3D-Printed Latticed Microneedle Array Patches for Tunable and Versatile Intradermal Delivery.

Using high-resolution 3D printing, a novel class of microneedle array patches (MAPs) is introduced, called latticed MAPs (L-MAPs). Unlike most MAPs which are composed of either solid structures or hollow needles, L-MAPs incorporate tapered struts that form hollow cells capable of trapping liquid droplets. The lattice structures can also be coated with traditional viscous coating formulations, enabling both liquid- and solid-state cargo delivery, on a single patch. Here, a library of 43 L-MAP designs is generated and in-silico modeling is used to down-select optimal geometries for further characterization. Compared to traditionally molded and solid-coated MAPs, L-MAPs can load more cargo with fewer needles per patch, enhancing cargo loading and drug delivery capabilities. Further, L-MAP cargo release kinetics into the skin can be tuned based on formulation and needle geometry. In this work, the utility of L-MAPs as a platform is demonstrated for the delivery of small molecules, mRNA lipid nanoparticles, and solid-state ovalbumin protein. In addition, the production of programmable L-MAPs is demonstrated with tunable cargo release profiles, enabled by combining needle geometries on a single patch.

A Decade of Computational Mass Spectrometry from Reference Spectra to Deep Learning.

Computational methods are playing an increasingly important role as a complement to conventional data evaluation methods in analytical chemistry, and particularly mass spectrometry. Computational mass spectrometry (CompMS) is the application of computational methods on mass spectrometry data. Herein, advances in CompMS for small molecule chemistry are discussed in the areas of spectral libraries, spectrum prediction, and tentative structure identification (annotation): Automatic spectrum curation is facilitating the expansion of openly available spectral libraries, a crucial resource both for compound annotation directly and as a resource for machine learning algorithms. Spectrum prediction and molecular fingerprint prediction have emerged as two key approaches to compound annotation. For both, multiple methods based on classical machine learning and deep learning have been developed. Driven by advances in deep learning-based generative chemistry, de novo structure generation from fragment spectra is emerging as a new field of research. This review highlights key publications in these fields, including our approaches RMassBank (automatic spectrum curation) and MSNovelist (de novo structure generation).

Targeting RNA with small molecules, from RNA structures to precision medicines: IUPHAR review: 40.

RNA plays important roles in regulating both health and disease biology in all kingdoms of life. Notably, RNA can form intricate three-dimensional structures, and their biological functions are dependent on these structures. Targeting the structured regions of RNA with small molecules has gained increasing attention over the past decade, because it provides both chemical probes to study fundamental biology processes and lead medicines for diseases with unmet medical needs. Recent advances in RNA structure prediction and determination and RNA biology have accelerated the rational design and development of RNA-targeted small molecules to modulate disease pathology. However, challenges remain in advancing RNA-targeted small molecules towards clinical applications. This review summarizes strategies to study RNA structures, to identify small molecules recognizing these structures, and to augment the functionality of RNA-binding small molecules. We focus on recent advances in developing RNA-targeted small molecules as potential therapeutics in a variety of diseases, encompassing different modes of actions and targeting strategies. Furthermore, we present the current gaps between early-stage discovery of RNA-binding small molecules and their clinical applications, as well as a roadmap to overcome these challenges in the near future.

Therapeutic Opportunities in Breast Cancer by Targeting Macrophage Migration Inhibitory Factor as a Pleiotropic Cytokine.

As a heterogeneous disease, breast cancer (BC) has been characterized by the uncontrolled proliferation of mammary epithelial cells. The tumor microenvironment (TME) also contains inflammatory cells, fibroblasts, the extracellular matrix (ECM), and soluble factors that all promote BC progression. In this sense, the macrophage migration inhibitory factor (MIF), a pleiotropic pro-inflammatory cytokine and an upstream regulator of the immune response, enhances breast tumorigenesis through escalating cancer cell proliferation, survival, angiogenesis, invasion, metastasis, and stemness, which then brings tumorigenic effects by activating key oncogenic signaling pathways and inducing immunosuppression. Against this background, this review was to summarize the current understanding of the MIF pathogenic mechanisms in cancer, particularly BC, and address the central role of this immunoregulatory cytokine in signaling pathways and breast tumorigenesis. Furthermore, different inhibitors, such as small molecules as well as antibodies (Abs) or small interfering RNA (siRNA) and their anti-tumor effects in BC studies were examined. Small molecules and other therapy target MIF. Considering MIF as a promising therapeutic target, further clinical evaluation of MIF-targeted agents in patients with BC was warranted.

