As society evolves and lifestyles change, there has been a notable rise in the incidence of cardiovascular diseases due to a parallel rise in associated risk factors. In recent years, considerable research has been conducted on the impact of histone modifications in relation to these conditions. Processes such as acetylation, methylation and phosphorylation of histones, mediated by specific enzymes, are essential in the regulation of gene expression, which in turn influences cellular functions and the progression of diseases. Research shows that alterations in specific histone modifications are closely linked to the onset and advancement of cardiovascular conditions. For instance, significant variations in histone deacetylases and H3K27 methylation have been observed in cases of heart failure and myocardial ischemia-reperfusion injury. In the present review, it was aimed to summarize recent findings in this area, providing a foundation for further exploration of the mechanisms by which histone modifications contribute to cardiovascular diseases.

Osimertinib is a third-generation Epidermal Growth Factor Receptor (EGFR) tyrosine kinase inhibitor (TKI) widely used to treat advanced non-small cell lung cancer with EGFR mutations. However, resistance to osimertinib frequently develops, limiting its long-term effectiveness.

This study aimed to establish a lung cancer TKI-resistant model and identify Traditional Chinese Medicine (TCM) components that could reverse TKI resistance, enhancing lung cancer sensitivity to targeted therapies, while exploring the underlying molecular mechanisms.

Osimertinib-resistant cell lines and organoids were developed using a dose-escalation approach. A screen of 302 traditional Chinese medicine monomers revealed compounds that increased sensitivity to osimertinib. RNA sequencing and limited proteolysis coupled with small molecule mapping were employed to investigate the molecular mechanisms by which jaceosidin reverses resistance. The efficacy of the jaceosidin and osimertinib combination was confirmed in cell lines, organoids, and a mouse model.

The osimertinib-resistant lung cancer model was successfully established, and 12 compounds were identified that enhanced the sensitivity of resistant cells to osimertinib. Among these, Jaceosidin, a flavonoid compound derived from Eupatorium lindleyanum DC., was confirmed to notably increase osimertinib sensitivity. Mechanistic studies, including limited proteolysis and RNA interference analysis, demonstrated that Jaceosidin directly interacts with Damage Specific DNA Binding Protein 1 (DDB1), promoting its protein expression and downregulating CDK1/Cyclin B1 levels. This interaction induced G2/M cell cycle arrest, thereby sensitizing lung cancer cells to osimertinib. Furthermore, both in vitro and in vivo experiments confirmed that the combination of Jaceosidin and osimertinib significantly inhibited tumor growth in osimertinib-resistant models.

These findings offer new insights into the role of DDB1 in overcoming osimertinib resistance and suggest that combining jaceosidin with osimertinib may serve as a promising therapeutic strategy to enhance the efficacy of EGFR-TKIs treatment in resistant Non-small Cell Lung Cancer (NSCLC).

Inducing the neogenesis of pancreatic insulin-producing β cells holds great promise for diabetes research. However, non-toxic compounds with such activities remain to be discovered. Herein, we report the identification of RSPO1, a key agonist of the Wnt/β-catenin pathway, as an inducer of β cell replication. Specifically, we provide evidence that RSPO1 promotes a significant increase in β cell neogenesis in vitro, ex vivo, and in vivo. Importantly, RSPO1 administration is sufficient to activate Wnt/β-catenin signaling in β cells and counter chemically induced or autoimmune-mediated diabetes. Similarly, an optimized analog of RSPO1, allowing for weekly administration, also prevents diabetes in vivo. Lastly, the treatment of transplanted human islets with RSPO1 induces a significant 2.78-fold increase in human β cell numbers in only 60 days, these cells being functional. Such activities of RSPO1 to promote β cell neogenesis could therefore represent an unprecedented hope in the continued search for diabetes alternative therapies.

Diabetes, a chronic metabolic disease, has many complex complications and an increasing prevalence in various societies. Despite conventional drug treatments and limited surgical and tissue transplant methods, a definitive diabetes treatment remains to be found. Restoring damaged beta cells to insulin production or prompting other pancreatic cells to secrete insulin is an essential goal of diabetes research. The present study investigated the antidiabetic and regenerative effects of Peganum harmala seed extract (PHSE) on streptozotocin (STZ)-induced diabetes in rats.

In this experimental in vivo study, male Wistar rats (200±10 g) were placed in 5 groups: control, untreated diabetic and diabetic groups treated with 100, 200, and 400 mg/kg doses of PHSE. Fasting blood sugar (FBS), C-peptide, insulin, and antioxidant parameters (total antioxidant capacity (TAC) and nitric oxide (NO)) of serum were measured. Pancreatic tissue was used for histologic staining and assessment of the expression of genes related to beta cell regeneration.

PHSE significantly improved FBS, weight loss, insulin, c-peptide, TAC, NO, and expression of pancreatic genes (insulin, PDX1 and neurogenin-3) (p<0.05). It also increased the number of pancreatic beta cells.

PHSE has considerable regenerative and antidiabetic effects on changes caused by diabetes in rats' serum and pancreas.

