EXCLI Journal最新文献

{"title":"TGF-beta inhibitors in cancer therapy: a review of the TGF-beta signal transduction pathway and current developments.","authors":"Shun-Ban Tai, Jenq-Lin Yang, Pei-Feng Liu, Chun-Lin Chen","doi":"10.17179/excli2026-9381","DOIUrl":"10.17179/excli2026-9381","url":null,"abstract":"<p><p>Transforming growth factor-β (TGF-β) belongs to a family of structurally and functionally related cytokines that play essential roles in embryonic development, tissue homeostasis, and cell fate regulation. Dysregulation of TGF-β signaling contributes to a broad spectrum of diseases, including cancer, fibrosis, and immune disorders. In cancer, TGF-β exhibits a context-dependent dual role, functioning as a tumor suppressor during early stages while promoting invasion, metastasis, escape from immune surveillance, and tumor microenvironment remodeling in advanced-stage cancer through effects on stromal cells, extracellular matrix deposition, and angiogenesis. This functional duality makes therapeutic targeting both attractive and challenging. Although current strategies mainly focus on ligand neutralization or receptor kinase inhibition, accumulating evidence indicates that TGF-β activity is also regulated beyond the receptor level, including receptor trafficking, co-receptor function, nucleocytoplasmic shuttling, indirect pathway modulation, and epigenetic regulation. In this review, we emphasize regulatory mechanisms that can be modulated by existing drugs, clinical candidates, or experimentally tractable compounds, rather than providing an exhaustive overview of the broader regulatory landscape of TGF-β signaling. We further highlight opportunities for drug repurposing and discuss how synergistic combination strategies may improve therapeutic efficacy and overcome resistance in TGF-β-driven cancers, supporting a broader therapeutic framework beyond canonical receptor inhibition. See also the graphical abstract(Fig. 1).</p>","PeriodicalId":12247,"journal":{"name":"EXCLI Journal","volume":"25 ","pages":"550-586"},"PeriodicalIF":6.2,"publicationDate":"2026-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13275060/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148276663","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Modulation of ion channels as emerging therapeutic targets in the treatment of diabetic neuropathy.","authors":"Tanya Gupta, Alimam Ansari, Rishabh Chalotra, Abhitinder Kumar, Thakur Gurjeet Singh, Randhir Singh","doi":"10.17179/excli2026-9383","DOIUrl":"10.17179/excli2026-9383","url":null,"abstract":"<p><p>Diabetic neuropathy (DN) is a prevalent microvascular complication of diabetes mellitus, characterized by hyperalgesia and allodynia that severely impair quality of life. Current treatment approaches do not provide adequate relief, largely due to the multifactorial nature of disease pathogenesis. Growing evidence indicates that dysregulation of multiple ion channel families is a central mechanism underlying sensory neuron hyperexcitability and chronic pain in DN. This review comprehensively discusses the roles of major ion channel families, including voltage-gated sodium (Naᵥ), calcium (Caᵥ), and potassium (Kᵥ) channels, transient receptor potential (TRP) channels, purinergic receptors (P2X/P2Y), and mechanosensitive PIEZO (PIEZO 1 and PIEZO 2) channels, in sensory transmission and pain modulation. Their dysregulation, induced by chronic hyperglycemia and oxidative stress, promotes ectopic firing, altered calcium homeostasis, and glial activation, sustaining nociceptive hypersensitivity. The review further evaluates current and emerging ion channel-targeted therapeutic approaches, highlighting mechanistic insights, translational challenges, and future research directions. Recent research highlights multi-target and combination strategies, such as Naᵥ1.8 inhibition with KCNQ activation or concurrent blockade of TRPV1 and P2X3, as promising avenues offering synergistic analgesic benefits and disease-modifying potential. Advances in nanocarrier-based delivery, gene modulation, and patient-specific electrophysiological profiling further enhance translational prospects. Ultimately, the therapeutic landscape of PDN is shifting from single-channel blockade toward integrated approaches that modulate excitability, inflammation, and metabolic stress concurrently. Ion channels thus represent not only crucial mediators of PDN pathophysiology but also versatile therapeutic targets whose selective and combinatorial modulation may transform the management of diabetic neuropathic pain. See also the graphical abstract(Fig. 1).