of Plant Hormones and Transcription Factors under Salt Stress.

The negative impacts of soil salinization on ion homeostasis provide a significant global barrier to agricultural production and development. Plant physiology and biochemistry are severely affected by primary and secondary NaCl stress impacts, which damage cellular integrity, impair water uptake, and trigger physiological drought. Determining how transcriptional factors (TFs) and hormone networks are regulated in plants in response to salt stress is necessary for developing crops that tolerate salt. This study investigates the complex mechanisms of several significant TF families that influence plant responses to salt stress, involving AP2/ERF, bZIP, NAC, MYB, and WRKY. It demonstrates how these transcription factors (TFs) help plants respond to the detrimental effects of salinity by modulating gene expression through mechanisms including hormone signaling, osmotic stress pathway activation, and ion homeostasis. Additionally, it explores the hormonal imbalances triggered by salt stress, which entail complex interactions among phytohormones like jasmonic acid (JA), salicylic acid (SA), and abscisic acid (ABA) within the hormonal regulatory networks. This review highlights the regulatory role of key transcription factors in salt-stress response, and their interaction with plant hormones is crucial for developing genome-edited crops that can enhance agricultural sustainability and address global food security challenges.

MicroRNAs in Hepatocellular Carcinoma Pathogenesis: Insights into Mechanisms and Therapeutic Opportunities.

Hepatocellular carcinoma (HCC) presents a significant global health burden, with alarming statistics revealing its rising incidence and high mortality rates. Despite advances in medical care, HCC treatment remains challenging due to late-stage diagnosis, limited effective therapeutic options, tumor heterogeneity, and drug resistance. MicroRNAs (miRNAs) have attracted substantial attention as key regulators of HCC pathogenesis. These small non-coding RNA molecules play pivotal roles in modulating gene expression, implicated in various cellular processes relevant to cancer development. Understanding the intricate network of miRNA-mediated molecular pathways in HCC is essential for unraveling the complex mechanisms underlying hepatocarcinogenesis and developing novel therapeutic approaches. This manuscript aims to provide a comprehensive review of recent experimental and clinical discoveries regarding the complex role of miRNAs in influencing the key hallmarks of HCC, as well as their promising clinical utility as potential therapeutic targets.

MED12 and CDK8/19 Modulate Androgen Receptor Activity and Enzalutamide Response in Prostate Cancer.

Prostate cancer progression is driven by androgen receptor (AR) activity, which is a target for therapeutic approaches. Enzalutamide is an AR inhibitor that prolongs the survival of patients with advanced prostate cancer. However, resistance mechanisms arise and impair its efficacy. One of these mechanisms is the expression of AR-V7, a constitutively active AR splice variant. The Mediator complex is a multisubunit protein that modulates gene expression on a genome-wide scale. MED12 and cyclin-dependent kinase (CDK)8, or its paralog CDK19, are components of the kinase module that regulates the proliferation of prostate cancer cells. In this study, we investigated how MED12 and CDK8/19 influence cancer-driven processes in prostate cancer cell lines, focusing on AR activity and the enzalutamide response. We inhibited MED12 expression and CDK8/19 activity in LNCaP (AR+, enzalutamide-sensitive), 22Rv1 (AR-V7+, enzalutamide-resistant), and PC3 (AR-, enzalutamide-insensitive) cells. Both MED12 and CDK8/19 inhibition reduced cell proliferation in all cell lines, and MED12 inhibition reduced proliferation in the respective 3D spheroids. MED12 knockdown significantly inhibited c-Myc protein expression and signaling pathways. In 22Rv1 cells, it consistently inhibited the AR response, prostate-specific antigen (PSA) secretion, AR target genes, and AR-V7 expression. Combined with enzalutamide, MED12 inhibition additively decreased the AR activity in both LNCaP and 22Rv1 cells. CDK8/19 inhibition significantly decreased PSA secretion in LNCaP and 22Rv1 cells and, when combined with enzalutamide, additively reduced proliferation in 22Rv1 cells. Our study revealed that MED12 and CDK8/19 regulate AR activity and that their inhibition may modulate response to enzalutamide in prostate cancer.

Alzheimer's disease CSF biomarkers correlate with early pathology and alterations in neuronal and glial gene expression.

Normal pressure hydrocephalus (NPH) patients undergoing cortical shunting frequently show early Alzheimer's disease (AD) pathology on cortical biopsy, which is predictive of progression to clinical AD. The objective of this study was to use samples from this cohort to identify cerebrospinal fluid (CSF) biomarkers for AD-related central nervous system (CNS) pathophysiologic changes using tissue and fluids with early pathology, free of post mortem artifact. We analyzed Simoa, proteomic, and metabolomic CSF data from 81 patients with previously documented pathologic and transcriptomic changes. AD pathology on biopsy correlates with CSF β-amyloid-42/40, neurofilament light chain (NfL), and phospho-tau-181(p-tau181)/β-amyloid-42, while several gene expression modules correlate with NfL. Proteomic analysis highlights seven core proteins that correlate with pathology and gene expression changes on biopsy, and metabolomic analysis of CSF identifies disease-relevant groups that correlate with biopsy data. As additional biomarkers are added to AD diagnostic panels, our work provides insight into the CNS pathophysiology these markers are tracking. AD CSF biomarkers correlate with CNS pathology and transcriptomic changes. Seven proteins correlate with CNS pathology and gene expression changes. Inflammatory and neuronal gene expression changes correlate with YKL-40 and NPTXR, respectively. CSF metabolomic analysis identifies pathways that correlate with biopsy data. Fatty acid metabolic pathways correlate with β-amyloid pathology.