Dual-specificity tyrosine phosphorylation-regulated kinase 1B (DYRK1B), a member of the CMGC group of kinases, is linked to metabolic syndrome, though the underlying molecular mechanisms remain unclear. In this study, we show that Dyrk1b expression is induced in the liver by fasting and in diabetic mice. Through both in vivo and in vitro experiments, we demonstrate that DYRK1B promotes hepatic gluconeogenesis and glucose intolerance. Liver-specific Dyrk1b conditional knockout mice were protected from diet-induced hyperglycemia. Mechanistically, DYRK1B interacts with and phosphorylates FOXO1, primarily at Thr467/Ser468, which is essential for its nuclear localization. Additionally, DYRK1B inhibits AKT-mediated FOXO1 phosphorylation at Thr24 and Ser256, enhancing its nuclear retention. DYRK1B-mediated phosphorylation increases the expression of gluconeogenic genes and promotes gluconeogenesis. Further, AZ191, a pharmacological inhibitor of DYRK1B, significantly reduced blood glucose levels in diabetic mice. Collectively, these findings provide new insights into the role of DYRK1B in glucose metabolism and identify it as a new therapeutic target for treating diabetes.

Glycine and β-alanine activate glycine receptors (GlyRs), with glycine known to enhance insulin secretion from pancreatic islet β cells, primarily through GlyR activation. However, the effects of GlyR activation on β cell proliferation have not been examined. Here, we aim to investigate the potential proliferative effects of glycine and β-alanine on islets. In vitro experiments on mouse and human islets revealed that glycine and β-alanine, via GlyR activation, stimulated the proliferation of β cells and α cells, without affecting insulin or glucagon secretion. Further analysis indicated the involvement of the PI3K/mTORC1/p70S6K signaling pathway in this process. Inhibition of GlyRs and PI3K/mTORC1/p70S6K signaling attenuated proliferative effects of glycine and β-alanine. In vivo and ex vivo studies supported these findings, showing increased β and α cell mass after 12 weeks of oral administration of glycine and β-alanine, with no changes in insulin secretion or glucose homeostasis under normal conditions. However, during an acute insulin resistance induced by insulin receptor antagonist S961, glycine and β-alanine enhanced insulin secretion and reduced blood glucose levels by increasing β cell secretory capacity. These findings demonstrate glycine and β-alanine in vivo and in vitro promote islet cell proliferation via GlyR activation and the PI3K/mTORC1/p70S6K pathway, potentially providing a target to enhance islet capacity.

Serotonin is one of the most potent gastrointestinal, peripheral, and neuronal signaling molecules and plays a key role in regulating energy metabolism. Accumulating evidence has shown the complex interplay between gut microbiota and host energy metabolism. In this review, we summarize recent findings on the role of gut microbiota in serotonin metabolism and discuss the complicated mechanisms by which serotonin, working in conjunction with the gut microbiota, affects total body energy metabolism in the host. Gut microbiota affects serotonin synthesis, storage, release, transport, and catabolism. In addition, serotonin plays an indispensable role in regulating host energy homeostasis through organ crosstalk and microbe-host communication, particularly with a wide array of serotonergic effects mediated by diverse serotonin receptors with unique tissue specificity. This fresh perspective will help broaden the understanding of serotonergic signaling in modulating energy metabolism, thus shedding light on the design of innovative serotonin-targeting strategies to treat metabolic diseases.

The Carbohydrate Response Element Binding Protein (ChREBP) is a glucose-responsive transcription factor (TF) with two major splice isoforms (α and β). In chronic hyperglycemia and glucolipotoxicity, ChREBPα-mediated ChREBPβ expression surges, leading to insulin-secreting β-cell dedifferentiation and death. 14-3-3 binding to ChREBPα results in cytoplasmic retention and suppression of transcriptional activity. Thus, small molecule-mediated stabilization of this protein-protein interaction (PPI) may be of therapeutic value. Here, we show that structure-based optimizations of a 'molecular glue' compound led to potent ChREBPα/14-3-3 PPI stabilizers with cellular activity. In primary human β-cells, the most active compound retained ChREBPα in the cytoplasm, and efficiently protected β-cells from glucolipotoxicity while maintaining β-cell identity. This study may thus not only provide the basis for the development of a unique class of compounds for the treatment of Type 2 Diabetes but also showcases an alternative 'molecular glue' approach for achieving small molecule control of notoriously difficult to target TFs.

Natural products and their derivatives play a crucial role in treating various diseases. Harmine, a tricyclic β-carboline alkaloid isolated from the seeds of Peganum harmala L., has emerged as a promising therapeutic candidate owing to its multifaceted biological activities. Recent studies have further highlighted the enhanced therapeutic potential of harmine derivatives. To assess the current research landscape on harmine and its derivatives, we conducted a comprehensive analysis of studies published between 2019 and 2024 in scientific databases, such as PubMed, Web of Science, and Google Scholar. In this review, the possible applications of harmine and its derivatives were systematically illustrated, including biological activities, structure-activity relationships, and nanotechnology applications. Notably, the biological activities of harmine and its derivatives mainly contained antitumor, neuroprotective, antiparasitic, anti-inflammatory, and antidiabetic properties. In addition, structural modifications and the application of nanocarriers make harmine and its derivatives more druggable. The aim of this review is to summarize the recent advancements in harmine and its derivatives research, analyze emerging trends, and explore their clinical value.

