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Variants in seven genes (LRRK2, GBA1, PRKN, SNCA, PINK1, PARK7 and VPS35) have been formally adjudicated as causal contributors to Parkinsons disease; however, individuals with Parkinsons disease are often unaware of their genetic status since clinical testing is infrequently offered. As a result, genetic information is not incorporated into clinical care, and variant-targeted precision medicine trials struggle to enrol people with Parkinsons disease. Understanding the yield of genetic testing using an established gene panel in a large, geographically diverse North American population would help patients, clinicians, clinical researchers, laboratories and insurers better understand the importance of genetics in approaching Parkinsons disease. PD GENEration is an ongoing multi-centre, observational study (NCT04057794, NCT04994015) offering genetic testing with results disclosure and genetic counselling to those in the US (including Puerto Rico), Canada and the Dominican Republic, through local clinical sites or remotely through self-enrolment. DNA samples are analysed by next-generation sequencing including deletion/duplication analysis (Fulgent Genetics) with targeted testing of seven major Parkinsons disease-related genes. Variants classified as pathogenic/likely pathogenic/risk variants are disclosed to all tested participants by either neurologists or genetic counsellors. Demographic and clinical features are collected at baseline visits. Between September 2019 and June 2023, the study enrolled 10 510 participants across >85 centres, with 8301 having received results. Participants were: 59% male; 86% White, 2% Asian, 4% Black/African American, 9% Hispanic/Latino; mean age 67.4 ± 10.8 years. Reportable genetic variants were observed in 13% of all participants, including 18% of participants with one or more high risk factors for a genetic aetiology: early onset (

Estimates of the spectrum and frequency of pathogenic variants in Parkinsons disease (PD) in different populations are currently limited and biased. Furthermore, although therapeutic modification of several genetic targets has reached the clinical trial stage, a major obstacle in conducting these trials is that PD patients are largely unaware of their genetic status and, therefore, cannot be recruited. Expanding the number of investigated PD-related genes and including genes related to disorders with overlapping clinical features in large, well-phenotyped PD patient groups is a prerequisite for capturing the full variant spectrum underlying PD and for stratifying and prioritizing patients for gene-targeted clinical trials. The Rostock Parkinsons disease (ROPAD) study is an observational clinical study aiming to determine the frequency and spectrum of genetic variants contributing to PD in a large international cohort. We investigated variants in 50 genes with either an established relevance for PD or possible phenotypic overlap in a group of 12 580 PD patients from 16 countries [62.3% male; 92.0% White; 27.0% positive family history (FH+), median age at onset (AAO) 59 years] using a next-generation sequencing panel. Altogether, in 1864 (14.8%) ROPAD participants (58.1% male; 91.0% White, 35.5% FH+, median AAO 55 years), a PD-relevant genetic test (PDGT) was positive based on GBA1 risk variants (10.4%) or pathogenic/likely pathogenic variants in LRRK2 (2.9%), PRKN (0.9%), SNCA (0.2%) or PINK1 (0.1%) or a combination of two genetic findings in two genes (∼0.2%). Of note, the adjusted positive PDGT fraction, i.e. the fraction of positive PDGTs per country weighted by the fraction of the population of the world that they represent, was 14.5%. Positive PDGTs were identified in 19.9% of patients with an AAO ≤ 50 years, in 19.5% of patients with FH+ and in 26.9% with an AAO ≤ 50 years and FH+. In comparison to the idiopathic PD group (6846 patients with benign variants), the positive PDGT group had a significantly lower AAO (4 years, P = 9 × 10-34). The probability of a positive PDGT decreased by 3% with every additional AAO year (P = 1 × 10-35). Female patients were 22% more likely to have a positive PDGT (P = 3 × 10-4), and for individuals with FH+ this likelihood was 55% higher (P = 1 × 10-14). About 0.8% of the ROPAD participants had positive genetic testing findings in parkinsonism-, dystonia/dyskinesia- or dementia-related genes. In the emerging era of gene-targeted PD clinical trials, our finding that ∼15% of patients harbour potentially actionable genetic variants offers an important prospect to affected individuals and their families and underlines the need for genetic testing in PD patients. Thus, the insights from the ROPAD study allow for data-driven, differential genetic counselling across the spectrum of different AAOs and family histories and promote a possible policy change in the application of genetic testing as a routine part of patient evaluation and care in PD.

AbstractThe introduction of Tyrosine Kinase Inhibitors (TKIs) has revolutionised cancer treatment, yet concerns regarding cardiovascular toxicity have surfaced. This piece delves into the interplay between AMP-activated protein kinase (AMPK) signalling and TKI-induced cardiovascular toxicity. The study unravels the intricate relationship between AMPK activation and TKI-induced cardiovascular toxicity, aiming to ascertain whether AMPK can play a strategic role in mitigating adverse effects. Beyond unravelling mechanistic insights, the research sets the stage for future therapeutic approaches, envisioning AMPK activation as a pivotal connection for balancing effective cancer treatment with cardiovascular well-being. As research advances, the potential of AMPK activation not only addresses challenges in TKI-induced cardiovascular toxicity but also shapes the future landscape of personalised anticancer therapies. The article explores the mechanisms of TKI-induced toxicity, AMPK’s impact on cardiovascular health, and the potential therapeutic implications of AMPK activation in alleviating TKI-associated toxicities. [ABSTRACT FROM AUTHOR]

In neurodegenerative diseases, the activation of microglia and the ensuing neuroinflammation are pivotal in regulating disease progression. Attenuating inflammation induced by microglial cells is considered a key strategy for slowing the progression of neurodegenerative diseases. γ‐glutamylcysteine (γ‐GC) has exhibited significant antioxidative and anti‐inflammatory effects; nevertheless, its potential role in modulating neuroinflammatory responses remains incompletely explored. The current investigation aimed to establish a neuroinflammation model by stimulating BV2 microglia cells with lipopolysaccharide (LPS) and to explore the protective effect of γ‐GC on neuroinflammation in BV2 microglia cells. The results demonstrated that γ‐GC significantly attenuated LPS‐induced oxidative damage in BV2 cells, reduced the levels of tumor necrosis factor‐α (TNF‐α) and interleukin‐1β (IL‐1β), inhibited the cytoplasmic translocation of high‐mobility group box 1 protein (HMGB1), and effectively mitigated the LPS‐induced inflammatory response in BV2 cells. We further investigated the regulatory mechanism of γ‐GC on LPS‐induced BV2 neuroinflammation and found that γ‐GC significantly enhances autophagy in BV2 cells, resulting in a marked reduction in mammalian target of rapamycin (mTOR) phosphorylation levels and an increase in AMP‐activated protein kinase (AMPK) phosphorylation levels. The use of autophagy inhibitors 3‐methyladenine (3‐MA) and AMPK inhibitors further corroborates the proposition that γ‐GC promotes autophagy in BV2 cells while suppressing the LPS‐induced inflammatory response of BV2 microglia through the activation of the AMPK‐mTOR pathway. The findings indicate that γ‐GC exerts a substantial inhibitory impact on neuroinflammation, making it a promising candidate for the development of therapeutic strategies against neuroinflammatory disorders and related conditions. [ABSTRACT FROM AUTHOR]

Salinity stress is a major concern in regions where irrigation relies on saline water. This study aimed to investigate the relative water content (RWC), electrolytic leakage (EL), total chlorophyll content, free amino acid content, and total soluble sugar content were analyzed in different groundnut species subjected to various salinity treatments. The results showed that salinity stress significantly reduced the RWC in groundnut leaves, with A. duranensis (wild type) exhibiting higher RWC values compared to the Arachis hypogaea species. RNA sequencing was performed to identify differentially expressed genes (DEGs) during salt stress. A total of 9079 DEGs were identified, with 1372 genes upregulated and 2509 genes downregulated. Genes belonging to transcription factor families, such as WRKY, MYB, bHLH, E2F, and Auxin efflux carrier proteins, were induced under salt stress in the tolerant genotype. Conversely, genes encoding NADH dehydrogenase, glutathione S-transferase, protein kinases, UDP-glycosyltransferase, and peroxidase were downregulated. Gene ontology and pathway analyses revealed several enriched categories and metabolic pathways associated with salt stress response, including catalytic activity, response to salt stress, ATP-dependent activity, and oxidative phosphorylation. The findings of this study provide insights into the physiological and molecular responses of groundnut to salinity stress. A. duranensis exhibited better salinity tolerance than Arachis hypogaea , as indicated by higher RWC values, lower electrolytic leakage, and differential gene expression patterns. These results contribute to our understanding of the mechanisms underlying salt stress tolerance in groundnut and may guide future efforts to develop salinity-tolerant groundnut species, ultimately improving crop yield in saline-affected regions. • Salinity stress decreases crop yield by affecting water content and leaf damage in groundnut plants. • A. duranensis variety shows higher tolerance to salinity stress compared to GG20. • Salinity stress reduces chlorophyll levels in groundnut leaves, with A. duranensis being more resilient. • Salinity stress triggers the accumulation of free amino acids and soluble sugars, especially in A. duranensis. • RNA-seq analysis reveals key genes involved in groundnut's response to salt stress, providing valuable insights. [ABSTRACT FROM AUTHOR]