</p>","PeriodicalId":12247,"journal":{"name":"EXCLI Journal","volume":"25 ","pages":"511-549"},"PeriodicalIF":6.2,"publicationDate":"2026-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13272903/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148276650","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The major toxins of Bacillus cereus - Current knowledge on distribution, regulation and mechanism of action.","authors":"Manar Albahri, Nadja Jessberger","doi":"10.17179/excli2026-9314","DOIUrl":"10.17179/excli2026-9314","url":null,"abstract":"<p><p>The ubiquitous soil bacterium <i>Bacillus cereus</i> is one of the major pathogens causing toxin-based foodborne diseases, manifesting as diarrhoeal or emetic syndrome. Main symptoms of the former are diarrhoea and abdominal pain, caused by the proteinaceous enterotoxins haemolysin BL (Hbl), non-haemolytic enterotoxin (Nhe) and cytotoxin K (CytK). Responsible for the latter is the cyclic dodecadepsipeptide cereulide, leading to nausea and vomiting, and, in severe and rare cases, also to organ failure and death. This review first addresses the complex taxonomy of the <i>B. cereus</i> group as well as the distribution of toxin genes within this group. Further, recent developments in studying the multifaceted intrinsic and extrinsic factors regulating enterotoxin and <i>ces</i> gene expression and toxin secretion are summarised. Special emphasis is placed on the latest findings regarding the mode of action of the pore-forming toxins, as well as on specific target structures and receptors, and the activation of cellular signalling pathways and inflammatory/apoptotic responses upon toxin exposure. Production and toxicity of the relatively new discovered cereulide isoforms are also discussed. A profound understanding of the fundamental processes of toxin formation and action is essential for accurate risk assessment of <i>B. cereus</i> isolates and for improving diagnostic procedures to increase food safety. See also the graphical abstract(Fig. 1).</p>","PeriodicalId":12247,"journal":{"name":"EXCLI Journal","volume":"25 ","pages":"481-510"},"PeriodicalIF":6.2,"publicationDate":"2026-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13247181/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148217033","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Reply to the letter to the editor by Manzoli, Acuti Martelucci and Flacco (doi: 10.17179/excli2025-9176).","authors":"Marco Alessandria, Franco Berrino, Giovanni M Malatesta, Alberto Donzelli","doi":"10.17179/excli2026-9442","DOIUrl":"10.17179/excli2026-9442","url":null,"abstract":"","PeriodicalId":12247,"journal":{"name":"EXCLI Journal","volume":"25 ","pages":"476-478"},"PeriodicalIF":6.2,"publicationDate":"2026-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13139733/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147835632","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Second reply to the second letter to the editor by Alessandria, Berrino, Malatesta and Donzelli (doi: 10.17179/excli2026-9442).","authors":"Lamberto Manzoli, Cecilia Acuti Martellucci, Maria Elena Flacco","doi":"10.17179/excli2026-9443","DOIUrl":"10.17179/excli2026-9443","url":null,"abstract":"","PeriodicalId":12247,"journal":{"name":"EXCLI Journal","volume":"25 ","pages":"479-480"},"PeriodicalIF":6.2,"publicationDate":"2026-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13139735/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147835600","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Genetic diagnosis and molecular characterization of three novel variations in the phenylalanine hydroxylase gene from Chinese patients with phenylketonuria.","authors":"Fan Yang, Hua-Feng Li, Wei-Jia Tang, Jin-Ping Zhu, Ji-Gang Qiu, Tian-E Cai, Li-Mei Yu, Ying Yu","doi":"10.17179/excli2026-9271","DOIUrl":"10.17179/excli2026-9271","url":null,"abstract":"<p><p>Loss-of-function variants in the human <i>phenylalanine hydroxylase</i> (<i>PAH</i>) gene are the most common genetic causal factors for Phenylketonuria (PKU). Currently, a broad spectrum of variations is recognized in the human <i>PAH</i> gene. However, the molecular function and clinical significance of some novel <i>PAH</i> variants remain unclear. Here, we report on five PKU-affected families carrying three novel <i>PAH</i> variants, including one missense variant (<i>PAH</i>: c.271C>A (p.Leu91Met)) and two deletions (<i>PAH</i>: c.206_208delCTT (p.Ser70del) and <i>PAH</i>: c.541_544delGAGG (p.Glu181Lysfs*13)). These