The development of resistance remains one of the biggest challenges in clinical cancer patient care and it comprises all treatment modalities from chemotherapy to targeted or immune therapy. In solid malignancies, drug resistance is the result of adaptive processes occurring in cancer cells or the surrounding tumor microenvironment (TME). Future therapy attempts will therefore benefit from targeting both, tumor and stroma compartments and drug targets which affect both sides will be highly appreciated. In this review, we describe a seemingly paradoxical oncogenic mediator with this potential: The dual-specificity tyrosine-phosphorylation regulated kinase 1B (DYRK1B). DYRK1B promotes proliferative quiescence and yet is overexpressed or amplified in many hyperproliferative malignancies including ovarian cancer and pancreatic cancer. In particular the latter disease is a paradigmatic example for a therapy-recalcitrant and highly stroma-rich cancer entity. Here, recent evidence suggests that DYRK1B exerts its oncogenic features by installing a protective niche for cancer cells by directly affecting cancer cells but also the TME. Specifically, DYRK1B not only fosters cell-intrinsic processes like cell survival, chemoresistance, and disease recurrence, but it also upregulates TME and cancer cell-protective innate immune checkpoints and down-modulates anti-tumoral macrophage functionality. In this article, we outline the well-established cell-autonomous roles of DYRK1B and extend its importance to the TME and the control of the tumor immune stroma. In summary, DYRK1B appears as a single novel key player creating a safe haven for cancer cells by acting cell-intrinsically and-extrinsically, leading to the promotion of cancer cell survival, chemoresistance, and relapse. Thus, DYRK1B appears as an attractive drug target for future therapeutic approaches.

Human pluripotent stem cell-derived β-cells (SC-β-cells) represent an alternative cell source for transplantation in diabetic patients. Although mitogens could in theory be used to expand β-cells, adult β-cells very rarely replicate. In contrast, newly formed β-cells, including SC-β-cells, display higher proliferative capacity and distinct transcriptional and functional profiles. Through bidirectional expression modulation and single-cell RNA-seq, we identified SPOCK2, an ECM protein, as an inhibitor of immature β-cell proliferation. Human β-cells lacking SPOCK2 presented elevated MMP2 expression and activity, leading to β-integrin-FAK-c-JUN pathway activation. Treatment with the MMP2 protein resulted in pronounced short- and long-term SC-β-cell expansion, significantly increasing glucose-stimulated insulin secretion in vitro and in vivo. These findings suggest that SPOCK2 mediates fetal β-cell proliferation and maturation. In summary, we identified a molecular mechanism that specifically regulates SC-β-cell proliferation and function, highlighting a unique signaling milieu of SC-β-cells with promise for the robust derivation of fully functional cells for transplantation.

Diabetes is characterized by variable loss of insulin-producing beta cells, and new regenerative approaches to increasing the functional beta cell mass of patients hold promise for reversing disease progression. In this Review, we summarize recent chemical biology breakthroughs advancing our knowledge of beta cell regeneration. We present current chemical-based tools, sensors and mechanistic insights into pathways that can be targeted to enhance beta cell regeneration in model organisms. We group the pathways according to the cellular processes they affect, that is, proliferation, conversion of other mature cell types to beta cells and beta cell differentiation from progenitor-like populations. We also suggest assays for assessing the functionality of the regenerated beta cells. Although regeneration processes differ between animal models, such as zebrafish, mice and pigs, regenerative mechanisms identified in any one animal model may be translatable to humans. Overall, chemical biology-based approaches in beta cell regeneration give hope that specific molecular pathways can be targeted to enhance beta cell regeneration.

Colorectal carcinomas (CRCs) are seldom eradicated by cytotoxic chemotherapy. Cancer cells with stem-like functional properties, often referred to as "cancer stem cells" (CSCs), display preferential resistance to several anti-tumor agents used in cancer chemotherapy, but the molecular mechanisms underpinning their selective survival remain only partially understood.

In this study, we used Transcription Factor Target Genes (TFTG) enrichment analysis to identify transcriptional regulators (activators or repressors) that undergo preferential activation by chemotherapy in CRC cells with a "bottom-of-the-crypt" phenotype (EPCAM+/CD44+/CD166+; CSC-enriched) as compared to CRC cells with a "top-of-the-crypt" phenotype (EPCAM+/CD44neg/CD166neg; CSC-depleted). The two cell populations were purified in parallel by fluorescence-activated cell sorting (FACS) from a patient-derived xenograft (PDX) line representative of a moderately differentiated human CRC, following in vivo chemotherapy with irinotecan (CPT-11). The transcriptional regulators identified as differentially activated were tested for differential expression in normal vs. cancer tissues, and in cell populations enriched in stem/progenitor cell-types as compared to differentiated lineages (goblet cells, enterocytes) in the mouse colon epithelium. Finally, the top candidate was tested for mechanistic contribution to drug-resistance by selective down-regulation using short-hairpin RNAs (shRNAs).

Our analysis identified E2F4 and TFDP1, two core components of the DREAM transcriptional repression complex, as transcriptional modulators preferentially activated by irinotecan in EPCAM+/CD44+/CD166+ as compared to EPCAM+/CD44neg/CD166neg cancer cells. The expression levels of both genes (E2F4, TFDP1) were found up-regulated in CRCs as compared to human normal colon tissues, and in a sub-population of mouse colon epithelial cells enriched in stem/progenitor elements (Epcam+/Cd44+/Cd66alow/Kitneg) as compared to other sub-populations enriched in either goblet cells (Epcam+/Cd44+/Cd66alow/Kit+) or enterocytes (Epcam+/Cd44neg/Cd66ahigh). Most importantly, E2F4 down-regulation using shRNAs dramatically enhanced the sensitivity of human CRCs to in vivo treatment with irinotecan, across three independent PDX models.

Our data identified E2F4 and the DREAM repressor complex as critical regulators of human CRC resistance to irinotecan, and as candidate targets for the development of chemo-sensitizing agents.

Glucagon-like peptide-1 (GLP-1) is a crucial incretin hormone secreted by intestinal endocrine L cells. Given its pivotal physiological role, researchers have developed GLP-1 receptor agonists (GLP-1 RAs) through structural modifications. These analogues display pharmacological effects similar to those of GLP-1 but with augmented stability and are regarded as an effective means of regulating blood glucose levels in clinical practice.