Background: Sodium-glucose cotransporter 2 (SGLT2) inhibitors have changed the therapeutic landscape for diabetic kidney disease (DKD) patients, but their underlying mechanisms are complicated and not fully understood. Mitochondria-associated endoplasmic reticulum membranes (MAMs), the dynamic contact sites between mitochondria and the endoplasmic reticulum (ER), serve as intracellular platforms important for regulating cellular fate and function. This study explored the roles and mechanisms of SGLT2 inhibitors in regulating MAMs formation in diabetic podocytes. Methods: We assessed MAMs formation in podocytes from DKD patients' renal biopsy samples and induced an increase in MAMs formation in cultured human podocytes by transfecting OMM-ER linker plasmid to investigate the effects of MAMs imbalance on podocyte injury. Empagliflozin-treated diabetic mice and podocyte-specific SGLT2 knockout diabetic mice (diabetic states were induced by streptozotocin and a high-fat diet), empagliflozin-treated podocytes, SGLT2-downregulated podocytes, and SGLT2-overexpressing podocytes were used to investigate the effects and mechanisms of SGLT2 inhibitors on MAMs formation in diabetic podocytes. Results: MAMs were increased in podocytes and were associated with renal dysfunction in DKD patients. Increased MAMs aggravated HG-induced podocyte injury. The expression of SGLT2 was increased in diabetic podocytes. In addition, empagliflozin-treatment and podocyte-specific SGLT2 knockout attenuated MAMs formation and podocyte injury in diabetic mice. Empagliflozin treatment and SGLT2 knockdown decreased podocyte MAMs formation by activating the AMP-activated protein kinase (AMPK) pathway, while SGLT2 overexpression had the opposite effect. Conclusions: Inhibition of SGLT2 attenuates MAMs imbalance in diabetic podocytes by activating the AMPK pathway. This study expands our knowledge of the roles of SGLT2 inhibitors in improving DKD podocyte injury and provides new insights into DKD treatment. [ABSTRACT FROM AUTHOR]

Introduction: Drug-induced sarcopenia has not received adequate attention. Meanwhile, there is growing recognition of the importance of effective pharmacovigilance in evaluating the benefits and risks of medications. Aims: The primary aim of this study is to investigate the potential association between drug use and sarcopenia through an analysis of adverse event reports from the Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) and to evaluate the genetic factors contributing to drug-induced sarcopenia using summary-data-based Mendelian randomization (SMR). Methods: We obtained reports of adverse drug reactions from FAERS. Primary outcomes included sarcopenia and potential sarcopenia. We calculated the Proportional reporting ratio (PRR) to assess the risk of specific adverse events associated with various drugs, applying chi-square tests for statistical significance. Additionally, we used SMR based on Genome-wide association study (GWAS) to evaluate the potential associations between drug target genes of some significant medications and sarcopenia outcomes. The outcome data for sarcopenia included metrics as hand grip strength and appendicular lean mass (ALM). Results: A total of 55 drugs were identified as inducing potential sarcopenia, and 3 drugs were identified as inducing sarcopenia. The top 5 drugs causing a potential risk of sarcopenia were levofloxacin (PRR = 9.96, χ2 = 1057), pregabalin (PRR = 7.20, χ2 = 1023), atorvastatin (PRR = 4.68, χ2 = 903), duloxetine (PRR = 4.76, χ2 = 527) and venlafaxine (PRR = 5.56, χ2 = 504), and the 3 drugs that had been proved to induced sarcopenia included metformin (PRR = 7.41, χ2 = 58), aspirin (PRR = 5.93, χ2 = 35), and acetaminophen (PRR = 4.73, χ2 = 25). We identified electron-transfer flavoprotein dehydrogenase (ETFDH) and protein Kinase AMP-Activated Non-Catalytic Subunit Beta 1 (PRKAB1) as the primary drug target genes for metformin, while Prostaglandin-endoperoxide Synthase 1 (PTGS1) and Prostaglandin-endoperoxide Synthase 2 (PTGS2) were considered the primary action target genes for aspirin and acetaminophen according to DrugBank database. SMR showed that the expression abundance of ETFDH was negatively correlated with right hand grip strength (blood: OR = 1.01, p-value = 1.27e-02; muscle: OR = 1.01, p-value = 1.42e-02) and negatively correlated with appendicular lean mass (blood: OR = 1.03, p-value = 7.73e-08; muscle: OR = 1.03, p-value = 1.67e-07). Conclusions: We find that metformin, aspirin, and acetaminophen are specifically noted for their potential to induce sarcopenia based on the analyses conducted. We perform signal mining for drug-associated sarcopenia events based on real-world data and provides certain guidance for the safe use of medications to prevent sarcopenia. [ABSTRACT FROM AUTHOR]

Metabolic‐associated fatty liver disease (MAFLD) has become one of the most widespread metabolic diseases nowadays, while no definitive agent is approved for practical treatment. Given excessive lipid deposition and cellular oxidative stress are two main inducers of MAFLD, developing synergistic therapeutic agents that enhance lipid metabolism and antioxidative ability are effective routes for MAFLD therapy. Herein, a novel kind of bio‐functional carbon dots (MTCDs) derived from metformin and tea polyphenols based on a fused pharmacophore strategy is developed. The surface of MTCDs retains abundant phenolic hydroxyl and guanidine groups, which are designed to reduce both lipid deposition and oxidative stress in the liver. Moreover, by finely controlling the surface charge, MTCDs exhibit excellent lysosome targeting functionality with favorable biocompatibility and low biotoxicity. Mechanistical studies further reveal that MTCDs treatment protects lysosomes from oxidative stress damage and activates hepatocyte AMP‐activated protein kinase signaling, which initiates lipophagy progress to accelerate lipolysis and lipid consumption. Collectively, these studies propose an effective "two birds with one stone" tool for MAFLD synergistic therapy and suggest a viable strategy for multi‐pharmacophore agent development. [ABSTRACT FROM AUTHOR]

Cancer, the world's second leading cause of death after cardiovascular diseases, is characterized by hallmarks such as uncontrolled cell growth, metastasis, angiogenesis, hypoxia, and resistance to therapy. Autophagy, a cellular process that can both support and inhibit cancer progression, plays a critical role in cancer development and progression. This process involves the formation of autophagosomes that ultimately fuse with lysosomes to degrade cellular components. A key regulator of this process is Sirtuin 1 (SIRT1), which significantly influences autophagy. This review delves into the role of SIRT1 in modulating autophagy and its broader impacts on carcinogenesis. SIRT1 regulates crucial autophagy mediators, such as AMP-activated protein kinase (AMPK) and mammalian target of rapamycin (mTOR), effectively promoting or suppressing autophagy. Beyond its direct effects on autophagy, SIRT1's regulatory actions extend to other cell death processes, including apoptosis and ferroptosis, thereby influencing tumor cell proliferation, metastasis, and chemotherapy responses. These insights underscore the complex interplay between SIRT1 and autophagy, with significant implications for cancer therapy. Targeting SIRT1 and its associated pathways presents a promising strategy to manipulate autophagy in cancer treatment. This review underscores the potential of SIRT1 as a therapeutic target, opening new avenues for enhancing cancer treatment efficacy. [ABSTRACT FROM AUTHOR]

Raf protein kinases act as Ras-GTP sensing components of the ERK signal transduction pathway in animal cells, influencing cell proliferation, differentiation, and survival. In humans, somatic and germline mutations in the genes BRAF and RAF1 are associated with malignancies and developmental disorders. Recent studies shed light on the structure of activated Raf, a heterotetramer consisting of Raf and 14-3-3 dimers, and raised the possibility that a Raf C-terminal distal tail segment (DTS) regulates activation. We investigated the role of the DTS using the Caenorhabditis elegans Raf ortholog lin-45. Truncations removing the DTS strongly enhanced lin-45 (S312A) , a weak gain-of-function allele equivalent to RAF1 mutations found in patients with Noonan Syndrome. We genetically defined three elements of the LIN-45 DTS, which we termed the active site binding sequence (ASBS), the KTP motif, and the aromatic cluster. In the context of lin-45 (S312A) , the mutation of each of these elements enhanced activity. We used AlphaFold to predict DTS protein interactions for LIN-45 , fly Raf, and human BRAF within the activated heterotetramer complex. We propose the following distinct functions for the LIN-45 DTS elements: (1) the ASBS binds the kinase active site as an inhibitor; (2) phosphorylation of the KTP motif modulates the DTS–kinase domain interaction; and (3) the aromatic cluster anchors the DTS in an inhibitory conformation. Human RASopathy-associated variants in BRAF affect residues of the DTS, consistent with these predictions. This work establishes that the Raf/ LIN-45 DTS negatively regulates signaling in C. elegans and provides a model for its function in other Raf proteins. [ABSTRACT FROM AUTHOR]

The mechanisms of epileptogenesis after brain injury, ischemic stroke, or brain tumors have been extensively studied. As a result, many effective antiseizure drugs have been developed. However, there are still many patients who are resistant to therapy. The molecular and genetic bases regarding such drug-resistant seizures have been poorly elucidated. In many cases, heavy seizures are instigated by brain development malformations and often caused by gene mutations. Such malformations can be demonstrated in mouse models by generating mutant strains. One of the most potent mutagens is ENU (N-ethyl-N-nitrosourea). In the present study, we describe three novel mutant strains generated by ENU-directed mutagenesis. Two of these strains present a very strong epileptic phenotype triggered by audiogenic stimuli (G9-1 and S5-1 strains). The third mouse strain is characterized by behavioral disorders and hyperexcitation of neuronal networks. We identified changes in the expression of those genes encoding neurotransmission proteins in the cerebral cortexes of these mice. It turned out that the G9-1 strain demonstrated the strongest disruptions in the expression of those genes encoding plasma membrane channels, excitatory glutamate receptors, and protein kinases. On the other hand, the number of GABAergic neurons was also affected by the mutation. All three lines are characterized by increased anxiety, excitability, and suppressed motor and orientational–exploratory activities. On the other hand, the strains with an epileptic phenotype—G9-1 and S5-1ave reduced learning ability, and the A9-2 mice line retains high learning ability. [ABSTRACT FROM AUTHOR]

