Pivotal Regulator Research Articles

RNA polymerase III is involved in regulating Plasmodium falciparum virulence

While often undetected and untreated, persistent seasonal asymptomatic malaria infections remain a global public health problem. Despite the presence of parasites in the peripheral blood, no symptoms develop. Disease severity is correlated with the levels of infected red blood cells (iRBCs) adhering within blood vessels. Changes in iRBC adhesion capacity have been linked to seasonal asymptomatic malaria infections, however how this is occurring is still unknown. Here, we present evidence that RNA polymerase III (RNA Pol III) transcription in Plasmodium falciparum is downregulated in field isolates obtained from asymptomatic individuals during the dry season. Through experiments with in vitro cultured parasites, we have uncovered an RNA Pol III-dependent mechanism that controls pathogen proliferation and expression of a major virulence factor in response to external stimuli. Our findings establish a connection between P. falciparum cytoadhesion and a non-coding RNA family transcribed by Pol III. Additionally, we have identified P. falciparum Maf1 as a pivotal regulator of Pol III transcription, both for maintaining cellular homeostasis and for responding adaptively to external signals. These results introduce a novel perspective that contributes to our understanding of P. falciparum virulence. Furthermore, they establish a connection between this regulatory process and the occurrence of seasonal asymptomatic malaria infections.

RNA polymerase III is involved in regulating Plasmodium falciparum virulence.

While often undetected and untreated, persistent seasonal asymptomatic malaria infections remain a global public health problem. Despite the presence of parasites in the peripheral blood, no symptoms develop. Disease severity is correlated with the levels of infected red blood cells (iRBCs) adhering within blood vessels. Changes in iRBC adhesion capacity have been linked to seasonal asymptomatic malaria infections, however how this is occurring is still unknown. Here, we present evidence that RNA polymerase III (RNA Pol III) transcription in Plasmodium falciparum is downregulated in field isolates obtained from asymptomatic individuals during the dry season. Through experiments with in vitro cultured parasites, we have uncovered an RNA Pol III-dependent mechanism that controls pathogen proliferation and expression of a major virulence factor in response to external stimuli. Our findings establish a connection between P. falciparum cytoadhesion and a non-coding RNA family transcribed by Pol III. Additionally, we have identified P. falciparum Maf1 as a pivotal regulator of Pol III transcription, both for maintaining cellular homeostasis and for responding adaptively to external signals. These results introduce a novel perspective that contributes to our understanding of P. falciparum virulence. Furthermore, they establish a connection between this regulatory process and the occurrence of seasonal asymptomatic malaria infections.

A novel signature constructed by mitochondrial function and cell death-related gene for the prediction of prognosis in bladder cancer

Bladder urothelial carcinoma (BLCA) presents a persistent challenge in clinical management. Despite recent advancements demonstrating the BLCA efficacy of immune checkpoint inhibitors (ICI) in BLCA patients, there remains a critical need to identify and expand the subset of individuals who benefit from this treatment. Mitochondria, as pivotal regulators of various cell death pathways in eukaryotic cells, exert significant influence over tumor cell fate and survival. In this study, our objective was to investigate biomarkers centered around mitochondrial function and cell death mechanisms to facilitate prognostic prediction and guide therapeutic decision-making in BLCA. Utilizing ssGSEA and LASSO regression, we developed a prognostic signature termed mitochondrial function and cell death (mtPCD). Subsequently, we evaluated the associations between mtPCD score and diverse clinical outcomes, including prognosis, functional pathway enrichment, immune cell infiltration, immunotherapy response analysis and drug sensitivity, within high- and low-risk subgroups. Additionally, we employed single-cell level functional assays, RT-qPCR, and immunohistochemistry to validate the differential expression of genes comprising the mtPCD signature. The mtPCD signature comprises a panel of 10 highly influential genes, strongly correlated with survival outcomes in BLCA patients and exhibiting robust predictive capabilities. Importantly, individuals classified as high-risk according to mtPCD score displayed a subdued overall immune response, characterized by diminished immunotherapeutic efficacy. In summary, our findings highlight the development of a novel prognostic signature, which not only holds promise as a biomarker for BLCA prognosis but also offers insights into the immune landscape of BLCA. This paradigm may pave the way for personalized treatment strategies in BLCA management.