This review aims to comprehensively summarize the role of GLP-1 RAs in the management of diabetes mellitus (DM) and cardiovascular disease (CVD), with a particular emphasis on the underlying signal transduction pathways and their therapeutic potential.

A comprehensive review was carried out through literature research.

In pancreatic β-cells, GLP-1 RAs regulate the secretion of insulin and glucagon in a glucosedependent manner by influencing signaling pathways such as cAMP, PI3K, and MAPK. They also contribute to the regulation of blood glucose levels by promoting the proliferation of β-cells and inhibiting apoptosis in these cells. Recent comprehensive studies have also demonstrated the favorable impact of GLP-1 RAs on cardiovascular wellbeing. In addition to the cardiovascular protection afforded by glucose metabolism regulation, a large body of evidence from animal and cellular studies has corroborated the beneficial effects of GLP-1 RAs on conditions such as heart failure (HF), hypertension, and ischemic cardiomyopathy. These benefits are mainly attributed to the alleviation of inflammatory responses, reduction of oxidative stress, and prevention of cell apoptosis. Clinical data shows that GLP-1 RAs can reduce the risk of major adverse cardiovascular events (MACE) in diabetic patients.

GLP-1 RAs play an important role in the management of both diabetes and cardiovascular diseases. They show potential therapeutic value through the modulation of multiple signal transduction pathways. However, there may still be some issues in practical applications that require further research and resolution.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline and memory impairments and is considered the most prevalent form of dementia. Among the contributing factors to AD lies the hyperphosphorylation of the microtubule-associated protein tau. Phosphorylated tau reduces its affinity for microtubules and triggers other posttranslational modifications that result in its aggregation and assembly into filaments. These structures progressively accumulate within neurons leading to neurodegeneration. While current AD medications often involve undesirable side effects, the exploration of natural products as a potential therapeutic alternative has gained considerable attention. Numerous compounds have shown potential capacity for reducing tau pathology through different mechanisms, such as inhibiting kinases to reduce tau hyperphosphorylation, enhancing phosphatase activity, and blocking fibril formation. Since tau hyperphosphorylation-induced aggregation is pivotal in AD onset, this review aims to elucidate the potential of natural products in modulating this crucial molecular mechanism.

Pulmonary arterial hypertension (PAH) is characterized by progressive vascular remodeling caused by the excessive proliferation and survival of pulmonary artery smooth muscle cells (PASMCs). Dual-specificity tyrosine regulated kinase 1A (DYRK1A) is a pleiotropic kinase involved in the regulation of multiple biological functions, including cell proliferation and survival. However, the role and underlying mechanisms of DYRK1A in PAH pathogenesis remain unclear. We found that DYRK1A was upregulated in PASMCs in response to hypoxia, both in vivo and in vitro. Inhibition of DYRK1A by harmine significantly attenuated hypoxia-induced pulmonary hypertension and pulmonary artery remodeling. Mechanistically, we found that DYRK1A promoted pulmonary arterial remodeling by enhancing the proliferation and survival of PASMCs through activating the STAT3/Pim-1/NFAT pathway, because STAT3 gain-of-function via adeno-associated virus serotype 2 (AAV2) carrying the constitutively active form of STAT3 (STAT3C) nearly abolished the protective effect of harmine on PAH. Collectively, our results reveal a significant role for DYRK1A in pulmonary arterial remodeling and suggest it as a drug target with translational potential for the treatment of PAH.

Pancreatic beta cells are among the slowest replicating cells in the human body and have not been observed to increase in number except during the fetal and neonatal period, in cases of obesity, during puberty, as well as during pregnancy. Pregnancy is associated with increased beta cell mass to meet heightened insulin demands. This phenomenon raises the intriguing possibility that factors present in the serum of pregnant individuals may stimulate beta cell proliferation and offer insights into expansion of the beta cell mass for treatment and prevention of diabetes. The primary objective of this study was to test the hypothesis that serum from pregnant donors contains bioactive factors capable of inducing human beta cell proliferation. An immortalized human beta cell line with protracted replication (EndoC-βH1) was cultured in media supplemented with serum from pregnant and non-pregnant female and male donors and assessed for differences in proliferation. This experiment was followed by assessment of proliferation of primary human beta cells. Sera from five out of six pregnant donors induced a significant increase in the proliferation rate of EndoC-βH1 cells. Pooled serum from the cohort of pregnant donors also increased the rate of proliferation in primary human beta cells. This study demonstrates that serum from pregnant donors stimulates human beta cell proliferation. These findings suggest the existence of pregnancy-associated factors that can offer novel avenues for beta cell regeneration and diabetes prevention strategies. Further research is warranted to elucidate the specific factors responsible for this effect.

Diabetes results from an inadequate number of insulin-producing human beta cells. There is currently no clinically available effective means to restore beta cell mass in millions of people with diabetes. Although the DYRK1A inhibitors, either alone or in combination with GLP-1 receptor agonists (GLP-1) or transforming growth factor β (TGF-β) superfamily inhibitors (LY), induce beta cell replication and increase beta cell mass, the precise mechanisms of action remain elusive. Here we perform single-cell RNA sequencing on human pancreatic islets treated with a DYRK1A inhibitor, either alone or with GLP-1 or LY. We identify cycling alpha cells as the most responsive cells to DYRK1A inhibition. Lineage trajectory analyses suggest that cycling alpha cells may serve as precursor cells that transdifferentiate into beta cells. Collectively, in addition to enhancing expression of beta cell phenotypic genes in beta cells, our findings suggest that regenerative drugs may be targeting cycling alpha cells in human islets.