Simple Summary: The Yes-associated protein (YAP) is part of a system that regulates cell proliferation in response to changes in cell–cell and cell–matrix interactions. In malignant tumors, that system is almost always disrupted in ways that promote the stability of YAP. Mutations in genes encoding Ras proteins are found in 30% of all human cancers, but the mechanisms by which these mutated proteins promote cancer are still incompletely understood. Here, we investigated the regulation of YAP stability by the Ras oncogenes and found that while Ras does not directly regulate YAP, the stability of YAP is directly controlled by one of Ras's own effectors, the Rac1 GTPase, a small regulatory protein involved in controlling cell shape and migration. This regulation of YAP by Rac1 could potentially play an important role in the development of therapeutic resistance to Ras inhibitors, which we know can be promoted by the overexpression of YAP. Background: Oncogenic mutations in the KRAS gene are detected in >90% of pancreatic cancers (PC). In genetically engineered mouse models of PC, oncogenic KRAS drives the formation of precursor lesions and their progression to invasive PC. The Yes-associated Protein (YAP) is a transcriptional coactivator required for transformation by the RAS oncogenes and the development of PC. In Ras-driven tumors, YAP can also substitute for oncogenic KRAS to drive tumor survival after the repression of the oncogene. Ras oncoproteins exert their transforming properties through their downstream effectors, including the PI3K kinase, Rac1 GTPase, and MAPK pathways. Methods: To identify Ras effectors that regulate YAP, YAP levels were measured in PC cells exposed to inhibitors of oncogenic K-Ras and its effectors. Results: In PC cells, the inhibition of Rac1 leads to a time-dependent decline in YAP protein, which could be blocked by proteosome inhibitor MG132. This YAP degradation after Rac1 inhibition was observed in a range of cell lines using different Rac1 inhibitors, Rac1 siRNA, or expression of dominant negative Rac1T17N mutant. Several E3 ubiquitin ligases, including SCFβTrCP, regulate YAP protein stability. To be recognized by this ligase, the βTrCP degron of YAP (amino acid 383–388) requires its phosphorylation by casein kinase 1 at Ser384 and Ser387, but these events must first be primed by the phosphorylation of Ser381 by LATS1/2. Using Flag-tagged mutants of YAP, we show that YAP degradation after Rac1 inhibition requires the integrity of this degron and is blocked by the silencing of βTrCP1/2 and by the inhibition of casein kinase 1. Unexpectedly, YAP degradation after Rac1 inhibition was still observed after the silencing of LATS1/2 or in cells carrying a LATS1/2 double knockout. Conclusions: These results reveal Rac1 as an oncogenic KRAS effector that contributes to YAP stabilization in PC cells. They also show that this regulation of YAP by Rac1 requires the SCFβTrCP ligase but occurs independently of the LATS1/2 kinases. [ABSTRACT FROM AUTHOR]

In this study, we uncovered the novel mechanism of IL-1α-mediated downregulated in adenoma (DRA) (SLC26A3) downregulation in the context of Brachyspira spp.-induced malabsorptive diarrhea. Experimentally infected pigs with Brachyspira spp. had significantly reduced DRA expression in the colon accompanied by IL-1α upregulation. This response was recapitulated in vitro by exposing Caco-2 cells to either Brachyspira lysate or IL-1α. Both p38 and MAPK-activated protein kinase 2 (MAPKAPK-2 also referred as MK-2) showed an increased phosphorylation after exposure to either. SB203580 application, a p38 inhibitor blocked the MK-2 phosphorylation and attenuated the DRA and IL-1α response to both lysate and IL-1α. Exposure to IL-1 receptor antagonist (IL-1RA) produced a similar response. In addition, exposure of cells to either of these blockers without IL-1α or lysate results in increased DRA and decreased IL-1α expression, revealing that DRA needs IL-1α signaling for basal physiological expression. Dual inhibition with both blockers completely inhibited the effect from IL-1α while significantly attenuating the response from Brachyspira lysate, suggesting a minor contribution from another pathway. Together this demonstrates that Brachyspira activates p38 MAPK signaling driving IL-1α expression, which activates IL-1R1 causing DRA downregulation while also driving upregulation of IL-1α through p38 in a positive feedback mechanism. In conclusion, we elucidated a major pathway involved in DRA downregulation and its role in Brachyspira-induced diarrhea. In addition, these observations will aid in our understanding of other inflammatory and infectious diarrhea conditions. NEW & NOTEWORTHY: The diarrheal disease caused by the two infectious spirochete spp. B. hyodysenteriae and B. hampsonii reduced the expression of DRA (SLC26A3), a major Cl−/HCO–3 exchanger involved in Cl− absorption. This is attributed to the upregulation of IL-1α driven by p38 MAPK. This work also describes a potential new mechanism in inflammatory diseases while showing the importance of IL-1α in maintaining DRA levels. [ABSTRACT FROM AUTHOR]

The PIM kinase family, consisting of PIM1, PIM2, and PIM3, is a group of serine/threonine protein kinases crucial for cellular growth, immunoregulation, and oncogenesis. PIM1 kinase is often overexpressed in solid and hematopoietic malignancies, promoting cell survival, proliferation, migration, and senescence by activating key genes. In vitro and in vivo studies have established the oncogenic potential of PIM1 kinases. These kinases have been implicated in tumor progression, metastasis, and resistance to chemotherapy, underscoring their potential as a therapeutic target for cancer therapy. This review delves into the intricate molecular mechanisms through which PIM1 interacts with specific substrates in different tumor tissues, leading to diverse outcomes in various human cancers. Over the past decade, the inhibition of PIM1 in cancers has garnered significant attention as a potential standalone treatment. Various in vitro, in vivo, and early clinical trial data have provided support for this approach to varying extents. Novel compounds that inhibit PIM1 kinase have shown effectiveness and a favorable toxicity profile in preclinical studies. Several of these substances are now being studied in clinical trials due to their promising outcomes. This article provides a thorough examination of the PIM1 kinase pathways and the recent advancements in producing PIM1 kinase inhibitors for the treatment of cancer. [ABSTRACT FROM AUTHOR]

Human phosphoglycerate kinase 1(hPGK1) is a key glycolytic enzyme that regulates the balance between ADP and ATP concentrations inside the cell. Phosphorylation of hPGK1 at S203 and S256 has been associated with enzyme import from the cytosol to the mitochondria and the nucleus respectively. These changes in subcellular locations drive tumorigenesis and are likely associated with site‐specific changes in protein stability. In this work, we investigate the effects of site‐specific phosphorylation on thermal and kinetic stability and protein structural dynamics by hydrogen–deuterium exchange (HDX) and molecular dynamics (MD) simulations. We also investigate the binding of 3‐phosphoglycerate and Mg‐ADP using these approaches. We show that the phosphomimetic mutation S256D reduces hPGK1 kinetic stability by 50‐fold, with no effect of the mutation S203D. Calorimetric studies of ligand binding show a large decrease in affinity for Mg‐ADP in the S256D variant, whereas Mg‐ADP binding to the WT and S203D can be accurately investigated using protein kinetic stability and binding thermodynamic models. HDX and MD simulations confirmed the destabilization caused by the mutation S256D (with some long‐range effects on stability) and its reduced affinity for Mg‐ADP due to the strong destabilization of its binding site (particularly in the apo‐state). Our research provides evidence suggesting that modifications in protein stability could potentially enhance the translocation of hPGK1 to the nucleus in cancer. While the structural and energetic basis of its mitochondrial import remain unknown. [ABSTRACT FROM AUTHOR]

The phosphoproteome is vast and intricate, with many aspects of its extent and site-specific functional roles still largely unexplored. While traditional studies have primarily focused on Ser/Thr and Tyr phosphorylation, new methodologies are emerging to study non-canonical phosphorylation events. Protein phosphatases play critical roles in cellular signaling, with recent studies highlighting their complexity and involvement in various biological processes. A significant portion of the kinome, referred to as the 'dark' kinome, remains understudied and holds great potential for novel discoveries. Pseudokinases and pseudophosphatases, despite lacking catalytic activity, play crucial roles in cell signaling. Recent advances in experimental and computational analyses have improved the understanding of kinase–substrate and phosphatase–substrate interactions. Protein phosphorylation is a crucial regulatory mechanism in cell signaling, acting as a molecular switch that modulates protein function. Catalyzed by protein kinases and reversed by phosphoprotein phosphatases, it is essential in both normal physiological and pathological states. Recent advances have uncovered a vast and intricate landscape of protein phosphorylation that include histidine phosphorylation and more unconventional events, such as pyrophosphorylation and polyphosphorylation. Many questions remain about the true size of the phosphoproteome and, more importantly, its site-specific functional relevance. The involvement of unconventional actors such as pseudokinases and pseudophosphatases adds further complexity to be resolved. This review explores recent discoveries and ongoing challenges, highlighting the need for continued research to fully elucidate the roles and regulation of protein phosphorylation. [ABSTRACT FROM AUTHOR]

Post‐flowering diseases (PFDs), such as ear rot, stalk rot and smut, affect maize yield and quality by damaging the reproductive organs, stalks and seeds. We hypothesized that quantitative trait loci (QTL) associated with different PFDs colocalize and share similar defence mechanisms. Hence, to find a stable consensus meta‐QTL (MQTL) for single or multiple PFDs, MQTL analysis was performed. QTL conferring resistance to PFD reported in 31 independent studies were collated to develop a consensus map. As many as 49 MQTL conferring PFD resistance were projected using appropriate algorithms. Most MQTL regions encompass genes encoding a wide range of defence‐related proteins. MQTL1.1 and MQTL10.5 included QTL/genes for resistance to all PFDs, which supported our hypothesis. Candidate genes for PFDs in MQTL7.1 were associated with pathogenesis‐related 1 protein and mitogen‐activated protein kinase (MAPK) signalling. MQTL5.2 encompassed chalcone flavanone isomerase and cinnamoyl coenzyme A (CoA) reductase genes involved in flavonoid and phenylpropanoid biosynthesis, respectively. Furthermore, MQTL10.4 was found to harbour genes encoding E3 ubiquitin ligase, WRKY‐TF11, calcium‐binding domains and zinc finger motifs. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis reiterated the role of genes within MQTL7.1 in the MAPK signalling pathway, phytohormone signal transduction and plant–pathogen interaction. Hence, we propose that these genes are potential candidates for PFD resistance. Furthermore, 75% of the genes within the MQTL showed orthology with sorghum and rice, indicating that these genes were conserved across species. The role of 27 MQTL, including the six most significant MQTL, was confirmed with reported genome‐wide association study (GWAS) results. Thus, the hotspots associated with PFDs identified in our study could be reliably used in marker‐assisted breeding for PFD resistance. [ABSTRACT FROM AUTHOR]