variations constitute different compound heterozygous genotypes with other known pathogenic variants such as <i>PAH</i>: c.721C>T (p.Arg241Cys), <i>PAH</i>: c.168+5G>C, and <i>PAH</i>: c.1238G>C (p.Arg413Pro), which probably led to the patients' PKU etiopathology. qRT-PCR and immunoblotting showed that the protein levels of PAH (S70del) and PAH (E181Kfs*13) were significantly reduced compared with the wild-type control, although their transcript levels were not. Also, the enzyme activity of PAH (S70del) and PAH (E181Kfs*13) mutants was significantly decreased relative to the wild type (<i>P</i> < 0.001). <i>PAH</i>: c.271C>A (p.Leu91Met) had no significant effect on <i>PAH</i> mRNA and protein levels or enzyme activity. Collectively, our data demonstrate that the two deletions <i>PAH</i>: c.206_208delCTT and <i>PAH</i>: c.541_544delGAGG are clinically significant for pathogenicity. Our findings are anticipated to contribute to the advancement of prenatal diagnosis, population-based carrier screening, and genetic counseling for individuals affected by PKU, and is expected to help reduce the incidence of PKU and ameliorate the associated disease burden. See also the graphical abstract(Fig. 1).</p>","PeriodicalId":12247,"journal":{"name":"EXCLI Journal","volume":"25 ","pages":"458-475"},"PeriodicalIF":6.2,"publicationDate":"2026-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13139738/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147835642","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Circadian clock regulation in lung health and disease: molecular mechanisms and therapeutic opportunities.","authors":"Prabesh Baniya, Swekriti Puri, Nisha Panth, Rajan Thapa, Madhu Gupta, Sachin Kumar Singh, Rohit Bhatia, Gaurav Gupta, Kamal Dua, Keshav Raj Paudel","doi":"10.17179/excli2026-9372","DOIUrl":"10.17179/excli2026-9372","url":null,"abstract":"<p><p>Circadian rhythms are endogenous time-keeping mechanisms that organize physiological and cellular functions into approximately 24-hour cycles. These rhythms are generated by conserved molecular clocks composed of interconnected transcription-translation feedback loops involving core regulators such as CLOCK, BMAL1, PERIOD, CRYPTOCHROME, REV-ERB, and ROR proteins. While circadian regulation is best known for governing sleep-wake behavior, mounting evidence demonstrates that peripheral clocks exert critical control over organ-specific physiology. The lung represents a highly rhythmic tissue in which local circadian oscillators coordinate airway tone, immune surveillance, inflammatory signaling, epithelial repair, and metabolic homeostasis. Disruption of circadian timing arising from genetic alterations, environmental stressors, shift work, irregular light exposure, or chronic inflammation has emerged as an important contributor to the development and progression of multiple respiratory diseases, including asthma, chronic obstructive pulmonary disease, pulmonary fibrosis, acute lung injury, sleep-disordered breathing, and lung cancer. At the mechanistic level, dysregulation of clock genes alters inflammatory pathways, oxidative stress responses, mitochondrial metabolism, and cell-cycle control, thereby exacerbating tissue injury and impairing resolution and repair. Recognition of these temporal influences has prompted growing interest in circadian-based therapeutic strategies. Chronotherapy, which aligns drug administration with endogenous biological rhythms, and pharmacological targeting of clock components such as REV-ERBs and RORs, offer promising avenues to improve treatment efficacy while limiting adverse effects. This review integrates current insights into circadian clock architecture, lung-specific regulation, disease mechanisms, and therapeutic potential, highlighting circadian biology as a critical yet underutilized dimension of respiratory medicine. See also the graphical abstract(Fig. 1).