Gluten proteins are key components in wheat flour that determine the formation of dough and the quality of flour-based products. Upon hydration and mixing, gluten proteins undergo complex structural transformations to form a gluten network, exhibiting a hierarchical multi-scale structure spanning molecular, aggregate, and network scales. Due to the extreme complexity of gluten proteins, accurately characterizing their multi-scale structures remains challenging, requiring the combined application of multiple techniques, which are still relatively limited and thus warrant further exploration. Therefore, this review presents the principles, operational details, and result presentations of current techniques at different structural scales, including electrophoresis, high-performance liquid chromatography, proteomics, Fourier transform infrared spectroscopy, and Fourier transform Raman spectroscopy at the molecular scale; size-exclusion chromatography, asymmetrical flow field-flow fractionation, dynamic light scattering, multi-angle light scattering, differential refractive index, and ultraviolet absorbance at the aggregate scale; and confocal laser scanning microscopy, scanning electron microscopy, confocal Raman microscopy, and two-photon excitation microscopy at the network scale, among others. It further compares the advantages and disadvantages of similar techniques, facilitating their scenario-based selective utilization. Finally, it outlines the ongoing challenges and future perspectives for the development and application of techniques for the multi-scale structural characterization of gluten proteins.

Halogens, particularly fluorine, chlorine, and bromine, play a pivotal role in modern drug discovery and development. Their incorporation into drug molecules significantly influences physicochemical properties, including lipophilicity, metabolic stability, and target binding affinity. Fluorine, the most commonly used halogen, enhances bioavailability and receptor interactions, as seen in several blockbuster drugs. Chlorine and bromine contribute to hydrophobic interactions and modulate pharmacokinetics, while iodine is less frequently utilized due to its larger atomic size and reactivity. The strategic placement of halogens in drug scaffolds has led to the success of numerous FDA-approved pharmaceuticals across therapeutic areas, including oncology, infectious diseases, and central nervous system disorders. This review explores the structure-activity relationships (SAR) of halogen-containing drugs, highlighting recent approvals (2025), their synthesis (with yields, when available), therapeutic use, and, when experimentally available, the interaction with their biological target macromolecules.

Normal pregnancy is associated with uterine and vascular remodeling by matrix metalloproteinases (MMPs) to facilitate placental blood flow and uterine expansion for the growing fetus. Increases in MMP-2 and MMP-9 in response to estrogen and progesterone promote placentation, uteroplacental vascularization and fetal growth during healthy pregnancy, but are altered in preeclampsia (PE). PE is characterized by hypertension in pregnancy (HTN-Preg) and fetal growth restriction (FGR). Predisposing genetic, demographic and environmental factors alter uteroplacental MMPs, immune response and integrins leading to apoptosis of invasive trophoblasts, inadequate spiral arteries remodeling, and reduced uteroplacental perfusion pressure (RUPP). Ensuing placental ischemia causes imbalance between anti-angiogenic soluble fms-like tyrosine kinase-1 (sFlt-1) and pro-angiogenic placental growth factor (PlGF) and promotes the release of tumor necrosis factor-α (TNF-α), hypoxia-inducible factor, reactive oxygen species, and angiotensin AT1 receptor agonistic autoantibodies. Systemically, these bioactive factors target vascular endothelial cells, smooth muscle cells, and extracellular matrix, causing endothelial dysfunction, vasoconstriction, inadequate vascular remodeling, and HTN-Preg, while locally they diminish uteroplacental remodeling and cause FGR. In support, animal models of HTN-Preg induced by RUPP or infusion of sFlt-1 or TNF-α show decreases in vascular MMP-2, MMP-9 and vasodilation, increases in MMP-1, MMP-7 and vasoconstriction, collagen accumulation, and arterial stiffness. Also, decreases in uterine MMP-2 and MMP-9 could impede uterine expansion and lead to preterm birth. Conversely, PlGF and TNF-α antagonist reversed MMPs imbalance and collagen accumulation, and improved vascular function, blood pressure, and pup weight in HTN-Preg models. Persistent postpartum changes in MMPs could affect maternal hemorrhage, future pregnancies, and HTN, and cause fetal programming of cardiovascular and metabolic diseases. Understanding the aberrant uteroplacental and vascular signaling and remodeling by MMPs could help design new biomarkers and remedies for PE. Targeting bioactive factors and rectifying MMP imbalance could improve vascular and uteroplacental remodeling, and manage HTN-Preg, FGR and PE.