AbstractEmerging data suggest that cocrystal of two compounds may have a different pharmacological effect from two compounds alone or their physical combination. Glimepiride (Gli) and metformin (Met) are two types of anti-diabetic drugs. Previously we generated the glimepiride/metformin cocrystal (GM). In this study, we evaluated the anti-diabetic effects of GM and explored the underlying mechanisms. Our result showed that GM reduced the blood glucose and HbA1c levels in db/db mice, and low doses of GM can achieve the hypoglycemic effect as Gli or Met alone, and high dose of GM was better than Gli and Met alone in improving the pathological changes of liver. In vivo studies showed that GM activated AMPK and STAT3 signaling, downregulated TXNIP expression and upregulated MaFA expression. Moreover, GM promoted the secretion of insulin in pancreas of db/db mice and in high glucose-treated INS-1 and MIN-6 cells. Together, GM possesses slightly better anti-diabetic effects than Met or Gli alone in db/db mice, and the mechanism of GM protecting β-cell dysfunction induced by glucotoxicity may be associated with activation of the AMPK/TXNIP/MaFA pathway. [ABSTRACT FROM AUTHOR]

Summary Nitrate (NO3−) serves as the primary inorganic nitrogen source assimilated by most terrestrial plants. The acquisition of nitrate from the soil is facilitated by NITRATE TRANSPORTERS (NRTs), with NRT2.1 being the key high‐affinity nitrate transporter. The activity of NRT2.1, which has multiple potential phosphorylation sites, is intricately regulated under various physiological conditions. Here, we discovered that CALCIUM‐DEPENDENT PROTEIN KINASE 28 (CPK28) positively regulates nitrate uptake under nitrogen deprivation conditions. We found CPK28 as the kinase targeted by immunoprecipitation followed by mass spectrometry and examined the in‐planta phosphorylation status of NRT2.1 in cpk28 mutant plants by employing quantitative MS‐based phosphoproteomics. Through a combination of in vitro phosphorylation experiment and immunoblotting using phospho‐specific antibody, we successfully demonstrated that CPK28 specifically phosphorylates NRT2.1 at Ser21. Functional analysis conducted in Xenopus oocytes revealed that co‐expression of CPK28 significantly enhanced high‐affinity nitrate uptake of NRT2.1. Further investigation using transgenic plants showed that the phosphomimic variant NRT2.1S21E, but not the nonphosphorylatable variant NRT2.1S21A, fully restored high‐affinity 15NO3− uptake ability in both nrt2.1 and cpk28 mutant backgrounds. This study clarifies that the kinase activity of CPK28 is promoted during nitrogen deprivation conditions. These significant findings provide valuable insights into the intricate regulatory mechanisms that govern nitrate‐demand adaptation. [ABSTRACT FROM AUTHOR]

Neuronal information processing depends on converting membrane depolarizations into compartmentalized biochemical signals that can modify neuronal activity and structure. However, our understanding of how neurons translate electrical signals into specific biochemical responses remains limited, especially in the soma where gene expression and ion channel function are crucial for neuronal activity. Here, I emphasize the importance of physically compartmentalizing action potential‐triggered biochemical reactions within the soma. Emerging evidence suggests that somatic endoplasmic reticulum–plasma membrane (ER‐PM) junctions are specialized organelles that coordinate electrical and biochemical signaling. The juxtaposition of ion channels and signaling proteins at a prominent subset of these sites enables compartmentalized calcium and cAMP‐dependent protein kinase (PKA) signaling. I explore the hypothesis that these PKA‐containing ER‐PM junctions serve as critical sites for translating membrane depolarizations into PKA signals and identify key gaps in knowledge of the assembly, regulation, and neurobiological functions of this somatic signaling system. [ABSTRACT FROM AUTHOR]

Cellular protein kinases are involved in diverse normal cellular functions. Many types of dysregulation of protein kinases are the molecular basis for development of common cancers and neurodegenerative diseases. More than 80 small-molecule protein kinase inhibitors are available now and approved by the US Food and Drug Administration for successful treatment of cancers and neurodegenerative diseases. Newly designed protein kinase inhibitors and related forms of therapy based on a greater understanding of molecular mechanisms have diminished the appearance of disease resistance to protein kinase inhibitors and other side effects. These advances will further promote the success of protein kinase inhibitors in treatment of common cancers, Alzheimer's disease, and other neurodegenerative conditions. [ABSTRACT FROM AUTHOR]

Summary: In Arabidopsis, the enzymatically active lysin motif‐containing receptor‐like kinase (LysM‐RLK) CHITIN ELICITOR RECEPTOR KINASE 1 (CERK1) and the pseudokinases LYSIN MOTIF‐CONTAINING RECEPTOR‐LIKE KINASE 5 (LYK5) and LYK4 are the core components of the canonical chitin receptor complex. CERK1 dimerizes and autophosphorylates upon chitin binding, resulting in activation of chitin signaling.In this study, we clarified and further elucidated the individual contributions of LYK4 and LYK5 to chitin‐dependent signaling using mutant (combination)s and stably transformed Arabidopsis plants expressing fluorescence‐tagged LYK5 and LYK4 variants from their endogenous promoters.Our analyses revealed that LYK5 interacts with CERK1 upon chitin treatment, independently of LYK4 and vice versa. We show that chitin‐induced autophosphorylation of CERK1 is predominantly dependent on LYK5, whereas chitin‐triggered ROS generation is almost exclusively mediated by LYK4. This suggests specific signaling functions of these two co‐receptor proteins apart from their redundant function in mitogen‐activated protein kinase (MAPK) signaling and transcriptional reprogramming.Moreover, we demonstrate that LYK5 is subject to chitin‐induced and CERK1‐dependent ubiquitination, which serves as a signal for chitin‐induced internalization of LYK5. Our experiments provide evidence that a combination of phosphorylation and ubiquitination events controls LYK5 removal from the plasma membrane via endocytosis, which likely contributes to receptor complex desensitization. [ABSTRACT FROM AUTHOR]

After ejaculation, mammalian sperm undergo a series of molecular events conducive to the acquisition of fertilizing competence. These events are collectively known as capacitation and involve acrosomal responsiveness and a vigorous sperm motility called hyperactivation. When mimicked in the laboratory, capacitating bovine sperm medium contains bicarbonate, calcium, albumin and heparin, among other components. In this study, we aimed at establishing a new capacitation protocol for bovine sperm, using calcium ionophore. Similar to our findings using mouse sperm, bovine sperm treated with Ca2+ ionophore A23187 were quickly immobilized. However, these sperm initiated capacitation after ionophore removal in fresh medium without heparin, and independent of the Protein Kinase A. When A23187-treated sperm were used on in vitro fertilization (IVF) procedures without heparin, eggs showed cleavage rates similar to standardized IVF protocols using heparin containg synthetic oviduct fluid (IVF-SOF). However, when A23187 pre-treated sperm were further used for inseminating eggs in complete IVF-SOF-heparin, a significantly higher percentage of embryo development was observed, suggesting a synergism between two different signaling pathways during bovine sperm capacitation. These results have the potential to improve current protocols for bovine IVF that could also be applied in other species of commercial interest. • Exposure calcium ionophore improves bovine sperm hyperactivation after washing. • Sperm capacitation is achieved by transient exposure to calcium ionophore. • Exposure calcium ionophore trigger capacitation events independent of PKA. • Calcium ionophore capacitated sperm improve embryo production when used in IVF. [ABSTRACT FROM AUTHOR]

Background: Gut microbiota dysbiosis induces intestinal barrier damage during parenteral nutrition (PN). However, the underlying mechanisms remain unclear. This study aimed to investigate gut microbiota dysbiosis, luminal short‐chain fatty acids, and autophagy in a mouse model and how these short‐chain fatty acids regulate autophagy. Methods: Eight‐week‐old male specific‐pathogen–free mice were randomly divided into a Chow group (standard diet and intravenous normal saline infusion) and a PN group (continuous infusion of PN nutrient solution) for 7 days. Caco‐2 cells were also treated with intestinal rinse solutions from Chow and PN mouse models. Results: Compared with the Chow group, the PN group exhibited increased Proteobacteria and decreased Firmicutes, correlating with decreased propyl acetate. In the PN group, intestinal tissue exhibited elevated adenosine monophosphate–activated protein kinase (AMPK) phosphorylation, LC3II protein levels, and Atg3 and Atg7 messenger RNA levels. P62 protein levels were decreased, indicating an increase of autophagy flux in the PN group. In the Caco‐2 cell model, cells treated with PN solution plus propyl acetate exhibited increased Claudin‐1 and occluding along with decreased interleukin‐6 and tumor necrosis factor α compared with those treated with PN solution alone. Propyl acetate addition inhibited the AMPK–mammalian target of rapamycin (mTOR) pathway, mitigating the excessive autophagy induced by the PN intestinal rinse solution in Caco‐2 cells. Conclusion: PN led to a significant reduction in propyl acetate levels in the intestine, excessive activation of autophagy, and barrier dysfunction. Propyl acetate inhibited excessive autophagy via the AMPK/mTOR signaling pathway and protected the intestinal barrier during PN. [ABSTRACT FROM AUTHOR]

Oxidative stress is a pivotal factor in the pathogenesis of various cardiovascular diseases. Rhodiola, a traditional Chinese medicine, is recognized for its potent antioxidant properties. Salidroside, a phenylpropanoid glycoside derived from Rhodiola rosea, has shown remarkable antioxidant capabilities. This study aimed to elucidate the potential protective mechanisms of Rhodiola and salidroside against H2O2‐induced cardiac apoptosis in H9c2 cardiomyoblast cells. H9c2 cells were exposed to H2O2 for 4 h, and subsequently treated with Rhodiola or salidroside for 24 h. Cell viability and apoptotic pathways were assessed. The involvement of insulin‐like growth factor 1 receptor (IGF1R) and the activation of extracellular regulated protein kinases 1/2 (ERK1/2) were investigated. H2O2 (100 μM) exposure significantly induced cardiac apoptosis in H9c2 cells. However, treatment with Rhodiola (12.5, 25, and 50 μg/mL) and salidroside (0.1, 1, and 10 nM) effectively attenuated H2O2‐induced cytotoxicity and apoptosis. This protective effect was associated with IGF1R‐activated phosphorylation of ERK1/2, leading to the inhibition of Fas‐dependent proteins, HIF‐1α, Bax, and Bak expression in H9c2 cells. The images from hematoxylin and eosin staining and immunofluorescence assays also revealed the protective effects of Rhodiola and salidroside in H9c2 cells against oxidative damage. Our findings suggest that Rhodiola and salidroside possess antioxidative properties that mitigate H2O2‐induced apoptosis in H9c2 cells. The protective mechanisms involve the activation of IGF1R and subsequent phosphorylation of ERK1/2. These results propose Rhodiola and salidroside as potential therapeutic agents for cardiomyocyte cytotoxicity and apoptosis induced by oxidative stress in heart diseases. Future studies may explore their clinical applications in cardiac health. [ABSTRACT FROM AUTHOR]