An update on small molecule compounds targeting synthetic lethality for cancer therapy.

Targeting cancer-specific vulnerabilities through synthetic lethality (SL) is an emerging paradigm in precision oncology. A SL strategy based on PARP inhibitors has demonstrated clinical efficacy. Advances in DNA damage response (DDR) uncover novel SL gene pairs. Beyond BRCA-PARP, emerging SL targets like ATR, ATM, DNA-PK, CHK1, WEE1, CDK12, RAD51, and RAD52 show clinical promise. Selective and bioavailable small molecule inhibitors have been developed to induce SL, but optimization for potency, specificity, and drug-like properties remains challenging. This article illuminated recent progress in the field of medicinal chemistry centered on the rational design of agents capable of eliciting SL specifically in neoplastic cells. It is envisioned that innovative strategies harnessing SL for small molecule design may unlock novel prospects for targeted cancer therapeutics going forward.

Small molecules targeting mitochondria as an innovative approach to cancer therapy.

Cellular death evasion is a defining characteristic of human malignancies and a significant contributor to therapeutic inefficacy. As a result of oncogenic inhibition of cell death mechanisms, established therapeutic regimens seems to be ineffective. Mitochondria serve as the cellular powerhouses, but they also function as repositories of self-destructive weaponry. Changes in the structure and activities of mitochondria have been consistently documented in cancer cells. In recent years, there has been an increasing focus on using mitochondria as a targeted approach for treating cancer. Considerable attention has been devoted to the development of delivery systems that selectively aim to deliver small molecules called "mitocans" to mitochondria, with the ultimate goal of modulating the physiology of cancer cells. This review summarizes the rationale and mechanism of mitochondrial targeting with small molecules in the treatment of cancer, and their impact on the mitochondria. This paper provides a concise overview of the reasoning and mechanism behind directing treatment towards mitochondria in cancer therapy, with a particular focus on targeting using small molecules. This review also examines diverse small molecule types within each category as potential therapeutic agents for cancer.

To Elucidate the Effective Role of Small Molecule Regulated lncRNAs in the Tumour Microenvironment in Immunotherapy.

The tumour microenvironment is a complex ecosystem comprising tumour cells, and cancer stem cells, and support cells that facilitate cancer growth and escape from treatment. Cancer immunotherapy focuses on immunological pathways such as PD-1/PD-L1 and CTLA-4 to target cancer stem cells via immune cells. Small molecules, immune checkpoint inhibitors, are employed to impede tumour growth by targeting cellular mediators in the cell cycle and tumour microenvironment. Long non-coding RNAs (lncRNAs) affect the growth, development, motility, and differentiation of cancer cells by regulating gene expression and are therefore considered important biomarkers. Small molecules demonstrate their effects on gene expression and behaviour of cancer cells by inducing lncRNAs. This relationship between lncRNAs and small molecules is of great importance in terms of their impact on cancer and the tumour microenvironment. The evaluation of this communication in clinical trials is of critical importance for the development of therapeutic strategies. This review provides a detailed description of the role of lncRNAs and small molecules in the tumour microenvironment and their relationship with cancer stem cells. Thus, the potential of controlling lncRNAs and using anti-cancer small molecules in TME to improve the efficacy of cancer therapy was evaluated.

Promising Therapeutic Strategies for Hematologic Malignancies: Innovations and Potential.