MiR-214–3p regulates Piezo1, lysyl oxidases and mitochondrial function in human cardiac fibroblasts

Cardiac fibroblasts are pivotal regulators of cardiac homeostasis and are essential in the repair of the heart after myocardial infarction (MI), but their function can also become dysregulated, leading to adverse cardiac remodelling involving both fibrosis and hypertrophy. MicroRNAs (miRNAs) are noncoding RNAs that target mRNAs to prevent their translation, with specific miRNAs showing differential expression and regulation in cardiovascular disease. Here, we show that miR-214–3p is enriched in the fibroblast fraction of the murine heart, and its levels are increased with cardiac remodelling associated with heart failure, or in the acute phase after experimental MI. Tandem mass tagging proteomics and in-silico network analyses were used to explore protein targets regulated by miR-214–3p in cultured human cardiac fibroblasts from multiple donors. Overexpression of miR-214–3p by miRNA mimics resulted in decreased expression and activity of the Piezo1 mechanosensitive cation channel, increased expression of the entire lysyl oxidase (LOX) family of collagen cross-linking enzymes, and decreased expression of an array of mitochondrial proteins, including mitofusin-2 (MFN2), resulting in mitochondrial dysfunction, as measured by citrate synthase and Seahorse mitochondrial respiration assays. Collectively, our data suggest that miR-214–3p is an important regulator of cardiac fibroblast phenotypes and functions key to cardiac remodelling, and that this miRNA represents a potential therapeutic target in cardiovascular disease.

Comparative transcriptome analysis reveals transcriptional regulation of anthocyanin biosynthesis in purple radish (Raphanus sativus L.)

Radish exhibits significant variation in color, particularly in sprouts, leaves, petals, fleshy roots, and other tissues, displaying a range of hues such as green, white, red, purple, and black. Although extensive research has been conducted on the color variation of radish, the underlying mechanism behind the variation in radish flower color remains unclear. To date, there is a lack of comprehensive research investigating the variation mechanism of radish sprouts, leaves, fleshy roots, and flower organs. This study aims to address this gap by utilizing transcriptome sequencing to acquire transcriptome data for white and purple radish flowers. Additionally, the published transcriptome data of sprouts, leaves, and fleshy roots were incorporated to conduct a systematic analysis of the regulatory mechanisms underlying anthocyanin biosynthesis in these four radish tissues. The comparative transcriptome analysis revealed differential expression of the anthocyanin biosynthetic pathway genes DFR, UGT78D2, TT12 and CPC in the four radish tissues. Additionally, the WGCNA results identified RsDFR.9c and RsUGT78D2.2c as hub genes responsible for regulating anthocyanin biosynthesis. By integrating the findings from the comparative transcriptome analysis, WGCNA, and anthocyanin biosynthetic pathway-related gene expression patterns, it is hypothesized that genes RsDFR.9c and RsUGT78D2.2c may serve as pivotal regulators of anthocyanins in the four radish tissues. Furthermore, the tissue-specific expression of the four copies of RsPAP1 is deemed crucial in governing anthocyanin synthesis and accumulation. Our results provide new insights into the molecular mechanism of anthocyanin biosynthesis and accumulation in different tissues of radish.

Strategic advancement of E3 ubiquitin ligase in the management of hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) presents a significant global health challenge due to its high incidence, poor prognosis, and limited treatment options. As a pivotal regulator of protein stability, E3 ubiquitin ligase plays a crucial role in tumorigenesis and development. This review provides an overview of the latest research on the involvement of E3 ubiquitin ligase in hepatocellular carcinoma and elucidates its significance in hepatocellular carcinoma cell proliferation, invasion, and evasion from immune surveillance. Special attention is given to the functions of RING, HECT, and RBR E3 ubiquitin ligases and their association with hepatocellular carcinoma progression. By dissecting the molecular mechanisms and regulatory networks governed by E3 ubiquitin ligase, several potential therapeutic strategies are proposed: including the development of specific inhibitors targeting E3 ligases; augmentation of their tumor suppressor activity through drug or gene therapy; utilization of E3 ubiquitin ligase to modulate immune checkpoint proteins for improved efficacy of immunotherapy; combination strategies integrating traditional therapies with E3 ubiquitin ligase inhibitors; as well as biomarker development based on E3 ubiquitin ligase activity. Furthermore, this review discusses the prospect of overcoming drug resistance in hepatocellular carcinoma treatment through these novel approaches. Overall, this review establishes a theoretical foundation and offers fresh insights into harnessing the potential of E3 ubiquitin ligase for treating hepatocellular carcinoma while highlighting future research directions that pave the way for clinical translation studies and new drug discoveries.