Background: Severe COVID-19 is associated with neutrophilic inflammation and immunothrombosis. Several members of the IL-17 cytokine family have been associated with neutrophilic inflammation and activation of the endothelium. Therefore, we investigated whether these cytokines were associated with COVID-19. Methods: We investigated the association between COVID-19 and circulating plasma levels of IL-17 cytokine family members in participants to the Biobanque québécoise de la COVID-19 (BQC19), a prospective observational cohort and an independent cohort from Western University (London, Ontario). We measured the in vitro impact of IL-17F on intercellular adhesion molecule 1 (ICAM-1) cell surface expression and neutrophil adhesion on endothelial cells in culture. The contribution of two Mitogen Activated Protein Kinase (MAPK) pathways was determined using small molecule inhibitors PD184352 (a MKK1/MKK2 inhibitor) and BIRB0796 (a p38 MAPK inhibitor). Results: We found increased IL-17D and IL-17F plasma levels when comparing SARS-CoV-2-positive vs negative hospitalized participants. Moreover, increased plasma levels of IL-17D, IL-17E and IL-17F were noted when comparing severe versus mild COVID-19. IL-17F, but not IL-17A, was significantly elevated in people with COVID-19 compared to healthy controls and with more severe disease. In vitro work on endothelial cells treated with IL-17F for 24h showed an increase cell surface expression of ICAM-1 accompanied by neutrophil adhesion. The introduction of two MAPK inhibitors significantly reduced the binding of neutrophils while also reducing ICAM-1 expression at the surface level of endothelial cells, but not its intracellular expression. Discussion: Overall, these results have identified an association between two cytokines of the IL-17 family (IL-17D and IL-17F) with COVID-19 and disease severity. Considering that IL-17F stimulation promotes neutrophil adhesion to the endothelium in a MAPK-dependent manner, it is attractive to speculate that this pathway may contribute to pathogenic immunothrombosis in concert with other molecular effectors. [ABSTRACT FROM AUTHOR]

The edible flower of Hemerocallis citrina Baroni, commonly known as “Huang Huacai” in China, has anti‐depressant effects. However, targets and molecular mechanisms of Hemerocallis citrina Baroni edible flowers (HEF) in depression treatment are still unclear. The potential anti‐depression targets in HEF were identified by the intersecting results from typical drug databases. The network construction and Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) enrichment analysis were carried out for core targets. The molecular docking was conducted to predict the binding affinity between the active components and the central targets. The intersecting results indicated that there were 24 active components in HEF, with 449 anti‐depression targets identified. After screening through degree centrality (DC), betweenness centrality (BC), and closeness centrality (CC), 166 core targets were determined. Tumor protein 53 (TP53) and interleukin 6 (IL‐6) had the highest degree values. The results of GO enrichment analysis associated with anti‐depression revealed that the biological processes were negative regulation of osteoclast differentiation and positive regulation of phosphorus metabolic process. KEGG enrichment analysis results revealed that pathways, such as the phosphatidylinositol 3‑kinase‐protein kinase B (PI3K‐Akt) signaling pathway and mitogen‐activated protein kinase (MAPK) signaling pathway, were primarily associated with anti‐depression. Molecular docking results indicated that the top 10 active ingredients in HEF could bind to the central targets. This study applied network pharmacology to unveil the potential anti‐depressive mechanisms of HEF, providing a theoretical basis for further exploration of the effective components in H. citrina edible flower parts. [ABSTRACT FROM AUTHOR]

Background: Neuroinflammation is widely recognized as a key factor in the pathogenesis of Alzheimer’s disease (AD), alongside ß-amyloid deposition and the formation of neurofibrillary tangles. The NLR family pyrin domain containing 3 (NLRP3) inflammasome, part of the innate immune system, has been implicated in the neuropathology of both preclinical amyloid and tau transgenic models. Activation of the NLRP3 pathway involves an initial priming step, which increases the expression of Nlrp3 and interleukin (IL)-1β, followed by the assembly of the NLRP3 inflammasome complex, comprising NLRP3, ASC, and caspase-1. This assembly leads to the proteolytic maturation of the pro-inflammatory cytokines IL-1β and IL-18. Additionally, the NLRP3 inflammasome induces Gasdermin D (GSDMD) cleavage, forming membrane pores through which IL-1β and IL-18 are secreted. Inhibition of NLRP3 has been shown to enhance plaque clearance by modulating microglial activation. Furthermore, blocking NLRP3 in tau transgenic mice has been found to reduce tau phosphorylation by affecting the activity of certain tau kinases and phosphatases. Methods: In this study, organotypic brain slice cultures from P301S transgenic mice were treated with lipopolysaccharide (LPS) plus nigericin as a positive control or exposed to tau seeds (K18) to evaluate NLRP3 inflammasome activation. The effect of tau seeding on NLRP3 activity was further examined using Meso Scale Discovery (MSD) assays to measure IL1β secretion levels in the presence and absence of NLRP3 inhibitors. The role of NLRP3 activity was investigated in fullbody Nlrp3 knockout mice crossbred with the tau transgenic P301S model. Additionally, full-body and microglia-selective Gsdmd knockout mice were crossbred with P301S mice, and tau pathology and neurodegeneration were evaluated at early and late stages of the disease using immunohistochemistry and biochemical assays. Results: Activation of the NLRP3 pathway was observed in the mouse organotypic slice culture (OSC) model following stimulation with LPS and nigericin or exposure to tau seeds. However, Nlrp3 deficiency did not mitigate tauopathy or neurodegeneration in P301S mice in vivo, showing only a minor effect on plasma neurofilament (NF-L) levels. Consistently, Gsdmd deficiency did not alter tau pathology in P301S mice. Furthermore, neither full-body nor microglia-selective Gsdmd deletion had an impact on neuronal pathology or the release of pro-inflammatory cytokines. Conclusion: The absence of key components of the NLRP3 inflammasome pathway did not yield a beneficial effect on tau pathology or neurodegeneration in the preclinical Tau-P301S mouse model of AD. Nonetheless, organotypic slice cultures could serve as a valuable ex vivo mechanistic model for evaluating NLRP3 pathway activation and pharmacological inhibitors. [ABSTRACT FROM AUTHOR]

The Aurora Kinases (AURKs) are a family of serine-threonine protein kinases critical for cell division. Somatic cells express only AURKA and AURKB. However, mammalian germ cells and some cancer cells express all three isoforms. A major question in the field has been determining the molecular and cellular changes when cells express three instead of two aurora kinases. Using a systematic genetic approach involving different Aurora kinase oocyte-specific knockout combinations, we completed an oocyte-AURK genetic interaction map and show that one genomic copy of Aurka is necessary and sufficient to support female fertility and oocyte meiosis. We further confirm that AURKB and AURKC alone cannot compensate for AURKA. These results highlight the importance of AURKA in mouse oocytes, demonstrating that it is required for spindle formation and proper chromosome segregation. Surprisingly, a percentage of oocytes that lack AURKB can complete meiosis I, but the quality of those eggs is compromised, suggesting a role in AURKB to regulate spindle assembly checkpoint or control the cell cycle. Together with our previous studies, we wholly define the genetic interplay among the Aurora kinases and reinforce the importance of AURKA expression in oocyte meiosis. [ABSTRACT FROM AUTHOR]

Background: Linarine is a natural chemical component widely found in Buddleja officinalis Maxim., Chrysanthemum indicum L., Mentha canadensis L., and other medicinal plants. Modern pharmacological studies have shown that linarine with good anti-inflammatory and antioxidant activities can inhibit the proliferation and induce apoptosis of many kinds of tumor cells. Moreover, linarine showed protective effect on the liver, kidneys, and other organs. Methods: Inflammation model of human corneal epithelial cell (HCEC) was constructed using NaCl induction, and cytotoxicity was detected by the CCK8 assay. The levels of inflammatory factors tumor necrosis factor-α (TNF-α) and interleukin 1β (IL-1β) were measured using Enzyme-linked immunoassay (ELISA). Chronic painful stimulation (tail clamping) in combination with Benzalkonium Chloride Solution drops in a desiccator established a mouse model of dry eye disease (DED). The following parameters were recorded: body mass, anal temperature, tear secretion, tear film rupture time, and corneal fluorescein staining. The levels of inflammatory factors mitogen activated protein kinase (MAPK), nuclear factor kappa-B (NF-kB), c-Jun N-terminal kinase (JNK), IL-1β, Interleukin 18(IL-18), A2A, A3, P2X4, P2X7, P2Y1 were measured by using immunofluorescence (IF) staining. Results: Linarine can inhibit the secreation of TNF-α, and IL-1β in HCECs. Linarine prolonged tear film rupture time, promoted tear secretion, repaired corneal damage, and reduced the levels of inflammatory factors of MAPK, NF-kB, JNK, IL-1β, IL-18, and modulated the levels of the purinergic receptor. Conclusions: Linarine is effective in treating dry eye in mice by inhibiting purinergic receptors-mediated inflammatory response. [ABSTRACT FROM AUTHOR]