It has been shown that growth factors and small molecules play an essential role in the proliferation of β cells and insulin production. In this study, we investigated the effects of small molecules (WS6 and 5-iodotubercidin) and growth factors (TGFβ, HGF, and EGF) on the proliferation of β-like human ipSCs.

iPSCs derived β cells were treated with small molecules and growth factors. Cytotoxic activity of small molecules and growth factors was determined using MTT assay. Insulin gene expression and secretion were measured by qPCR and ELISA, respectively. The protein expression of insulin was evaluated by western blot as well.

Simltananeous addition of WS6 and Harmine into the culture media increased insulin gene expression compared to treatment by each molecule alone (p < 0.05). It was found that the simultaneous recruitment of EGH, HGF, and TGF-β increased insulin expression compared to treatment by each molecule alone (p < 0.05). Results showed that EGF, HGF, TGF-β growth factors increased insulin gene expression, eventually leading to insulin secretion from β cells (p < 0.05).

Growth factors and small molecules synergistically enhanced the proliferation of β cells and insulin production.

Cell and Gene therapy are referred to as advanced therapies that represent overlapping fields of regenerative medicine. They have similar therapeutic goals such as to modify cellular identity, improve cell function, or fight a disease. These two therapeutic avenues, however, possess major differences. While cell therapy involves introduction of new cells, gene therapy entails introduction or modification of genes. Furthermore, the aim of cell therapy is often to replace, or repair damaged tissue, whereas gene therapy is used typically as a preventive approach. Diabetes mellitus severely affects the quality of life of afflicted individuals and has various side effects including cardiovascular, ophthalmic disorders, and neuropathy while putting enormous economic pressure on both the healthcare system and the patient. In recent years, great effort has been made to develop cutting-edge therapeutic interventions for diabetes treatment, among which cell and gene therapies stand out. This review aims to highlight various cell- and gene-based therapeutic approaches leading to the generation of new insulin-producing cells as a topmost "panacea" for treating diabetes, while deliberately avoiding a detailed molecular description of these approaches. By doing so, we aim to target readers who are new to the field and wish to get a broad helicopter overview of the historical and current trends of cell- and gene-based approaches in β-cell regeneration.

Down syndrome (DS) is the most common genetic cause of intellectual impairment, characterised by an extra copy of chromosome 21. After the age of 40, DS individuals are highly susceptible to accelerated ageing and the development of early-onset Alzheimer-like neuropathology. In the context of DS, the brain presents a spectrum of neuropathological mechanisms and metabolic anomalies. These include heightened desensitisation of brain insulin and insulin-like growth factor-1 (IGF-1) reactions, compromised mitochondrial functionality, escalated oxidative stress, reduced autophagy, and the accumulation of amyloid beta and tau phosphorylation. These multifaceted factors intertwine to shape the intricate landscape of DS-related brain pathology. Altered brain insulin signalling is linked to Alzheimer's disease (AD). This disruption may stem from anomalies in the extracellular aspect (insulin receptor) or the intracellular facet, involving the inhibition of insulin receptor substrate 1 (IRS1). Both domains contribute to the intricate mechanism underlying this dysregulation. The PI3K-Akt/mammalian target of the rapamycin (mTOR) axis is a crucial intracellular element of the insulin signalling pathway that connects numerous physiological processes in the cell cycle. In age-related neurodegenerative disorders like AD, aberrant modulation of the PI3K-Akt signalling cascade is a key factor contributing to their onset. Aberrant and sustained hyperactivation of the PI3K/Akt-mTOR axis in the DS brain is implicated in early symptoms of AD development. Targeting the PI3K-Akt/mTOR pathway may help delay the onset of early-onset AD in individuals with DS, offering a potential way to slow disease progression and enhance their quality of life.

The pandemic scale of diabetes mellitus is alarming, its complications remain devastating, and current treatments still pose a major burden on those affected and on the healthcare system as a whole. As the disease emanates from the destruction or dysfunction of insulin-producing pancreatic β-cells, a real cure requires their restoration and protection. An attractive strategy is to regenerate β-cells directly within the pancreas; however, while several approaches for β-cell regeneration have been proposed in the past, clinical translation has proven challenging. This review scrutinizes recent findings in β-cell regeneration and discusses their potential clinical implementation. Hereby, we aim to delineate a path for innovative, targeted therapies to help shift from 'caring for' to 'curing' diabetes.

Harmine is a component of the hallucinogenic brew, Ayahuasca, which also contains the psychoactive compound, N, N-dimethyltryptamine. Whether pharmaceutical-grade harmine hydrochloride (HCl) has psychoactive effects, the doses at which these might occur, and the dose-response relationship to side effects and safety in humans are unknown.

We conducted a Phase 1, open-label single ascending dose trial in healthy adults with normal body mass index and no prior psychiatric illness. The primary goal was to determine the maximum tolerated dose (MTD) of oral pharmaceutical-grade harmine HCl and to characterize safety and tolerability. A secondary goal was to ascertain whether any oral dose has psychoactive effects.

Thirty-four adult participants, aged 18-55 years, were screened for study eligibility. Twenty-five participants met eligibility criteria and were randomized to a single dose of 100, 200, 300, or 500 mg of harmine HCl, respectively, using a continuous reassessment method. The most common adverse events (AEs) observed were gastrointestinal and/or neurological, dose-related, and of mild to moderate severity. The MTD was determined to be between 100 and 200 mg and is weight-based, with 90% of those participants receiving >2.7 mg/kg experiencing a dose-limiting toxicity. No serious AEs of harmine HCl were identified.