Anti-Inflammatory Response of New Postbiotics in TNF-α/IFN-γ-Induced Atopic Dermatitis-like HaCaT Keratinocytes.

This study examines the synergistic interaction between the immunomodulatory functions of lactic acid bacteria postbiotics and the anti-inflammatory properties of Smilax china L. extract through a combined fermentation process. Using atopic dermatitis (AD) as a model, characterized by an immune imbalance that leads to skin inflammation, we developed a fermented product, MB-2006, and compared its effects to those of the heat-killed probiotics Lactobacillus acidophilus (LAC) and Lactobacillus rhamnosus (LRH). Our experiments focused on elucidating the mechanism of action of MB-2006 in AD-like HaCaT keratinocyte cells, particularly its impact on the NF-κB pathway, a pivotal regulator of inflammation. MB-2006 proved more effective in reducing inflammation markers, such as IL-4 and thymic stromal lymphopoietin (TSLP), and in inhibiting NF-κB activation compared to LAC and LRH. Significantly, MB-2006 also reduced the expression of thymus- and activation-regulated chemokine (TARC), highlighting a synergistic effect that enhances its therapeutic potential. These results suggest that the combined fermentation of Smilax china L. extract with lactic acid bacteria enhanced both the anti-inflammatory and immunomodulatory effects, presenting a promising integrative approach to treating conditions like AD. Further studies are needed to validate these results in clinical settings and fully explore the potential of this synergistic fermentation process.

Microneedle electrochemical sensor based on disposable stainless-steel wire for real-time analysis of indole-3-acetic acid and salicylic acid in tomato leaves infected by Pst DC3000 in situ

BackgroundIndole-3-acetic acid (IAA) and salicylic acid (SA), pivotal regulators in plant growth, are integral to a variety of plant physiological activities. The ongoing and simultaneous monitoring of these hormones in vivo enhances our comprehension of their interactive and regulatory roles. Traditional detection methods, such as liquid chromatography-mass spectrometry, cannot obtain precise and immediate information on IAA and SA due to the complexity of sample processing. In contrast, the electrochemical detection method offers high sensitivity, rapid response times, and compactness, making it well-suited for in vivo or real-time detection applications. ResultsA microneedle electrochemical sensor system crafted from disposable stainless steel (SS) wire was specifically designed for the real-time assessment of IAA and SA in plant in situ. This sensor system included a SS wire (100 μm diameter) coated with carbon cement and multi-walled carbon nanotubes, a plain platinum wire (100 μm diameter), and an Ag/AgCl wire (100 μm diameter). Differential pulse voltammetry and amperometry were adopted for detecting SA and IAA within the range of 0.1–20 μM, respectively. This sensor was applied to track IAA and SA fluctuations in tomato leaves during PstDC3000 infection, offering continuous data. Observations indicated an uptick in SA levels following infection, while IAA production was suppressed. The newly developed disposable SS wire-based microneedle electrochemical sensor system is economical, suitable for mass production, and inflicts minimal damage during the monitoring of SA and IAA in plant tissues. SignificanceThis disposable microneedle electrochemical sensor facilitates in vivo detection of IAA and SA in smaller plant tissues and allows for long-time monitoring of their concentrations, which not only propels research into the regulatory and interaction mechanisms of IAA and SA but also furnishes essential tools for advancing precision agriculture.

Hydrogen peroxide positively regulates ABA signaling via oxidative modification of the C2H2-type zinc finger protein ZFP36 in rice

The rice zinc finger protein ZFP36 serves as a pivotal regulator of the hydrogen peroxide (H2O2) signaling pathway in response to abscisic acid (ABA). Its role is crucial for integrating H2O2 signals with the plant defense mechanisms against water deficit and oxidative stress. However, it remains unclear whether ZFP36 directly modulates ABA-induced H2O2 signaling. This study explored the effects of oxidative post-translational modifications (OxiPTMs) on ZFP36 in rice, with an emphasis on the H2O2-induced oxidation through its cysteine (Cys) residues. We found that ZFP36 undergoes oxidative modification as a target of H2O2 in the presence of ABA, specifically at Cys32. Employing quantitative detection and fluorescence assays, we observed that ZFP36 oxidation enhances the expression and activity of genes encoding protective antioxidant enzymes. Moreover, our investigation into the thioredoxin (Trx) and glutaredoxin (Grx) families revealed that OsTrxh1 facilitates the reduction of oxidized ZFP36. Genetic evidence indicates that ZFP36 positively influences rice resilience to oxidative and water stress, while OsTrxh1 exerts an opposing effect. These insights reveal a distinctive pathway for plant cells to perceive ABA-induced H2O2 signaling, advance our comprehension of H2O2 signaling dynamics, and ABA-related plant responses, and lay a vital groundwork for enhancing crop stress tolerance.