PIM1, the proviral integration site for Moloney murine leukemia virus, is a member of the serine/threonine protein kinase family. It is involved in many biological events, such as cell survival, cell cycle progression, cell proliferation, and cell migration, and has been widely studied in malignant diseases. However, recent studies have shown that PIM1 plays a prominent role in immunoinflammatory diseases, including autoimmune uveitis, inflammatory bowel disease, asthma, and rheumatoid arthritis. PIM1 can function in inflammatory signal transduction by phosphorylating multiple inflammatory protein substrates and mediating macrophage activation and T lymphocyte cell specification, thus participating in the development of multiple immunoinflammatory diseases. Moreover, the inhibition of PIM1 has been demonstrated to ameliorate certain immunoinflammatory disorders. Based on these studies, we suggest PIM1 as a potential therapeutic target for immunoinflammatory diseases and a valid candidate for future research. Herein, for the first time, we provide a detailed review that focuses on the roles of PIM1 in the pathogenesis of immunoinflammatory diseases. [ABSTRACT FROM AUTHOR]

Starch biosynthesis involves numerous enzymes and is a crucial metabolic activity in plant storage organs. Sucrose non-fermenting related protein kinase 2 (SnRK2) is an abscisic acid (ABA)-dependent kinase and a significant regulatory enzyme in the ABA signaling pathway. However, whether SnRK2 kinases regulate starch biosynthesis is unclear. In this study, we identified that MeSnRK2.3 , encoding an ABA-dependent kinase, was highly expressed in the storage roots of cassava (Manihot esculenta) and was induced by ABA. Overexpression of MeSnRK2.3 in cassava significantly increased the starch content in the storage roots and promoted plant growth. MeSnRK2.3 was further found to interact with the cassava basic helix–loop–helix 68 (MebHLH68) transcription factor in vivo and in vitro. MebHLH68 directly bound to the promoters of sucrose synthase 1 (MeSUS1), granule-bound starch synthase I a (MeGBSSIa), and starch-branching enzyme 2.4 (MeSBE2.4), thereby up-regulating their transcriptional activities. Additionally, MebHLH68 negatively regulated the transcriptional activity of sucrose phosphate synthase B (MeSPSB). Moreover, MebHLH68 phosphorylated by MeSnRK2.3 up-regulated the transcription activity of MeSBE2.4. These findings demonstrated that the MeSnRK2.3–MebHLH68 module connects the ABA signaling pathway and starch biosynthesis in cassava, thereby providing direct evidence of ABA-mediated participation in the sucrose metabolism and starch biosynthesis pathways. [ABSTRACT FROM AUTHOR]

Cuticular wax (CW) is the first defensive barrier of plants that forms a waterproof barrier, protects the plant from desiccation, and defends against insects, pathogens, and UV radiation. Sorghum, an important grass crop with high heat and drought tolerance, exhibits a much higher wax load than other grasses and the model plant Arabidopsis. In this study, we explored the regulation of sorghum CW biosynthesis using a bloomless mutant. The CW on leaf sheaths of the bloomless 41 (bm41) mutant showed significantly reduced very long-chain fatty acids (VLCFAs), triterpenoids, alcohols, and other wax components, with an overall 86% decrease in total wax content compared with the wild type. Notably, the 28-carbon and 30-carbon VLCFAs were decreased in the mutants. Using bulk segregant analysis, we identified the causal gene of the bloomless phenotype as a leucine-rich repeat transmembrane protein kinase. Transcriptome analysis of the wild-type and bm41 mutant leaf sheaths revealed BM41 as a positive regulator of lipid biosynthesis and steroid metabolism. BM41 may regulate CW biosynthesis by regulating the expression of the gene encoding 3-ketoacyl-CoA synthase 6. Identification of BM41 as a new regulator of CW biosynthesis provides fundamental knowledge for improving grass crops' heat and drought tolerance by increasing CW. [ABSTRACT FROM AUTHOR]

Background: Protein kinases are a diverse superfamily of proteins common to organisms across the tree of life that are typically involved in signal transduction, allowing organisms to sense and respond to biotic or abiotic environmental factors. They have important roles in organismal physiology, including development, reproduction, acclimation to environmental stress, while their dysregulation can lead to disease, including several forms of cancer. Identifying the complement of protein kinases (the kinome) of any organism is useful for understanding its physiological capabilities, limitations and adaptations to environmental stress. The increasing availability of genomes makes it now possible to examine and compare the kinomes across a broad diversity of organisms. Here we present a pipeline respecting the FAIR principles (findable, accessible, interoperable and reusable) that facilitates the search and identification of protein kinases from a predicted proteome, and classifies them according to group of serine/threonine/tyrosine protein kinases present in eukaryotes. Results: KiNext is a Nextflow pipeline that regroups a number of existing bioinformatic tools to search for and classify the protein kinases of an organism in a reproducible manner, starting from a set of amino acid sequences. Conventional eukaryotic protein kinases (ePKs) and atypical protein kinases (aPKs) are identified by using Hidden Markov Models (HMMs) generated from the catalytic domains of kinases. Furthermore, KiNext categorizes ePKs into the eight kinase groups by employing dedicated Hidden Markov Models (HMMs) tailored for each group. The performance of the KiNext pipeline was validated against previously identified kinomes obtained with other tools that were already published for two marine species, the Pacific oyster Crassostrea gigas and the unicellular green alga Ostreoccocus tauri. KiNext outperformed previous results by finding previously unidentified kinases and by attributing a large proportion of previously unclassified kinases to a group in both species. These results demonstrate improvements in kinase identification and classification, all while providing traceability and reproducibility of results in a FAIR pipeline. The default HMM models provided with KiNext are most suitable for eukaryotes, but the pipeline can be easily modified to include HMM models for other taxa of interest. Conclusion: The KiNext pipeline enables efficient and reproducible identification of kinomes based on predicted amino acid sequences (i.e. proteomes). KiNext was designed to be easy to use, automated, portable and scalable. [ABSTRACT FROM AUTHOR]

Protein tyrosine kinase 7 (PTK7) is an evolutionarily conserved transmembrane receptor and a specialized tyrosine kinase protein lacking kinase activity. PTK7 has been found to be strongly associated with a variety of diseases, including cancer. In this review, we will provide a comprehensive overview of the involvement of PTK7 in human cancer, focusing on the changing research landscape of PTK7 in cancer research, the molecular mechanisms of PTK7 involved in cancer progression, the targetability of PTK7 in cancer therapy, and the potential application of PTK7 in cancer management, thus demonstrating that PTK7 may be an underestimated contributor to human cancer. [ABSTRACT FROM AUTHOR]

Sepsis is a global health challenge marked by limited clinical options and high mortality rates. AMP-activated protein kinase (AMPK) is a cellular energy sensor that mediates multiple crucial metabolic pathways that may be an attractive therapeutic target in sepsis. Pre-clinical experimental studies have demonstrated that pharmacological activation of AMPK can offer multiple potential benefits during sepsis, including anti-inflammatory effects, induction of autophagy, promotion of mitochondrial biogenesis, enhanced phagocytosis, antimicrobial properties, and regulation of tight junction assembly. This review aims to discuss the existing evidence supporting the therapeutic potential of AMPK activation in sepsis management. [ABSTRACT FROM AUTHOR]

Objective: Invasive lobular breast cancer (ILC) is the most common special type of breast cancer and has unique clinicopathological and molecular hallmarks that differentiate it from the more common invasive carcinoma—no special type (NST). Despite these differences, ILC and NST are treated as a single entity and there is a lack of ILC-targeted therapies. To fill this gap, we sought to identify novel molecular alterations in ILC that could be exploited for targeted therapies. Methods: Differential gene expression and Geneset Enrichment and Variation analyses were performed on RNA-seq data from three large public breast cancer databases—the Sweden Cancerome Analysis Network-Breast (SCAN-B; luminal A ILC N = 263, luminal A NST N = 1162), The Cancer Genome Atlas (TCGA; luminal A ILC N = 157, luminal A NST N = 307) and Molecular Taxonomy of Breast Cancer International Consortium (METABRIC; luminal A ILC N = 65, luminal A NST N = 533). Pathways enriched in overlapping differentially expressed genes from these datasets were clustered using Jaccard similarity to identify pathways enriched in ILC. The cAMP/PKA/CREB signaling was studied in ILC, ILC-like and NST cell lines and patient-derived organoids (PDOs) using forskolin, an activator of the pathway. Results: Clinicopathological features of patients with ILC and NST in SCAN-B were similar to prior population-based studies. There was a consistent pattern of up-regulation of cAMP/PKA/CREB related signaling in ILC compared to NST in SCAN-B, TCGA and METABRIC. Treatment with forskolin resulted in a greater increase in phospho-CREB in ILC cell lines and organoids than NST. CRISPR deletion of CDH1 in NST cell lines did not alter response of cells to forskolin as measured by phospho-CREB. Forskolin treatment caused growth inhibition in ILC and NST, with ILC cell lines being more sensitive to forskolin-mediated growth inhibition. Conclusion: In three separate datasets, cAMP/PKA/CREB signaling was identified to be higher in ILC than NST. This in silico finding was validated in cell line and organoid models. Loss of CDH1 was not sufficient to mediate this phenotype. Future studies should investigate the mechanisms for differential cAMP/PKA/CREB signaling and the potential for therapeutic targeting in patients with ILC. [ABSTRACT FROM AUTHOR]