Necroptosis is a regulated form of programmed cell death that helps the body defend itself against infections and cellular stress, especially when apoptosis is blocked. At the center of this process is mixed lineage kinase domain-like (MLKL) protein, the final effector of necroptosis, which is activated downstream of receptor-interacting protein kinase 3 (RIPK3). Once phosphorylated, MLKL changes shape, assembles into oligomers, moves to cellular membranes, and disrupts membrane integrity, ultimately causing cell death. While this RIPK3-MLKL pathway has been well described, it is becoming increasingly clear that MLKL regulation is more complex than originally thought. Recent findings show that MLKL can be modified and activated through alternative mechanisms, even in the absence of RIPK3, and that post-translational modifications such as ubiquitination further fine-tune its activity. Notably, deleting RIPK3 or MLKL does not consistently resolve inflammatory phenotypes in experimental models, suggesting that MLKL has context-dependent functions that extend beyond its role in necroptosis. In line with this idea, MLKL has been implicated in inflammatory signaling, interferon responses, and innate immunity, and is frequently targeted by viruses seeking to evade host defenses. Beyond infections, aberrant MLKL activation contributes to a wide range of chronic diseases, including atherosclerosis, cardiometabolic disorders, liver disease, neurodegeneration, and cancer. In these settings, sustained MLKL-mediated membrane damage and release of danger signals drive ongoing inflammation and tissue injury rather than protective cell elimination. In this review, we provide an overview of MLKL structure, activation, and regulation in both necroptotic and non-necroptotic contexts. We also discuss emerging therapeutic strategies aimed at targeting MLKL activation, membrane engagement, and stability, and highlight key unanswered questions that must be addressed to translate MLKL biology into effective clinical interventions.

Herein, a novel series of 4-piperidinylphenyl-linked thiazoles was synthesized as VEGFR2 inhibitors with potential cytotoxic activity against renal cancer. Most of the target compounds inhibited VEGFR2 enzyme at sub-micromolar IC50 values. Compounds 7c (IC50 = 0.073 ± 0.002 µM), 9b (IC50 = 0.049 ± 0.002 µM), and 9c (IC50 = 0.093 ± 0.003 µM) were the most potent, showing VEGFR2 inhibition superior to that of sunitinib (IC50 = 0.118 ± 0.003 µM). Furthermore, compounds 7c, 9b, and 9c effectively inhibited the growth of A498 renal cancer cells, with compound 7c being the most potent showing a one-digit IC50 value of 7.866 ± 0.27 µM. In addition, compound 7c revealed a potentially improved safety profile against non-cancerous normal cells, relative to sunitinib. The treatment of A498 renal cancer cells with compound 7c led to an apparent cell cycle arrest and a significant induction of apoptosis. A docking study was also conducted and revealed a proper orientation of compound 7c into the active site of VEGFR2.

Epigenetic and stress-response pathways play central roles in cancer progression and represent attractive therapeutic targets. In this study, a series of dipyridothiazine-1,2,3-triazole hybrids bearing p-fluorophenyl and p-trifluoromethylphenyl substituents was synthesized via efficient dipolar cycloaddition reactions. Structural characterization was performed using 1H, 13C, and 19F NMR spectroscopy and high-resolution mass spectrometry. Anticancer activity was evaluated using WST-1 and MTT assays against human cancer cell lines SNB-19 (glioblastoma), C32 (amelanotic melanoma), A549 (lung carcinoma), and MDA-MB-231 and MCF-7 (breast cancer), as well as normal HFF-1 fibroblasts and HaCaT keratinocytes, with doxorubicin and cisplatin as reference drugs. The hybrids TDT2b and TDT3b containing a p-trifluoromethylphenyl moiety showed the highest cytotoxicity and cancer cell selectivity. RT-qPCR analysis of H3, TP53, CDKN1A, BCL-2, and BAX expression for the lead compound TDT2b revealed modulation of chromatin organization, p53-dependent stress responses, apoptosis, and cell cycle regulation. Molecular docking studies with human histone deacetylase 6 (HDAC6) demonstrated favorable binding of TDT2b and TDT3b, supporting their role as potential epigenetic anticancer agents.

Nonsyndromic hearing loss (NSHL) is a highly prevalent, genetically heterogeneous condition, yet its molecular basis in the Singaporean population remains underexplored. We performed whole-exome sequencing and integrative bioinformatics analysis in 115 patients with NSHL to define population-specific genetic biomarkers. A molecular diagnosis was achieved in 57% of cases, with 76% of identified variants classified as pathogenic or likely pathogenic and 24% exhibiting high pathogenic potential. Common East Asian NSHL genes, including GJB2, SLC26A4, and OTOF, were frequently detected alongside less prevalent genes such as ACTG1, CEACAM16, COL11A2, DIAPH1, KCQN4, MYH14, MYO6, MYO7A, MYO15A, SLC17A8, SMPX, STRC, TJP2, TMC1, TMPRSS3, highlighting extensive genetic heterogeneity. Notably, multiple novel variants, including MYO6 c.554-2A>G, and TNC p.N750Y, were identified, expanding the known mutational spectrum of NSHL. Genotype-phenotype correlations revealed that GJB2 variants were primarily associated with mild to moderate hearing loss, whereas SLC26A4 variants correlated with severe to profound phenotypes in the Singaporean populations. Collectively, our study provides important insights into the genetic architecture of NSHL in Singapore's population. In addition, it supports improved molecular diagnosis yield and informed clinical management decisions as well as the advancement of precision medicine approaches aimed at reducing the burden of hearing loss in the region.