Population Density-Dependent Developmental Regulation in Migratory Locust.

Insect development is intricately governed by hormonal signaling pathways, yet the pivotal upstream regulator that potentiates hormone activation remains largely elusive. The migratory locust, Locusta migratoria, exhibits population density-dependent phenotypic plasticity, encompassing traits such as flight capability, body coloration, and behavior. In this study, we elucidated a negative correlation between population density and ontogenetic development during the nymphal stage of locusts. We found that the level of density influences the developmental trajectory by modulating transcript abundance within the ecdysone signaling pathway, with knockdown of the prothoracicotropic hormone (PTTH) resulting in developmental delay. Transcriptomic analysis of locust brains across solitary and gregarious phases revealed significant differential expression of genes involved in various pathways, including protein synthesis, energy metabolism, hormonal regulation, and immunity. Notably, knockdown experiments targeting two energy regulators, adipokinetic hormone (AKH) and insulin-like polypeptide 1 (ilp1), failed to elicit changes in the developmental process in solitary locusts. However, knockdown of immunoglobulin (IG) significantly shortened the developmental time in higher-density populations. Collectively, our findings underscore the regulatory role of population density in determining developmental duration and suggest that an immune-related gene contributes to the observed differences in developmental patterns.

Beneficial islet inflammation in health depends on pericytic TLR/MyD88 signaling.

While inflammation is beneficial for insulin secretion during homeostasis, its transformation adversely affects β cells and contributes to diabetes. However, the regulation of islet inflammation for maintaining glucose homeostasis remains largely unknown. Here, we identified pericytes as pivotal regulators of islet immune and β cell function in health. Islets and pancreatic pericytes express various cytokines in healthy humans and mice. To interfere with the pericytic inflammatory response, we selectively inhibited the TLR/MyD88 pathway in these cells in transgenic mice. The loss of MyD88 impaired pericytic cytokine production. Furthermore, MyD88-deficient mice exhibited skewed islet inflammation with fewer cells, an impaired macrophage phenotype, and reduced IL-1β production. This aberrant pericyte-orchestrated islet inflammation was associated with β cell dedifferentiation and impaired glucose response. Additionally, we found that Cxcl1, a pericytic MyD88-dependent cytokine, promoted immune IL-1β production. Treatment with either Cxcl1 or IL-1β restored the mature β cell phenotype and glucose response in transgenic mice, suggesting a potential mechanism through which pericytes and immune cells regulate glucose homeostasis. Our study revealed pericyte-orchestrated islet inflammation as a crucial element in glucose regulation, implicating this process as a potential therapeutic target for diabetes.

The miR-30-5p/TIA-1 axis directs cellular senescence by regulating mitochondrial dynamics

Senescent cells exhibit a diverse spectrum of changes in their morphology, proliferative capacity, senescence-associated secretory phenotype (SASP) production, and mitochondrial homeostasis. These cells often manifest with elongated mitochondria, a hallmark of cellular senescence. However, the precise regulatory mechanisms orchestrating this phenomenon remain predominantly unexplored. In this study, we provide compelling evidence for decreases in TIA-1, a pivotal regulator of mitochondrial dynamics, in models of both replicative senescence and ionizing radiation (IR)-induced senescence. The downregulation of TIA-1 was determined to trigger mitochondrial elongation and enhance the expression of senescence-associated β-galactosidase, a marker of cellular senescence, in human foreskin fibroblast HS27 cells and human keratinocyte HaCaT cells. Conversely, the overexpression of TIA-1 mitigated IR-induced cellular senescence. Notably, we identified the miR-30-5p family as a novel factor regulating TIA-1 expression. Augmented expression of the miR-30-5p family was responsible for driving mitochondrial elongation and promoting cellular senescence in response to IR. Taken together, our findings underscore the significance of the miR-30-5p/TIA-1 axis in governing mitochondrial dynamics and cellular senescence.