Background: Regulated cell death (RCD) is a genetically controlled form of cell death that plays an important role in organogenesis, tissue remodeling, and pathogenesis of cancers. Transforming growth factor-beta-activation kinase 1 (TAK1) is a member of the serine/threonine protein kinase family, which can respond to internal and external stimuli and participate in inflammatory responses through multiple signaling pathways and cellular processes. In the last two decades, the regulatory roles of TAK1 at the crossroads of multiple RCD pathways, including apoptosis, necroptosis, pyroptosis, and PANoptosis were revealed by 801 articles retrieved from the Web of Science Core Collection database. To analyze global research trends and hotspots concerning the role of TAK1 in RCD, the bibliometric and visualized analysis were applied in the current study. Methods: The data for this bibliometrics study were retrieved from the Web of Science Core Collection database. The search formula was (TS=(Apoptosis) OR TS=(pyroptosis) OR TS=(Necroptosis) OR TS=(PANoptosis) OR TS=(Autophagy) OR TS=(Ferroptosis) OR TS=(cuproptosis)) AND ((TS=(TAK1)) OR TS=(MAP3K7)). The co-occurrence and co-cited analysis on basic bibliometric parameters were conducted by VOSviewer. The dual-map overlay of journals, citation bursts, keyword timelines, and keyword bursts were analyzed by CiteSpace. Results: A total of 801 articles from 46 countries have been included in the analysis. The number of publications demonstrates a consistent increase from 1999 to 2024. The primary research institutions driving this field are Osaka University Notably, the Journal of Biological Chemistry stands out as the most popular journal in this domain. These publications collectively involve contributions from 4663 authors, with Jun Tsuji emerging as a prolific author. Jun Tsuji also gains the highest co-citation frequency. Emerging research hotspots are encapsulated by keywords, including apoptosis, NF-kB, inflammation, autophagy, and TNFa. Conclusion: This is the first bibliometric and visualized study to analyze the global trends and hotspots of TAK1 in RCD. Based on the analysis of 801 articles, the results provide a retrospective and comprehensive visualized view of the research hotspots and frontiers of TAK1 at the crossroads of multiple RCD signaling pathways and propose ideas for guiding their future investigations in molecular mechanisms and therapeutic strategies in this field. [ABSTRACT FROM AUTHOR]

Background: The myelin sheath ensures efficient nerve impulse transmission along the axons. Remyelination is a spontaneous process that restores axonal insulation, promoting neuroprotection and recovery after myelin damage. There is an urgent need for new pharmacological approaches to remyelination and to improve the most effective molecules. Some glucocorticoids (GC) were identified through phenotypical screens for their promyelinating properties. These GC compounds share the ability to bind the Smoothened (Smo) receptor of the Hedgehog (Hh) pathway. Gaining a deeper insight into how they modulate Smo receptor activity could guide structure-based studies to leverage the GCs' potent promyelinating activity for a more targeted approach to remyelination. Methods: Here we focused on clarifying the mechanism of action of Budesonide, a GC known to bind the Smo cysteine-rich domain (CRD) and prevent Smo translocation to the cilium in fibroblasts. Our study employed a combination of cellular, biochemical and molecular dynamics approaches. Results: We show that treating oligodendroglial cells with Budesonide promotes myelination of synthetic axons and reduces Smo CRD conformational flexibility. This inhibits the Smo-mediated canonical signaling while activating the Liver Kinase B1 (LKB1)/AMP-activated protein kinase (AMPK) pathway, leading to Myelin basic protein (MBP) expression. Discussion: These insights pave the way for pharmacological targeting of Smo CRD to enhance oligodendrocyte precursor cells (OPCs) differentiation and improve remyelination. [ABSTRACT FROM AUTHOR]

Mitochondrial dysfunction is a salient feature of myocardial ischemia/reperfusion injury (MIRI), while the potential mechanism of mitochondrial dynamics disorder remains unclear. This study sought to explore whether activation of Adenosine monophosphate-activated protein kinase (AMPK) could alleviate MIRI by regulating GTPase dynamin-related protein 1 (Drp1)-mediated mitochondrial dynamics. Isolated mouse hearts in a Langendorff perfusion system were subjected to ischemia/reperfusion (I/R) treatment, and H9C2 cells were subjected to hypoxia/reoxygenation (H/R) treatment in vitro. The results showed that AICAR, the AMPK activator, could significantly improve the function of left ventricular, decrease arrhythmia incidence and myocardial infarction area of isolated hearts. Meanwhile, AICAR increased superoxide dismutase (SOD) activity and decreased malondialdehyde (MDA) content in myocardial homogenate. Mechanistically, AICAR inhibited the phosphorylation of Drp1 at Ser 616 while enhanced phosphorylation of Drp1 at Ser 637. In addition, AICAR reduced the expression of inflammatory cytokines including TNF-α, IL-6, and IL-1β, as well as mitochondrial fission genes Mff and Fis1, while improved the expression of mitochondrial fusion genes Mfn1 and Mfn2. Similar results were also observed in H9C2 cells. AICAR improved mitochondrial membrane potential (MMP), reduced reactive oxygen species (ROS) production, and inhibited mitochondrial damage. To further prove if Drp1 regulated mitochondrial dynamics mediated AMPK protection effect, the mitochondrial fission inhibitor Mdivi-1 was utilized. We found that Mdivi-1 significantly improved MMP, inhibited ROS production, reduced the expression of TNF-α, IL-6, IL-1β, Fis1, and Mff, and improved the expression of Mfn1 and Mfn2. However, the protection effect of Mdivi-1 was not reversed by AMPK inhibitor Compound C. In conclusion, this study confirmed that activation of AMPK exerted the protective effects on MIRI, which were largely dependent on the inhibition of Drp1-mediated mitochondrial fission. [ABSTRACT FROM AUTHOR]

Background: Hepatocellular carcinoma (HCC) is a global health concern. Due to late diagnosis and limited therapeutic strategies, HCC based mortality rate is exponentially increasing globally. Genetic predisposition is a non-avoidable intrinsic factor that could alter the genome sequence, ultimately leading to HCC. Protein kinase C eta (PKCη) is involved in key physiological roles, hence alteration in PKCη could aid in cancer progression. Research indicates association between non-synonymous (ns) SNPs and HCC onset. However, effect of nsSNP variants of PKCη on HCC development has not been explored yet. Hence, this study aimed to investigate the association between pathogenic nsSNPs of PKCη with HCC. Methods: Non-synonymous (missense) variants of PKCη were obtained from Ensembl genome browser. These variants were filtered out to obtain pathogenic nsSNPs of PKCη. Genotyping of nsSNPs was done through Tetra ARMS PCR. For that, blood samples of 348 HCC patients and 337 controls were collected. The clinical factors that influence HCC were studied. Relative risk (RR) and Odds Ratio (OR) with 95% confidence interval was calculated by Chi-square test and P-value < 0.05 was deemed significant. Results: Five nsSNP variants of PKCη including rs1162102190 (T/C), rs868127012 (G/T), rs750830348 (G/T), rs768619375 (T/C), and rs752329416 (T/C) were identified. The retrieved nsSNPs were frequently identified in HCC patients. However, rs752329416 T/C was significantly prevalent in patients having HCC family history. Moreover, all the variants were found in HCC patients manifesting the stage II than the advance stages of HCC. Conclusion: This study can be utilized to identify potential genetic markers for early screening of HCC. Moreover, consideration of further clinical factors, and mechanistic approach would enhance the understanding that how alteration in nsSNPs could impact the HCC onset. [ABSTRACT FROM AUTHOR]

The neurotoxicant trimethyltin (TMT) triggers cognitive impairment and hippocampal neurodegeneration. TMT is a useful research tool for the study of Alzheimer's disease (AD) pathogenesis and treatment. Although the antidiabetic agent metformin has shown promising neuroprotective effects, however, its precise modes of action in neurodegenerative disorders need to be further elucidated. In this study, we investigated whether metformin can mitigate TMT cognition impairment and hippocampal neurodegeneration. To induce an AD-like phenotype, TMT was injected i.p. (8 mg/kg) and metformin was administered daily p.o. for 3 weeks at 200 mg/kg. Our results showed that metformin administration to the TMT group mitigated learning and memory impairment in Barnes maze, novel object recognition (NOR) task, and Y maze, attenuated hippocampal oxidative, inflammatory, and cell death/pyroptotic factors, and also reversed neurodegeneration-related proteins such as presenilin 1 and p-Tau. Hippocampal level of AMP-activated protein kinase (AMPK) as a key regulator of energy homeostasis was also improved following metformin treatment. Additionally, metformin reduced hippocampal acetylcholinesterase (AChE) activity, glial fibrillary acidic protein (GFAP)-positive reactivity, and prevented the loss of CA1 pyramidal neurons. This study showed that metformin mitigated TMT-induced neurodegeneration and this may pave the way to develop new therapeutics to combat against cognitive deficits under neurotoxic conditions. [ABSTRACT FROM AUTHOR]

Summary The calcium‐dependent protein kinase CPK28 regulates several stress pathways in multiple plant species. Here, we aimed to discover CPK28‐associated proteins in Arabidopsis thaliana. We used affinity‐based proteomics and identified several potential CPK28 binding partners, including the C7 Raf‐like kinases MRK1, RAF26, and RAF39. We used biochemistry, genetics, and physiological assays to gain insight into their function. We define redundant roles for these kinases in stomatal opening, immune‐triggered reactive oxygen species (ROS) production, and resistance to a bacterial pathogen. We report that CPK28 associates with and trans‐phosphorylates RAF26 and RAF39, and that MRK1, RAF26, and RAF39 are active kinases that localize to endomembranes. Although Raf‐like kinases share some features with mitogen‐activated protein kinase kinase kinases (MKKKs), we found that MRK1, RAF26, and RAF39 are unable to trans‐phosphorylate any of the 10 Arabidopsis mitogen‐activated protein kinase kinases (MKKs). Overall, our study suggests that C7 Raf‐like kinases associate with and are phosphorylated by CPK28, function redundantly in stomatal opening and immunity, and possess substrate specificities distinct from canonical MKKKs. [ABSTRACT FROM AUTHOR]

Licorice is a therapeutic herb in traditional Chinese herbal medicine. Licorice is considered as an anti‐inflammatory agent due to its suppression and inhibition of inflammatory pathways. Licorice has many bioactive compounds such as glycyrrhetinic acid, glycyrrhizin, liquiritigenin, and isoliquirtigenin which are principally accountable for its therapeutic benefits. These bioactive components reduce inflammation by preventing the activation of important inflammatory pathways including mitogen‐activated protein kinases (MAPKs) and nuclear factor‐kappa B (NF‐κB). As a result of this tumor necrosis factor‐alpha (TNF‐α), interleukin‐1 beta (IL‐1β) and interleukin‐6 (IL‐6) are among the proinflammatory cytokines whose production is inhibited. Components present in licorice inhibit the activation by suppressing the IκBα phosphorylation and degradation. Moreover, licorice compounds also attenuate the MAPK signaling cascades by inhibiting the MAPK kinase phosphorylation and downstream MAPKs such as extracellular signal–regulated kinase (ERK), p38 MAPK, and c‐Jun N‐terminal kinase (JNK). The present review focuses on the current understanding of licorice effect on the NF‐κB and MAPK inflammatory cell signaling pathways at molecular level. Furthermore, emerging evidence suggested that licorice‐derived bioactive compounds may attenuate the molecular mechanism which is associated with inflammation, providing the additional insights into the therapeutic potential. Further studies explained the precise molecular mechanism at the cellular level underlying the licorice anti‐inflammatory effect and potential application in managing inflammatory disorders. In conclusion, licorice has a complex mode of action and is a valuable natural anti‐inflammatory. Its natural origin and effectiveness in clinical applications make it an intriguing topic for additional study. As licorice becomes more widely used in medicine, future research should focus on refining its formulations to optimize therapeutic advantages. [ABSTRACT FROM AUTHOR]