In this review we explore innovative approaches in the treatment of hematologic cancers by combining various therapeutic modalities. We discuss the synergistic potential of combining inhibitors targeting different cellular pathways with immunotherapies, molecular therapies, and hormonal therapies. Examples include combining PI3K inhibitors with proteasome inhibitors, NF-κB inhibitors with immunotherapy checkpoint inhibitors, and neddylation inhibitors with therapies targeting the tumor microenvironment. Additionally, we discuss the potential use of small molecules and peptide inhibitors in hematologic cancer treatment. These multidimensional therapeutic combinations present promising strategies for enhancing treatment efficacy and overcoming resistance mechanisms. However, further clinical research is required to validate their effectiveness and safety profiles in hematologic cancer patients.

Reviewing the Synthesis and Clinical Application of FDA-Approved Anticancer Medications.

Cancer is a disease that affects people of all ages, socioeconomic backgrounds, genders, and demographics. It places a significant burden not just on those who are diagnosed but also on their families and communities. Targeted therapeutic medications have surpassed more conventional forms of chemotherapy in terms of both their effectiveness and safety, which leads to their rapid ascent to the forefront of cancer treatment. A growing number of small molecules have been created for the treatment of cancer, and several of these drugs have been approved to be sold in the market by the Food and Drug Administration of the United States. Small molecule targeted anticancer therapies have made significant progress in recent years, yet they continue to struggle with a number of obstacles, including a low response rate and drug resistance. We have carried out an exhaustive study on approved small-molecule targeted anticancer medications, as well as important drug candidates. This review describes the significance of approved anticancer drugs from 2021 to 2024, clinically active anticancer drugs, and the methods used for their synthesis.

Small Molecule-Mediated Stage-Specific Reprogramming of MSCs to Hepatocyte-Like Cells and Hepatic Tissue for Liver Injury Treatment.

BACKGROUND: Derivation of hepatocytes from stem cells has been established through various protocols involving growth factor (GF) and small molecule (SM) agents, among others. However, mesenchymal stem cell-based derivation of hepatocytes still remains expensive due to the use of a cocktail of growth factors, and a long duration of differentiation is needed, thus limiting its potential clinical application. METHODS: In this study, we developed a chemically defined differentiation strategy that is exclusively based on SM and takes 14 days, while the GF-based protocol requires 23-28 days. RESULTS: We optimized a stage-specific differentiation protocol for the differentiation of rat bone marrow-derived mesenchymal stem cells (MSCs) into functional hepatocyte-like cells (dHeps) that involved four stages, i.e., definitive endoderm (DE), hepatic competence (HC), hepatic specification (HS) and hepatic differentiation and growth. We further generated hepatic tissue using human decellularized liver extracellular matrix and compared it with hepatic tissue derived from the growth factor-based protocol at the transcriptional level. dHep, upon transplantation in a rat model of acute liver injury (ALI), was capable of ameliorating liver injury in rats and improving liver function and tissue damage compared to those in the ALI model. CONCLUSIONS: In summary, this is the first study in which hepatocytes and hepatic tissue were derived from MSCs utilizing a stage-specific strategy by exclusively using SM as a differentiation factor.

Central nervous system metastases in advanced non-small cell lung cancer: A review of the therapeutic landscape.

Up to 40% of patients with non-small cell lung cancer (NSCLC) develop central nervous system (CNS) metastases. Current treatments for this subgroup of patients with advanced NSCLC include local therapies (surgery, stereotactic radiosurgery, and, less frequently, whole-brain radiotherapy), targeted therapies for oncogene-addicted NSCLC (small molecules, such as tyrosine kinase inhibitors, and antibody-drug conjugates), and immune checkpoint inhibitors (as monotherapy or combination therapy), with multiple new drugs in development. However, confirming the intracranial activity of these treatments has proven to be challenging, given that most lung cancer clinical trials exclude patients with untreated and/or progressing CNS metastases, or do not include prespecified CNS-related endpoints. Here we review progress in the treatment of patients with CNS metastases originating from NSCLC, examining local treatment options, systemic therapies, and multimodal therapeutic strategies. We also consider challenges regarding assessment of treatment response and provide thoughts around future directions for managing CNS disease in patients with advanced NSCLC.