</p>","PeriodicalId":12247,"journal":{"name":"EXCLI Journal","volume":"25 ","pages":"427-457"},"PeriodicalIF":6.2,"publicationDate":"2026-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13139736/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147835628","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Paracetamol in pregnancy: Navigating clinical uncertainty and avoiding the communication pitfalls of the \"measles, mumps, and rubella\" - autism controversy: A narrative review.","authors":"Helmi Ben Saad, Chamseddine Barki, Ismail Dergaa, Wissem Dhahbi, Halil Ibrahim Ceylan, Nasr Chalghaf, Abdelfatteh El Omri, Hanene Boussi Rahmouni","doi":"10.17179/excli2026-9237","DOIUrl":"10.17179/excli2026-9237","url":null,"abstract":"<p><p>On September 22, 2025, the United States government announced that the Food and Drug Administration (FDA) would modify paracetamol (acetaminophen) labelling to warn of possible associations with autism, advising pregnant individuals to avoid the medication. This contradicts professional medical consensus and high-quality evidence, replicating communication failures of the 1998 MMR-autism controversy that caused vaccine hesitancy, disease outbreaks, and trust erosion. This narrative review synthesized epidemiological evidence on paracetamol safety in pregnancy, analyzed the September 2025 announcement through the measles, mumps, and rubella (MMR)-autism crisis lens, and proposed an evidence-based communication framework. We searched <i>PubMed</i>, <i>Embase</i>, <i>Web of Science</i>, and <i>Google Scholar</i>, supplemented with governmental statements, professional responses, and media analysis. The two highest-quality sibling-control studies (Swedish: 2.5 million; Japanese: 200,000 children) reported no causal associations between prenatal paracetamol exposure and neurodevelopmental outcomes after controlling genetic and familial confounding. Conversely, untreated maternal fever and pain carry established risks including neural tube defects, preterm birth, and maternal morbidity. The governmental announcement employed inflammatory categorical warnings contradicting FDA's nuanced advisory and scientific consensus. Professional organizations immediately issued strong rebuttals. This replicates MMR failures: governmental statements contradicting evidence, false media balance, and public confusion. The September 2025 announcement represents failure to apply MMR lessons. Healthcare providers must employ evidence-based shared decision-making emphasizing sibling-controlled studies show no causal relationship while untreated conditions carry established harms. The Precautionary Communication Principle provides framework for transparent uncertainty discussion without disproportionate alarm or undermining evidence-based medicine trust. See also the graphical abstract(Fig. 1).</p>","PeriodicalId":12247,"journal":{"name":"EXCLI Journal","volume":"25 ","pages":"400-426"},"PeriodicalIF":6.2,"publicationDate":"2026-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13139739/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147835629","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Marine algae as emerging therapeutics in lung health.","authors":"Prisca Deviani Pakan, Kiruthika Narayanan, Dennis Chang, Keshav Raj Paudel, Kamal Dua","doi":"10.17179/excli2026-9388","DOIUrl":"10.17179/excli2026-9388","url":null,"abstract":"","PeriodicalId":12247,"journal":{"name":"EXCLI Journal","volume":"25 ","pages":"396-399"},"PeriodicalIF":6.2,"publicationDate":"2026-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13139734/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147835560","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Polymorphism engineering of mefenamic acid for enhanced pharmacokinetic performance.","authors":"Parteek Prasher, Mousmee Sharma","doi":"10.17179/excli2026-9258","DOIUrl":"10.17179/excli2026-9258","url":null,"abstract":"<p><p>Mefenamic acid, a BCS Class II drug, continues to face the longstanding challenges related to its suboptimal solubility and variable absorption, which necessitates frequent dosing of the drug resulting in ulcerogenicity. Guided by its polymorphic forms, the co-crystallization of mefenamic acid offers a unique advantage over the other advanced formulation strategies, including hydrotropy, nanosizing, and complexation for improving the drug bioavailability. However, the contemporary research limited only to the proof-of-concept studies fails to provide a clinical evidence or translational insights, which necessitates the rational design of synthons and engineering of the solid-state landscape of the drug for developing the co-crystallization formulation of mefenamic acid. This commentary provides critical insights into the polymorphism-driven co-crystal design of mefenamic acid aimed at filling the critical gaps in scalability and clinical translation.</p>","PeriodicalId":12247,"journal":{"name":"EXCLI Journal","volume":"25 ","pages":"390-395"},"PeriodicalIF":6.2,"publicationDate":"2026-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13139737/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147835613","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}