Clade A type 2C protein phosphatases (PP2Cs) are crucial components of the abscisic acid (ABA) signaling pathway. Research on clade A PP2Cs has focused more on their roles related to ABA signaling and stress responses than on the molecular mechanisms mediating their effects on plant growth and grain yield. Rice (Oryza sativa L.) is an important food crop worldwide. We previously determined that OsPP2C49, which encodes a rice clade A PP2C family member, negatively controls rice responses to drought, salt, and high-temperature stresses. In this study, we investigated the regulatory effects of OsPP2C49 on ABA responses and rice grain yield. By analyzing potential interactions with core ABA components, including pyrabactin resistance 1 (PYR1)/PYR1-like (PYL)/regulatory component of the ABA receptor (RCAR) and stress-activated protein kinases (SAPKs), we confirmed that OsPP2C49 is involved in the ABA signaling pathway. OsPP2C49 overexpression led to decreased ABA sensitivity and increased rice grain yield; the opposite phenotypes were observed in the ospp2c49 knockout mutants. Therefore, OsPP2C49 negatively regulates ABA responses, but positively modulates rice grain yield. Furthermore, we found that OsPP2C49 can interact with and dephosphorylate five OsSAPKs in vitro. Unlike OsPP2C49, these OsSAPKs positively modulate ABA responsiveness, but negatively affect rice yield. These findings indicate that OsPP2C49 may partially regulate ABA responses and rice grain production by dephosphorylating OsSAPKs. This study preliminarily explored the molecular basis of the regulatory effects of OsPP2C49 on rice plant growth and grain yield. [ABSTRACT FROM AUTHOR]

Carney Complex (CNC) is a rare syndrome characterized by spotty skin pigmentation and multiple neoplasms, notably cardiac myxomas, schwannomas, and endocrine tumours. It is often inherited in an autosomal dominant manner with PRKAR1A gene mutations found in the majority of cases. Male infertility is established as part of the CNC phenotype and is largely associated with Large cell calcifying Sertoli cell tumours (LCCSCT). We describe a case of a 30-year-old male patient with Carney Complex, presenting with severe oligoasthenozoospermia and primary pigmented nodular adrenocortical disease (PPNAD). During follow-up consults, the severe oligozoospermia and impaired semen motility persisted and the patient was also diagnosed with a recurring cardiac myxoma and LCCSCT. Molecular testing identified a novel PRKAR1A mutation involving a deletion of exons 4 to 7. Our findings suggest this mutation causes PRKAR1A haploinsufficiency, which may be directly linked to male infertility, irrespective of the presence of testicular tumours. Accordingly, in male patients with CNC, detection of a PRKAR1A gene mutation may serve as a predictive marker for infertility. This case report illustrates the importance of early consideration and management of infertility in male patients diagnosed with CNC. Plain Language Summary: Male infertility associated with a novel PRKAR1A mutation in carney complex Carney Complex (CNC) is a rare genetic disorder that leads to the development of various tumours, including in the heart and endocrine glands. Most cases are linked to mutations in a gene called PRKAR1A and are inherited in an autosomal dominant manner. This case report presents a detailed examination of a patient diagnosed with Carney Complex (CNC), followed over nearly 10 years. The patient initially consulted due to infertility, which led to extensive investigations and diagnosis of several type of tumours: Primary pigmented nodular adrenocortical disease (PPNAD) in the adrenal glands, a cardiac myxoma, and Large cell calcifying Sertoli cell tumours (LCCSCT) in the testes - all tumours are characteristic features of CNC. Notably, genetic testing revealed a novel mutation in the PRKAR1A gene. Through this case, we highlight how this genetic mutation might cause PRKAR1A haploinsufficiency and be solely responsible for infertility in CNC irrespective of testicular tumours, providing valuable insights into a condition where male infertility is rarely documented. This report contributes important new information to the limited existing research on the connection between CNC and male infertility. [ABSTRACT FROM AUTHOR]

AbstractCasein kinase 2 (CK2) is an ubiquitous, essential, and highly pleiotropic protein kinase whose abnormally high constitutive activity is suspected to underlie its pathogenic potential in neoplasia and other diseases. Recently, there has been a notable increase in interest in the use of casein kinase 2 (CK2) inhibitors to improve the treatment of a specific form of cancer while minimizing the risk of undesirable side effects. Recently, using different virtual screening approaches, we have identified several novel CK2 inhibitors. In particular, we have discovered that the coumarin moiety can be considered an attractive CK2 inhibitor scaffold. In the present work, quantitative structure-activity relationship (QSAR) analysis has been employed to envisage the inhibitory effects of 32 coumarin derivatives on the CK2 protein. The most efficient model is found by using multiple linear regression (MLR). Its capability is considered by the external and internal validation values found (R2 = 0.884, Q2cv = 0.822, R2pred = 0.821, and R2p = 0.811), which aligned well with Tropsha and Golbraikh’s approach. The highest docking score founded for the newly designed coumarins is −7.50 kcal mol-1, which indicates that candidates can bind to the CK2 receptor with greater affinity. Based on the results of the ADMET properties and drug similarity analyses, a DFT investigation was conducted to confirm the stability of the newly explored compounds. It appears that the most stable complexes are those of compound with the highest binding affinity with a lower risk of toxicité. [ABSTRACT FROM AUTHOR]

Emerged evidence indicated that stimulating hippocampal neurogenesis is a potential strategy for restoring cognition in AD. Mitogen‐activated protein kinases (MAPKs) play an essential role in neurogenesis. Meanwhile, the enzymatic power of the phosphatases is much greater than that of kinases. Dual‐specificity phosphatase 16 (DUSP16), known to as a phosphatase negatively regulate MAPKs, may be implicated in neural differentiation. Nevertheless, the effect of DUSP16 on cognitive disorders by stimulating neural progenitor cell (NPC) differentiation in AD mice remains unclear. Our study demonstrates an association between DUSP16 SNPs and clinical progression in individuals with mild cognitive impairment (MCI). Besides, increased DUSP16 expression was detected in both 3xTg and SAMP8 mouse models of AD, accompanied by NPC neural differentiation impairments. By silencing DUSP16, the induction of neural differentiation, synaptic transmission, and cognitive benefits were observed in both AD mice. Furthermore, DUSP16 was involved in the process of NPC differentiation through regulating c‐Jun N‐terminal kinase (JNK) phosphorylation and SOX2 expression. Moreover, ETS transcription factor (ELK1) was involved in the DUSP16 transcription, which resulted in the upregulation of DUSP16 at the state of AD. Our data uncovers a potential regulatory role for DUSP16 in adult hippocampal neurogenesis (AHN) and provides a possibility to find a novel strategy for AD intervention. [ABSTRACT FROM AUTHOR]

Background and Purpose Experimental Approach Key Results Conclusions and Implications Cannabis stimulates several G‐protein‐coupled‐receptors and causes bradycardia and hypotension upon sustained consumption. Moreover, in vitro studies suggest an interference of cannabinoid‐signalling with cardiomyocyte contractility and hypertrophy. We aimed at revealing a functional contribution of the cannabinoid‐sensitive receptor GPR55 to cardiomyocyte homeostasis and neurohumorally induced hypertrophy in vivo.Gpr55−/− and wild‐type (WT) mice were characterized after 28‐day angiotensin II (AngII; 1·μg·kg−1 min−1) or vehicle infusion. In isolated adult Gpr55−/− and WT cardiomyocytes, mitochondrial function was assessed under naïve conditions, while cytosolic Ca2+ handling was additionally determined following application of the selective GPR55 antagonist CID16020046.Gpr55 deficiency did not affect angiotensin II (AngII) mediated hypertrophic growth, yet, especially in females, it alleviated maladaptive pro‐hypertrophic and ‐inflammatory gene expression and improved inotropy and adrenergic responsiveness compared to WT. In‐depth analyses implied increased cytosolic Ca2+ concentrations and transient amplitudes, and accelerated sarcomere contraction kinetics in Gpr55−/− myocytes, which could be mimicked by GPR55 blockade with CID16020046 in female WT cells. Moreover, Gpr55 deficiency up‐regulated factors involved in glucose and fatty acid transport independent of the AngII challenge, accelerated basal mitochondrial respiration and reduced basal protein kinase (PK) A, G and C activity and phospholemman (PLM) phosphorylation.Our study suggests GPR55 as crucial regulator of cardiomyocyte hypertrophy and homeostasis presumably by regulating PKC/PKA‐PLM and PKG signalling, and identifies the receptor as potential target to counteract maladaptation, adrenergic desensitization and metabolic shifts as unfavourable features of the hypertrophied heart in females. [ABSTRACT FROM AUTHOR]

The serine/threonine-specific protein kinases (STKs) are important for cell survival, proliferation, differentiation, and apoptosis. In B cells, these kinases play indispensable roles in regulating important cellular functions. Multiple studies on human and other animal cells have shown that multiple STKs are involved in different stages of B cell development and antibody production. However, how STKs affect B cell development and function is still not completely understood. Considering that B cells are clinically important in immunity and diseases, our understanding of STKs' roles in B cells is in great need of investigation with current technologies. Investigating serine/threonine kinases will not only deepen our insight into B cell-related disorders but also facilitate the identification of more effective drug targets for conditions like lymphoma and systemic lupus erythematosus. [ABSTRACT FROM AUTHOR]