CircRNA Regulation of T Cells in Cancer: Unraveling Potential Targets.

T lymphocytes play a critical role in antitumor immunity, but their exhaustion poses a significant challenge for immune evasion by malignant cells. Circular RNAs (circRNAs), characterized by their covalently closed looped structure, have emerged as pivotal regulators within the neoplastic landscape. Recent studies have highlighted their multifaceted roles in cellular processes, including gene expression modulation and protein function regulation, which are often disrupted in cancer. In this review, we systematically explore the intricate interplay between circRNAs and T cell modulation within the tumor microenvironment. By dissecting the regulatory mechanisms through which circRNAs impact T cell exhaustion, we aim to uncover pathways crucial for immune evasion and T cell dysfunction. These insights can inform innovative immunotherapeutic strategies targeting circRNA-mediated molecular pathways. Additionally, we discuss the translational potential of circRNAs as biomarkers for therapeutic response prediction and as intervention targets. Our comprehensive analysis aims to enhance the understanding of immune evasion dynamics in the tumor microenvironment by facilitating the development of precision immunotherapy.

Epigenetic Regulation of DLK1-DIO3 Region in Thyroid Carcinoma.

Non-coding RNAs (ncRNAs) have emerged as pivotal regulators in cellular biology, dispelling their former perception as 'junk transcripts'. Notably, the DLK1-DIO3 region harbors numerous ncRNAs, including long non-coding RNAs (lncRNAs) and over 50 microRNA genes. While papillary thyroid cancer showcases a pervasive decrease in DLK1-DIO3-derived ncRNA expression, the precise mechanisms driving this alteration remain elusive. We hypothesized that epigenetic alterations underlie shifts in ncRNA expression during thyroid cancer initiation and progression. This study aimed to elucidate the epigenetic mechanisms governing DLK1-DIO3 region expression in this malignancy. We have combined the analysis of DNA methylation by bisulfite sequencing together with that of histone modifications through ChIP-qPCR to gain insights into the epigenetic contribution to thyroid cancer in cell lines representing malignancies with different genetic backgrounds. Our findings characterize the region's epigenetic signature in thyroid cancer, uncovering distinctive DNA methylation patterns, particularly within CpG islands on the lncRNA MEG3-DMR, which potentially account for its downregulation in tumors. Pharmacological intervention targeting DNA methylation combined with histone deacetylation restored ncRNA expression. These results contribute to the understanding of the epigenetic mechanisms controlling the DLK1-DIO3 region in thyroid cancer, highlighting the combined role of DNA methylation and histone marks in regulating the locus' expression.

Exploring the Role of Circular RNA in Bone Biology: A Comprehensive Review.

Circular RNAs (circRNAs) have emerged as pivotal regulators of gene expression with diverse roles in various biological processes. In recent years, research into circRNAs' involvement in bone biology has gained significant attention, unveiling their potential as novel regulators and biomarkers in bone-related disorders and diseases. CircRNAs, characterized by their closed-loop structure, exhibit stability and resistance to degradation, underscoring their functional significance. In bone tissue, circRNAs are involved in critical processes such as osteogenic differentiation, osteoclastogenesis, and bone remodeling through intricate molecular mechanisms including microRNA regulation. Dysregulated circRNAs are associated with various bone disorders, suggesting their potential as diagnostic and prognostic biomarkers. The therapeutic targeting of these circRNAs holds promise for addressing bone-related conditions, offering new perspectives for precision medicine. Thus, circRNAs constitute integral components of bone regulatory networks, impacting both physiological bone homeostasis and pathological conditions. This review provides a comprehensive overview of circRNAs in bone biology, emphasizing their regulatory mechanisms, functional implications, and therapeutic potential.

Decoding the Non-coding: Tools and Databases Unveiling the Hidden World of "Junk" RNAs for Innovative Therapeutic Exploration.