Harmine HCl can be orally administered to healthy participants in doses <2.7 mg/kg with minimal or no AEs. Doses >2.7 mg/kg are associated with vomiting, drowsiness, and limited psychoactivity. This study is the first to systematically characterize the psychoactive effects of pharmaceutical quality harmine in healthy participants.

Survival motor neuron protein (SMN), which is linked to spinal muscular atrophy, is a key component of the Gemin complex, which is essential for the assembly of small nuclear RNA-protein complexes (snRNPs). After initial snRNP assembly in the cytoplasm, both snRNPs and SMN migrate to the nucleus and associate with Cajal bodies, where final snRNP maturation occurs. It is assumed that SMN must be free from the Cajal bodies for continuous snRNP biogenesis. Previous observation of the SMN granules docked in the Cajal bodies suggests the existence of a separation mechanism. However, the precise processes that regulate the spatial separation of SMN complexes from Cajal bodies remain unclear. Here, we have employed a super-resolution microscope alongside the β-carboline alkaloid harmine, which disrupts the Cajal body in a reversible manner. Upon removal of harmine, SMN and Coilin first appear as small interconnected condensates. The SMN condensates mature into spheroidal structures encircled by Coilin, eventually segregating into distinct condensates. Expression of a multimerization-deficient SMN mutant leads to enlarged, atypical Cajal bodies in which SMN is unable to segregate into separate condensates. These findings underscore the importance of multimerization in facilitating the segregation of SMN from Coilin within Cajal bodies.

Introduction: Obesity is a major risk factor associated with multiple pathological conditions including diabetes and cardiovascular disease. Endothelial dysfunction is an early predictor of obesity. However, little is known regarding how early endothelial changes trigger obesity. In the present work we report a novel endothelial-mediated mechanism essential for regulation of metabolic homeostasis, driven by c-Myc. Methods: We used conditional knockout (EC-Myc KO) and overexpression (EC-Myc OE) mouse models to investigate the endothelial-specific role of c-Myc in metabolic homeostasis during aging and high-fat diet exposure. Body weight and metabolic parameters were collected over time and tissue samples collected at endpoint for biochemical, pathology and RNA-sequencing analysis. Animals exposed to high-fat diet were also evaluated for cardiac dysfunction. Results: In the present study we demonstrate that EC-Myc KO triggers endothelial dysfunction, which precedes progressive increase in body weight during aging, under normal dietary conditions. At endpoint, EC-Myc KO animals showed significant increase in white adipose tissue mass relative to control littermates, which was associated with sex-specific changes in whole body metabolism and increase in systemic leptin. Overexpression of endothelial c-Myc attenuated diet-induced obesity and visceral fat accumulation and prevented the development of glucose intolerance and cardiac dysfunction. Transcriptome analysis of skeletal muscle suggests that the protective effects promoted by endothelial c-Myc overexpression are associated with the expression of genes known to increase weight loss, energy expenditure and glucose tolerance. Conclusion: Our results show a novel important role for endothelial c-Myc in regulating metabolic homeostasis and suggests its potential targeting in preventing obesity and associated complications such as diabetes type-2 and cardiovascular dysfunction.

Five hundred thirty-seven million people globally suffer from diabetes. Insulin-producing β cells are reduced in number in most people with diabetes, but most individuals still have some residual β cells. However, none of the many diabetes drugs in common use increases human β cell numbers. Recently, small molecules that inhibit dual tyrosine-regulated kinase 1A (DYRK1A) have been shown to induce immunohistochemical markers of human β cell replication, and this is enhanced by drugs that stimulate the glucagon-like peptide 1 (GLP1) receptor (GLP1R) on β cells. However, it remains to be demonstrated whether these immunohistochemical findings translate into an actual increase in human β cell numbers in vivo. It is also unknown whether DYRK1A inhibitors together with GLP1R agonists (GLP1RAs) affect human β cell survival. Here, using an optimized immunolabeling-enabled three-dimensional imaging of solvent-cleared organs (iDISCO+) protocol in mouse kidneys bearing human islet grafts, we demonstrate that combination of a DYRK1A inhibitor with exendin-4 increases actual human β cell mass in vivo by a mean of four- to sevenfold in diabetic and nondiabetic mice over 3 months and reverses diabetes, without alteration in human α cell mass. The augmentation in human β cell mass occurred through mechanisms that included enhanced human β cell proliferation, function, and survival. The increase in human β cell survival was mediated, in part, by the islet prohormone VGF. Together, these findings demonstrate the therapeutic potential and favorable preclinical safety profile of the DYRK1A inhibitor-GLP1RA combination for diabetes treatment.

Pancreatic regeneration is a complex process observed in both normal and pathological conditions. The aim of this review is to provide a comprehensive understanding of the emergence of a functionally active population of insulin-secreting β-cells in the adult pancreas. The renewal of β-cells is governed by a multifaceted interaction between cellular sources of genetic and epigenetic factors. Understanding the development and heterogeneity of β-cell populations is crucial for functional β-cell regeneration. The functional mass of pancreatic β-cells increases in situations such as pregnancy and obesity. However, the specific markers of mature β-cell populations and postnatal pancreatic progenitors capable of increasing self-reproduction in these conditions remain to be elucidated. The capacity to regenerate the β-cell population through various pathways, including the proliferation of pre-existing β-cells, β-cell neogenesis, differentiation of β-cells from a population of progenitor cells, and transdifferentiation of non-β-cells into β-cells, reveals crucial molecular mechanisms for identifying cellular sources and inducers of functional cell renewal. This provides an opportunity to identify specific cellular sources and mechanisms of regeneration, which could have clinical applications in treating various pathologies, including in vitro cell-based technologies, and deepen our understanding of regeneration in different physiological conditions.