An investigation of nano- and micron-sized carriers based on calcium carbonate and polylactic acid for oral administration of siRNA.

BACKGROUND: Oral delivery of small interfering RNAs (siRNAs) draws significant attention, but the gastrointestinal tract (GIT) has many biological barriers that limit the drugs' bioavailability. The aim of this work was to investigate the potential of micro- and nano-sized CaCO3 and PLA carriers for oral delivery of siRNA and reveal a relationship between the physicochemical features of these carriers and their biodistribution. RESEARCH DESIGN AND METHODS: In vitro stability of carriers was investigated in simulated gastric and intestinal fluids. Toxicity and cellular uptake were investigated on Caco-2 cells. The biodistribution profiles of the developed CaCO3 and PLA carriers were examined using different visualization methods, including SPECT, fluorescence imaging, radiometry, and histological analysis. The delivery efficiency of siRNA loaded carriers was investigated both in vitro and in vivo. RESULTS: Micro-sized carriers were accumulated in the stomach and later localized in the colon tissues. The nanoscale particles (100-250 nm) were distributed in the colon tissues. nPLA was also detected in small intestine. The developed carriers can prevent siRNA from premature degradation in GIT media. CONCLUSION: Our results reveal how the physicochemical properties of the particles, including their size and material type can affect their biodistribution profile and oral delivery of siRNA.

Selective, Temporary Postoperative Inhibition of Lymphangiogenesis by Integrin α5ß1 Blockade Improves Allograft Survival in a Murine Model of High-Risk Corneal Transplantation.

Background: Corneal inflammatory hem- and lymphangiogenesis significantly increase the risk for immune rejection after subsequent allogeneic corneal transplantation. The purpose of this study was to analyze the impact of temporary selective inhibition of lymphangiogenesis after transplantation on graft survival. Methods: Allogeneic transplantation from C57BL/6 mice to BalbC mice was performed as "high-risk" keratoplasty in a prevascularized corneal host bed (suture-induced inflammatory corneal neovascularization). The treatment group received integrin α5ß1-blocking small molecules (JSM6427) at the time of transplantation and for two weeks afterwards. Control mice received a vehicle solution. Grafts were evaluated weekly for graft rejection using an opacity score. At the end of the follow-up, immunohistochemical staining of corneal wholemounts for lymphatic vessels as well as CD11b+ immune cells was performed. Results: Temporary postoperative inhibition of lymphangiogenesis by JSM6427 improved the corneal graft survival significantly. At the end of the follow-up, no significant reduction in CD11b+ immunoreactive cells within the graft compared to controls was found. Conclusions: The significant improvement of corneal graft survival by the selective, temporary postoperative inhibition of lymphangiogenesis after keratoplasty using integrin antagonists shows the impact of lymphatic vessels in the early postoperative phase. Retarding lymphatic vessel ingrowth into the graft might be sufficient for the shift to immunological tolerance in the postoperative period, even after high-risk keratoplasty.

Structural Unfolding of G-Quadruplexes: From Small Molecules to Antisense Strategies.

G-quadruplexes (G4s) are non-canonical nucleic acid secondary structures that have gathered significant interest in medicinal chemistry over the past two decades due to their unique structural features and potential roles in a variety of biological processes and disorders. Traditionally, research efforts have focused on stabilizing G4s, while in recent years, the attention has progressively shifted to G4 destabilization, unveiling new therapeutic perspectives. This review provides an in-depth overview of recent advances in the development of small molecules, starting with the controversial role of TMPyP4. Moreover, we described effective metal complexes in addition to G4-disrupting small molecules as well as good G4 stabilizing ligands that can destabilize G4s in response to external stimuli. Finally, we presented antisense strategies as a promising approach for destabilizing G4s, with a particular focus on 2'-OMe antisense oligonucleotide, peptide nucleic acid, and locked nucleic acid. Overall, this review emphasizes the importance of understanding G4 dynamics as well as ongoing efforts to develop selective G4-unfolding strategies that can modulate their biological function and therapeutic potential.