Non-coding RNAs are pivotal regulators of gene and protein expression, exerting crucial influences on diverse biological processes. Their dysregulation is frequently implicated in the onset and progression of diseases, notably cancer. A profound comprehension of the intricate mechanisms governing ncRNAs is imperative for devising innovative therapeutic interventions against these debilitating conditions. Significantly, nearly 80% of our genome comprises ncRNAs, underscoring their centrality in cellular processes. The elucidation of ncRNA functions is pivotal for grasping the complexities of gene regulation and its implications for human health. Modern genome sequencing techniques yield vast datasets, stored in specialized databases. To harness this wealth of information and to understand the crosstalk of non-coding RNAs, knowledge of available databases is required, and many new sophisticated computational tools have emerged. These tools play a pivotal role in the identification, prediction, and annotation of ncRNAs, thereby facilitating their experimental validation. This Review succinctly outlines the current understanding of ncRNAs, emphasizing their involvement in disease development. It also highlights the databases and tools instrumental in classifying, annotating, and evaluating ncRNAs. By extracting meaningful biological insights from seemingly "junk" data, these tools empower scientists to unravel the intricate roles of ncRNAs in shaping human health.

Impact of Hypoxia-Inducible Factor-1α on Host Immune Metabolism and Tissue Damage During Mycobacterium bovis Infection

Abstract Hypoxia-inducible factor-1α (HIF-1α) is a pivotal regulator of metabolic and inflammatory responses. This study investigated the role of HIF-1α in Mycobacterium bovis infection and its effects on host immune metabolism and tissue damage. We evaluated the expression of immunometabolism markers and matrix metalloproteinases (MMPs) in cells infected with M. bovis, and following HIF-1α inhibition in vitro. To understand the implications of HIF-1α inhibition on disease progression, mice at different infection stages were treated with the HIF-1α inhibitor, YC-1. Our results revealed an upregulation of HIF-1α in macrophages after M. bovis infection, facilitating enhanced M1 macrophage polarization. Blockade of HIF-1α moderated these responses but escalated MMP activity, hindering bacterial control. Consistent with our in vitro results, early-stage treatment of mice with YC-1 aggravated pathological alterations and tissue damage, while late-stage HIF-1α inhibition proved beneficial in managing the disease. Our findings underscored the nuanced role of HIF-1α across different phases of M. bovis infection.

Thyroid Hormones and Their Role in Male Infertility: A Comprehensive Review

Thyroid hormones are pivotal regulators of various physiological processes, including reproductive function. While the impact of thyroid dysfunction on female fertility has been extensively studied, its association with male infertility has gained increasing recognition. This comprehensive review explores the role of thyroid hormones in male infertility, focusing on their effects on spermatogenesis, sperm quality, and reproductive outcomes. The review delves into the physiology of thyroid hormones, the presence of thyroid hormone receptors in the male reproductive system, and the influence of thyroid dysfunction on spermatogenesis and semen parameters. Additionally, it examines the molecular mechanisms underlying thyroid hormone action in the male reproductive system and discusses potential therapeutic strategies targeting thyroid hormone pathways to improve male fertility. Understanding the intricate relationship between thyroid hormones and male infertility is crucial for advancing diagnostic and therapeutic approaches in the management of male infertility associated with thyroid dysfunction.

Pyroptosis and mitochondrial function participated in miR-654-3p-protected against myocardial infarction

Myocardial infarction (MI) is one of the leading causes of heart failure with highly complicated pathogeneses. miR-654-3p has been recognized as a pivotal regulator of controlling cell survival. However, the function of miR-654-3p in cardiomyocytes and MI has yet to be reported. This study aimed to identify the role of miR-654-3p in the regulation of myocardial infarction. To understand the contribution of miR-654-3p on heart function, we generated cardiac-specific knockdown and overexpression mice using AAV9 technology in MI injury. Mechanically, we combined cellular and molecular techniques, pharmaceutical treatment, RNA sequencing, and functional testing to elucidate the potential pathological mechanisms. We identified that mice subjected to MI decreased the expression of miR-654-3p in the border and infarcted area. Mice lacking miR-654-3p in the heart showed some inflammation infiltration and myocardial fibrosis, resulting in a mild cardiac injury. Furthermore, we found a deficiency of miR-654-3p in cardiomyocytes resulted in pyroptotic cell death but not other programmed cell death. Intriguingly, miR-654-3p deficiency aggravated MI-induced cardiac dysfunction, accompanied by higher myocardial fibrosis and cardiac enzymes and augmented pyroptosis activation. Cardiac elevating miR-654-3p prevented myocardial fibrosis and inflammation infiltration and decreased pyroptosis profile, thereby attenuating MI-induced cardiac damage. Using RNA sequence and molecular biological approaches, we found overexpression of miR-654-3p in the heart promoted the metabolic ability of the cardiomyocytes by promoting mitochondrial metabolism and mitochondrial respiration function. Our finding identified the character of miR-654-3p in protecting against MI damage by mediating pyroptosis and mitochondrial metabolism. These findings provide a new mechanism for miR-654-3p involvement in the pathogenesis of MI and reveal novel therapeutic targets.miR-654-3p expression was decreased after MI. Mice lacking miR-654-3p in the heart showed some inflammation infiltration and myocardial fibrosis, resulting in a mild cardiac injury. The deficiency of miR-654-3p in cardiomyocytes resulted in pyroptotic cell death. miR-654-3p deficiency aggravated MI-induced cardiac dysfunction, accompanied by higher myocardial fibrosis and cardiac enzymes and augmented pyroptosis activation. Overexpression of miR-654-3p prevented myocardial fibrosis and inflammation infiltration and decreased pyroptosis profile, thereby attenuating MI-induced cardiac damage. Overexpression of miR-654-3p in the heart promoted the metabolic ability of the cardiomyocytes by promoting mitochondrial metabolism and mitochondrial respiration function.