The prevalence of diabetes is increasing worldwide. Massive death of pancreatic beta-cells causes type 1 diabetes. Progressive loss of beta-cell function and mass characterizes type 2 diabetes. To date, none of the available antidiabetic drugs promotes the maintenance of a functional mass of endogenous beta-cells, revealing an unmet medical need. Dysfunction and apoptotic death of beta-cells occur, in particular, through the activation of intracellular protein kinases. In recent years, protein kinases have become highly studied targets of the pharmaceutical industry for drug development. A number of drugs that inhibit protein kinases have been approved for the treatment of cancers. The question of whether safe drugs that inhibit protein kinase activity can be developed and used to protect the function and survival of beta-cells in diabetes is still unresolved. This review presents arguments suggesting that several protein kinases in beta-cells may represent targets of interest for the development of drugs to treat diabetes.

Nowadays, the focus of diabetes treatment has switched from lowering the glucose level to preserving glycemic homeostasis and slowing the disease progression. The main pathophysiology of both type 1 diabetes and long-standing type 2 diabetes is pancreatic β-cell mass loss and dysfunction. According to recent research, human pancreatic β-cells possess the ability to proliferate in response to elevated insulin demands. It has been demonstrated that in insulin-resistant conditions in humans, such as obesity or pregnancy, the β-cell mass increases. This ability could be helpful in developing novel treatment approaches to restore a functional β-cell mass. Treatment strategies aimed at boosting β-cell function and mass may be a useful tool for managing diabetes mellitus and stopping its progression. This review outlines the processes of β-cell failure and detail the many β-cell abnormalities that manifest in people with diabetes mellitus. We also go over standard techniques for determining the mass and function of β-cells. Lastly, we provide the therapeutic implications of utilizing antidiabetic drugs in controlling the mass and function of pancreatic β-cells.

Inhibition of the bromodomain and extraterminal domain (BET) protein family is a potential strategy to prevent and treat diabetes; however, the clinical use of BET bromodomain inhibitors (BETis) is associated with adverse effects. Here, we explore a strategy for targeting BETis to β cells by exploiting the high-zinc (Zn2+) concentration in β cells relative to other cell types. We report the synthesis of a novel, Zn2+-chelating derivative of the pan-BETi (+)-JQ1, (+)-JQ1-DPA, in which (+)-JQ1 was conjugated to dipicolyl amine (DPA). As controls, we synthesized (+)-JQ1-DBA, a non-Zn2+-chelating derivative, and (-)-JQ1-DPA, an inactive enantiomer that chelates Zn2+. Molecular modeling and biophysical assays showed that (+)-JQ1-DPA and (+)-JQ1-DBA retain potent binding to BET bromodomains in vitro. Cellular assays demonstrated (+)-JQ1-DPA attenuated NF-ĸB target gene expression in β cells stimulated with the proinflammatory cytokine interleukin 1β. To assess β-cell selectivity, we isolated islets from a mouse model that expresses green fluorescent protein in insulin-positive β cells and mTomato in insulin-negative cells (non-β cells). Surprisingly, Zn2+ chelation did not confer β-cell selectivity as (+)-JQ1-DPA was equally effective in both β and α cells; however, (+)-JQ1-DPA was less effective in macrophages, a nonendocrine islet cell type. Intriguingly, the non-Zn2+-chelating derivative (+)-JQ1-DBA displayed the opposite selectivity, with greater effect in macrophages compared with (+)-JQ1-DPA, suggesting potential as a macrophage-targeting molecule. These findings suggest that Zn2+-chelating small molecules confer endocrine cell selectivity rather than β-cell selectivity in pancreatic islets and provide valuable insights and techniques to assess Zn2+ chelation as an approach to selectively target small molecules to pancreatic β cells.NEW & NOTEWORTHY Inhibition of BET bromodomains is a novel potential strategy to prevent and treat diabetes mellitus. However, BET inhibitors have negative side effects. We synthesized a BET inhibitor expected to exploit the high zinc concentration in β cells to accumulate in β cells. We show our inhibitor targeted pancreatic endocrine cells; however, it was less effective in immune cells. A control inhibitor showed the opposite effect. These findings help us understand how to target specific cells in diabetes treatment.

The small molecule DYRK1A inhibitor, harmine, induces human beta cell proliferation, expands beta cell mass, enhances expression of beta cell phenotypic genes, and improves human beta cell function i n vitro and in vivo . It is unknown whether the "pro-differentiation effect" is a DYRK1A inhibitor class-wide effect. Here we compare multiple commonly studied DYRK1A inhibitors. Harmine, 2-2c and 5-IT increase expression of PDX1, MAFA, NKX6.1, SLC2A2, PCSK1, MAFB, SIX2, SLC2A2, SLC30A8, ENTPD3 in normal and T2D human islets. Unexpectedly, GNF4877, CC-401, INDY, CC-401 and Leucettine fail to induce expression of these essential beta cell molecules. Remarkably, the pro-differentiation effect is independent of DYRK1A inhibition: although silencing DYRK1A induces human beta cell proliferation, it has no effect on differentiation; conversely, harmine treatment enhances beta cell differentiation in DYRK1A-silenced islets. A careful screen of multiple DYRK1A inhibitor kinase candidate targets was unable to identify pro-differentiation pathways. Overall, harmine, 2-2c and 5-IT are unique among DYRK1A inhibitors in their ability to enhance both beta cell proliferation and differentiation. While beta cell proliferation is mediated by DYRK1A inhibition, the pro-differentiation effects of harmine, 2-2c and 5-IT are distinct, and unexplained in mechanistic terms. These considerations have important implications for DYRK1A inhibitor pharmaceutical development.