The Inferential Binding Sites of GCGR for Small Molecules Using Protein Dynamic Conformations and Crystal Structures.

Glucagon receptor (GCGR) is a class B1 G-protein-coupled receptor that plays a crucial role in maintaining human blood glucose homeostasis and is a significant target for the treatment of type 2 diabetes mellitus (T2DM). Currently, six small molecules (Bay 27-9955, MK-0893, MK-3577, LY2409021, PF-06291874, and LGD-6972) have been tested or are undergoing clinical trials, but only the binding site of MK-0893 has been resolved. To predict binding sites for other small molecules, we utilized both the crystal structure of the GCGR and MK-0893 complex and dynamic conformations. We docked five small molecules and selected the best conformation based on binding mode, docking score, and binding free energy. We performed MD simulations to verify the binding mode of the selected small molecules. Moreover, when selecting conformations, results of competitive binding were referred to. MD simulation indicated that Bay 27-9955 exhibits moderate binding stability in Pocket 3. MK-3577, LY2409021, and PF-06291874 exhibited highly stable binding to Pocket 2, consistent with experimental results. However, LY2409021 may also bind to Pocket 5. Additionally, LGD-6972 exhibited relatively stable binding in Pocket 5. We also conducted structural modifications of LGD-6972 based on the results of MD simulations and predicted its analogues' bioavailability, providing a reference for the study of GCGR small molecules.

Upadacitinib for Acute Severe Ulcerative Colitis: A Systematic Review.

Acute severe ulcerative colitis (ASUC) remains a clinical challenge associated with considerable morbidity, including colectomy. Upadacitinib (UPA), a selective Janus kinase (JAK)-1 inhibitor, is approved for moderate-to-severe ulcerative colitis in patients intolerant or not responding to tumor necrosis factor-alpha inhibitors. It has also increasingly been used off-label for ASUC. We performed a systematic review of all available literature on UPA in ASUC. We identified 11 studies, with a pooled total of 55 patients. Most patients experienced rapid and sustained improvement. Colectomy rate at 90 days was 16.3%. Among those who did not get colectomy, 80% were in steroid-free remission at follow-up. The reported adverse events were low, including 2 venous thromboembolic events. Overall, UPA appears to represent a safe and effective therapy for ASUC.

This systematic review evaluates the efficacy and safety of upadacitinib in treating acute severe ulcerative colitis (ASUC). Results indicate that upadacitinib is a promising option for ASUC patients, with a low colectomy rate and high rates of steroid-free clinical remission.

Recent advances on metal-organic framework-based electrochemical sensors for determination of organic small molecules.

Metal-organic frameworks (MOFs) are an extraordinarily versatile class of porous materials renowned for their intricate three-dimensional skeletal architectures and exceptional chemical properties. These extraordinary attributes have pushed MOFs into the vanguard of diverse disciplines such as microporous conduction, catalysis, separation, biomedical engineering, and electrochemical sensing. The focus of this review is to offer a comprehensive summary of recent advancements in designing MOF-based electrochemical sensors for detecting organic small molecules. offer a comprehensive survey of the recent progress in the methodologies adopted for the construction of MOF composites, covering template-assisted synthesis, Modification in synthesis, and post-synthesis modification. In addition, we discuss the practical application of MOF-based electrochemical sensors in the detection of organic small molecules. Our findings highlight the superior electrochemical sensing capabilities of these novel composites compared to those of their pristine counterparts. In conclusion, we provide a condensed perspective on the potential future trajectories in this domain, underscoring the impetus for continued enquiry and enhancement of MOF composite assemblies. With sustained investigation, the horizon appears bright for electrochemical sensing of small organic molecules and their myriad applications.

GNN-DDAS: Drug discovery for identifying anti-schistosome small molecules based on graph neural network.