Endogenous Hormone Levels and Transcriptomic Analysis Reveal the Mechanisms of Bulbil Initiation in Pinellia ternata.

Pinellia ternata is a medicinal plant that has important pharmacological value, and the bulbils serve as the primary reproductive organ; however, the mechanisms underlying bulbil initiation remain unclear. Here, we characterized bulbil development via histological, transcriptomic, and targeted metabolomic analyses to unearth the intricate relationship between hormones, genes, and bulbil development. The results show that the bulbils initiate growth from the leaf axillary meristem (AM). In this stage, jasmonic acid (JA), abscisic acid (ABA), isopentenyl adenosine (IPA), and salicylic acid (SA) were highly enriched, while indole-3-acetic acid (IAA), zeatin, methyl jasmonate (MeJA), and 5-dexoxystrigol (5-DS) were notably decreased. Through OPLS-DA analysis, SA has emerged as the most crucial factor in initiating and positively regulating bulbil formation. Furthermore, a strong association between IPA and SA was observed during bulbil initiation. The transcriptional changes in IPT (Isopentenyltransferase), CRE1 (Cytokinin Response 1), A-ARR (Type-A Arabidopsis Response Regulator), B-ARR (Type-B Arabidopsis Response Regulator), AUX1 (Auxin Resistant 1), ARF (Auxin Response Factor), AUX/IAA (Auxin/Indole-3-acetic acid), GH3 (Gretchen Hagen 3), SAUR (Small Auxin Up RNA), GA2ox (Gibberellin 2-oxidase), GA20ox (Gibberellin 20-oxidase), AOS (Allene oxide synthase), AOC (Allene oxide cyclase), OPR (Oxophytodienoate Reductase), JMT (JA carboxy l Methyltransferase), COI1 (Coronatine Insensitive 1), JAZ (Jasmonate ZIM-domain), MYC2 (Myelocytomatosis 2), D27 (DWARF27), SMAX (Suppressor of MAX2), PAL (Phenylalanine Ammonia-Lyase), ICS (Isochorismate Synthase), NPR1 (Non-expressor of Pathogenesis-related Genes1), TGA (TGACG Sequence-specific Binding), PR-1 (Pathogenesis-related), MCSU (Molybdenium Cofactor Sulfurase), PP2C (Protein Phosphatase 2C), and SnRK (Sucrose Non-fermenting-related Protein Kinase 2) were highly correlated with hormone concentrations, indicating that bulbil initiation is coordinately controlled by multiple phytohormones. Notably, eight TFs (transcription factors) that regulate AM initiation have been identified as pivotal regulators of bulbil formation. Among these, WUS (WUSCHEL), CLV (CLAVATA), ATH1 (Arabidopsis Thaliana Homeobox Gene 1), and RAX (Regulator of Axillary meristems) have been observed to exhibit elevated expression levels. Conversely, LEAFY demonstrated contrasting expression patterns. The intricate expression profiles of these TFs are closely associated with the upregulated expression of KNOX(KNOTTED-like homeobox), suggesting a intricate regulatory network underlying the complex process of bulbil initiation. This study offers a profound understanding of the bulbil initiation process and could potentially aid in refining molecular breeding techniques specific to P. ternata.