Recent advances in single-cell RNA sequencing (scRNA-seq) have substantially deepened our understanding of adult hippocampal neurogenesis (AHN), enabling the detection of neural stem cells, progenitors, and immature neurons in postmortem human brain tissue and revealing how these populations are altered in neurological disease. Additionally, scRNA-seq enables the identification of disease-specific cell subtypes and distinct gene expression signatures associated with neurological disorders, many of which are linked to alterations in AHN and cognitive function. Such cellular- and molecular-level insights into neurological disease mechanisms provide a strong foundation for the development of targeted therapeutic strategies. Indeed, scRNA-seq has also emerged as a powerful tool in drug discovery and development across multiple disease areas, including cancer, cardiovascular disorders, and neurological conditions. In this review, we offer a comprehensive and integrative perspective on the cellular and molecular landscape of human hippocampal neurogenesis, the pathological mechanisms underlying neurological disorders, and their implications for therapeutic development.

Glutamate metabotropic receptors (mGluRs) and their molecular partners at the postsynaptic density (PSD) represent a highly dynamic molecular hub that integrates multiple neurotransmitter signals and regulates synaptic plasticity and metaplasticity, which are putatively involved in the pathophysiology of psychiatric illnesses, including schizophrenia. Group I mGluRs (mGluR1 and mGluR5) interact with PSD adaptor and scaffolding proteins, such as Homer, Shank, Norbin, and PICK1, as well as intracellular downstream effectors, creating a molecular network that resembles a Lego-like structure, where modular protein interactions fine-tune glutamatergic transmission. Evidence from preclinical research indicates that dysregulation of mGluR expression and function, along with disrupted PSD protein expression, may contribute to the pathophysiology of schizophrenia by altering glutamatergic neurotransmission and synaptic stability. Antipsychotic mechanisms of action may involve, at least in part, the modulation of mGluR activity mediated through PSD proteins. Notably, novel agents that enhance spinogenesis by acting at the level of PSD proteins, such as SPG302, may open promising avenues for therapeutics aimed at restoring synaptic integrity. While Group I mGluRs dominate postsynaptic regulation, Group II (mGluR2/3) and III (mGluR4/6/7/8) receptors -primarily presynaptic- inhibit neurotransmitter release and plasticity, offering complementary therapeutic avenues. Emerging strategies, such as allosteric modulators of mGluRs, aim to rebalance synaptic signaling in treatment-resistant schizophrenia. This review synthesizes how PSD proteins and mGluRs interact in schizophrenia, exploring their potential as druggable targets for novel therapies.

Nintedanib (NTD) is an inhibitor of several tyrosine kinases whose role in the pathogenesis of idiopathic pulmonary fibrosis (IPF) is well recognized. Therefore, NTD was approved for the management of IPF about ten years ago. NTD has been demonstrated to have immunomodulatory effects in vitro. We now evaluated the effects of NTD on monocyte/macrophage phenotype isolated from IPF patients treated with NTD. Monocytes were isolated from IPF patients naïve for treatments and used as such or differentiated into M1- and M2-like macrophages. The cellular phenotype (characterized by the expression pro- and anti-fibrotic surface markers) and responsiveness (characterized by oxidative stress and cytokine expression/release) were evaluated, at T0 (before treatment starts) and after 6 months of treatment with a 150 mg capsule of NTD twice a day (T1). Following differentiation, both M1 and M2 macrophage populations, derived from monocytes isolated from patients treated with NTD, present a higher percentage of cells positive for anti-fibrotic CD80/CD86 and expressing less profibrotic CD206/CD163. Importantly, gene expression and release of the pro-fibrotic factor TGF-β were significantly decreased at T1. These results show that although it does not have a direct effect on monocyte phenotype/responsiveness, NTD in vivo appears to prime monocytes to differentiate preferentially towards an anti-fibrotic macrophage phenotype, suggesting that it has an immunomodulatory effect on macrophage polarization. This data leads us to hypothesize that NTD could also induce this change in vivo, thus contributing to the improvement of the patient's fibrotic state.