Islet transplantation can cure type 1 diabetes, but peri-transplant beta cell death limits this procedure to those with low insulin requirements. Improving human beta cell survival or proliferation may make islet transplantation a possibility for more type 1 patients. To identify novel regulators of beta cell survival and proliferation, we conducted a pooled small hairpin RNA (shRNA) screen in primary human beta cells transplanted into immunocompromised mice. shRNAs targeting several cyclin dependent kinase inhibitors were enriched after transplant. Here, we focused on the Gi/o-coupled GPCR, serotonin 1F receptor ( HTR1F, 5-HT 1F ) which our screen identified as a negative regulator of beta cell numbers after transplant. In vitro , 5-HT 1F knockdown induced human beta cell proliferation but only when combined with harmine and exendin-4. In vivo , knockdown of 5-HT 1F reduced beta cell death during transplant. To demonstrate the feasibility of targeting 5-HT 1F in islet transplant, we identified and validated a small molecule 5-HT 1F antagonist. This antagonist increased glucose stimulated insulin secretion from primary human islets and cAMP accumulation in primary human beta cells. Finally, the 5-HT 1F antagonist improved glycemia in marginal mass, human islet transplants into immunocompromised mice. We identify 5-HT 1F as a novel druggable target to improve human beta cell survival in the setting of islet transplantation.

Serotonin 1F receptor (5-HT 1F ) negatively regulates insulin secretion and beta cell survival during transplant.

The field of transcriptional regulation has revealed the vital role of chromatin modifiers in human diseases from the beginning of functional exploration to the process of participating in many types of disease regulatory mechanisms. Chromatin modifiers are a class of enzymes that can catalyze the chemical conversion of pyrimidine residues or amino acid residues, including histone modifiers, DNA methyltransferases, and chromatin remodeling complexes. Chromatin modifiers assist in the formation of transcriptional regulatory circuits between transcription factors, enhancers, and promoters by regulating chromatin accessibility and the ability of transcription factors to acquire DNA. This is achieved by recruiting associated proteins and RNA polymerases. They modify the physical contact between cis-regulatory factor elements, transcription factors, and chromatin DNA to influence transcriptional regulatory processes. Then, abnormal chromatin perturbations can impair the homeostasis of organs, tissues, and cells, leading to diseases. The review offers a comprehensive elucidation on the function and regulatory mechanism of chromatin modifiers, thereby highlighting their indispensability in the development of diseases. Furthermore, this underscores the potential of chromatin modifiers as biomarkers, which may enable early disease diagnosis. With the aid of this paper, a deeper understanding of the role of chromatin modifiers in the pathogenesis of diseases can be gained, which could help in devising effective diagnostic and therapeutic interventions.

Pancreatic β-cell failure due to a reduction in function and mass has been defined as a primary contributor to the progression of type 2 diabetes (T2D). Reserving insulin-producing β-cells and hence restoring insulin production are gaining attention in translational diabetes research, and β-cell replenishment has been the main focus for diabetes treatment. Significant findings in β-cell proliferation, transdifferentiation, pluripotent stem cell differentiation, and associated small molecules have served as promising strategies to regenerate β-cells. In this review, we summarize current knowledge on the mechanisms implicated in β-cell dynamic processes under physiological and diabetic conditions, in which genetic factors, age-related alterations, metabolic stresses, and compromised identity are critical factors contributing to β-cell failure in T2D. The article also focuses on recent advances in therapeutic strategies for diabetes treatment by promoting β-cell proliferation, inducing non-β-cell transdifferentiation, and reprograming stem cell differentiation. Although a significant challenge remains for each of these strategies, the recognition of the mechanisms responsible for β-cell development and mature endocrine cell plasticity and remarkable advances in the generation of exogenous β-cells from stem cells and single-cell studies pave the way for developing potential approaches to cure diabetes.

Selective inhibitors of DYRK1A are of interest for the treatment of cancer, Type 2 diabetes and neurological disorders. Optimization of imidazo [1,2-b]pyridazine fragment 1 through structure-activity relationship exploration and in silico drug design efforts led to the discovery of compound 17 as a potent cellular inhibitor of DYRK1A with selectivity over much of the kinome. The binding mode of compound 17 was elucidated with X-ray crystallography, facilitating the rational design of compound 29, an imidazo [1,2-b]pyridazine with improved kinase selectivity with respect to closely related CLK kinases.

In the quest to combat insulin-dependent diabetes mellitus (IDDM), allogenic pancreatic islet cell therapy sourced from deceased donors represents a significant therapeutic advance. However, the applicability of this approach is hampered by donor scarcity and the demand for sustained immunosuppression. Human induced pluripotent stem cells are a game-changing resource for generating synthetic functional insulin-producing β cells. In addition, novel methodologies allow the direct expansion of pancreatic progenitors and mature β cells, thereby circumventing prolonged differentiation. Nevertheless, achieving practical reproducibility and scalability presents a substantial challenge for this technology. As these innovative approaches become more prominent, it is crucial to thoroughly evaluate existing expansion techniques with an emphasis on their optimization and scalability. This manuscript delineates these cutting-edge advancements, offers a critical analysis of the prevailing strategies, and underscores pivotal challenges, including cost-efficiency and logistical issues. Our insights provide a roadmap, elucidating both the promises and the imperatives in harnessing the potential of these cellular therapies for IDDM.