Schistosomiasis is a tropical disease that poses a significant risk to hundreds of millions of people, yet often goes unnoticed. While praziquantel, a widely used anti-schistosome drug, has a low cost and a high cure rate, it has several drawbacks. These include ineffectiveness against schistosome larvae, reduced efficacy in young children, and emerging drug resistance. Discovering new and active anti-schistosome small molecules is therefore critical, but this process presents the challenge of low accuracy in computer-aided methods. To address this issue, we proposed GNN-DDAS, a novel deep learning framework based on graph neural networks (GNN), designed for drug discovery to identify active anti-schistosome (DDAS) small molecules. Initially, a multi-layer perceptron was used to derive sequence features from various representations of small molecule SMILES. Next, GNN was employed to extract structural features from molecular graphs. Finally, the extracted sequence and structural features were then concatenated and fed into a fully connected network to predict active anti-schistosome small molecules. Experimental results showed that GNN-DDAS exhibited superior performance compared to the benchmark methods on both benchmark and real-world application datasets. Additionally, the use of GNNExplainer model allowed us to analyze the key substructure features of small molecules, providing insight into the effectiveness of GNN-DDAS. Overall, GNN-DDAS provided a promising solution for discovering new and active anti-schistosome small molecules.

Current Treatments, Emerging Therapeutics, and Natural Remedies for Inflammatory Bowel Disease.

Inflammatory bowel disease (IBD) is a chronic, lifelong disorder characterized by inflammation of the gastrointestinal (GI) tract. The exact etiology of IBD remains incompletely understood due to its multifaceted nature, which includes genetic predisposition, environmental factors, and host immune response dysfunction. Currently, there is no cure for IBD. This review discusses the available treatment options and the challenges they present. Importantly, we examine emerging therapeutics, such as biologics and immunomodulators, that offer targeted treatment strategies for IBD. While many IBD patients do not respond adequately to most biologics, recent clinical trials combining biologics with small-molecule drugs (SMDs) have provided new insights into improving the IBD treatment landscape. Furthermore, numerous novel and specific therapeutic targets have been identified. The high cost of IBD drugs poses a significant barrier to treatment, but this challenge may be alleviated with the development of more affordable biosimilars. Additionally, emerging point-of-care protein biomarkers from serum and plasma are showing potential for enhancing the precision of IBD diagnosis and prognosis. Several natural products (NPs), including crude extracts, small molecules, and peptides, have demonstrated promising anti-inflammatory activity in high-throughput screening (HTS) systems and advanced artificial intelligence (AI)-assisted platforms, such as molecular docking and ADMET prediction. These platforms are advancing the search for alternative IBD therapies derived from natural sources, potentially leading to more affordable and safer treatment options with fewer side effects.

Rational Design and Facile Preparation of Palladium-based Electrocatalysts for Small Molecules Oxidation.

Direct liquid fuel cells (DLFCs) can convert the chemical energy of small organic molecules directly into electrical energy, which is a promising technique and always calls for electrocatalysts with high activity, stability and selectivity. Palladium (Pd)-based catalysts for DLFCs have been widely studied with the pursuit of ultra-high performance, however, most of the preparation routes require complex agents, multi-operation steps, even extreme experimental conditions, which are high-cost, energy-consuming, and not conducive to the scalable and sustainable production of catalysts. In this review, the recent progresses on not only the rational design strategies, but also the facile preparation methods of Pd-based electrocatalysts for small molecules oxidation reaction (SMOR) are comprehensively summarized. Based on the principles of green chemistry in material synthesis, the basic rules of "facile method" have been restricted, and the fabrication processes, perks and drawbacks, as well as practical applications of the "real" facile methods have been highlighted. The landscape of this review is to facilitate the mild preparation of efficient Pd-based electrocatalysts for SMOR, that is, to achieve a balance between "facile preparation" and "outstanding performance", thereby to stimulate the huge potential of sustainable nano-electrocatalysts in various research and industrial fields.