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Copyright of University Chemistry is the property of Peking University, College of Chemistry & Molecular Engineering and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Immune checkpoint inhibitors (ICIs) are used to relieve and refuel anti-tumor immunity by blocking the interaction, transcription, and translation of co-inhibitory immune checkpoints or degrading co-inhibitory immune checkpoints. Thousands of small molecule drugs or biological materials, especially antibody-based ICIs, are actively being studied and antibodies are currently widely used. Limitations, such as anti-tumor efficacy, poor membrane permeability, and unneglected tolerance issues of antibody-based ICIs, remain evident but are thought to be overcome by small molecule drugs. Recent structural studies have broadened the scope of candidate immune checkpoint molecules, as well as innovative chemical inhibitors. By way of comparison, small molecule drug-based ICIs represent superior oral bioavailability and favorable pharmacokinetic features. Several ongoing clinical trials are exploring the synergetic effect of ICIs and other therapeutic strategies based on multiple ICI functions, including immune regulation, anti-angiogenesis, and cell cycle regulation. In this review we summarized the current progression of small molecule ICIs and the mechanism underlying immune checkpoint proteins, which will lay the foundation for further exploration. [ABSTRACT FROM AUTHOR]

Snakebite envenoming results in ~100,000 deaths per year, with close to four times as many victims left with life-long sequelae. Current antivenom therapies have several limitations including high cost, variable cross-snake species efficacy and a requirement for intravenous administration in a clinical setting. Nextgeneration snakebite therapies are being widely investigated with the aim to improve cost, efficacy, and safety. In recent years several small molecule drugs have shown considerable promise for snakebite indication, with oral bioavailability particularly promising for community delivery rapidly after a snakebite. However, only two such drugs have entered clinical development for snakebite. To offset the risk of attrition during clinical trials and to better explore the chemical space for small molecule venom toxin inhibitors, here we describe the first high throughput drug screen against snake venom metalloproteinases (SVMPs)--a pathogenic toxin family responsible for causing haemorrhage and coagulopathy. Following validation of a 384-well fluorescent enzymatic assay, we screened a repurposed drug library of 3,547 compounds against five geographically distinct and toxin variable snake venoms. Our drug screen resulted in the identification of 14 compounds with pan-species inhibitory activity. Following secondary potency testing, four SVMP inhibitors were identified with nanomolar EC50s comparable to the previously identified matrix metalloproteinase inhibitor marimastat and superior to the metal chelator dimercaprol, doubling the current global portfolio of SVMP inhibitors. Following analysis of their chemical structure and ADME properties, two hit-tolead compounds were identified. These clear starting points for the initiation of medicinal chemistry campaigns provide the basis for the first ever designer snakebite specific small molecules. [ABSTRACT FROM AUTHOR]

Copyright of Journal of Diagnosis & Therapy on Dermato-venereology is the property of Dermatology Hospital of Southern Medical University and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

China recently proposed a 6-year regulatory exclusivity period to incentivize research and development in new drugs, orphan drugs, and pediatric drugs. Our study assessed the generic entry status and the duration of market exclusivity for 356 new small-molecule drugs approved in China from 2003 to 2020. Of these, 155 drugs (43.5%) experienced generic entry, with a median market exclusivity period of 5.6 years (interquartile range: 2.4-9.4). Imported drugs, oral common-release agents, and drugs for the nervous system were more prone to generic entry (P < 0.001, P = 0.039, and P < 0.001, respectively). Domestic new drugs had a longer median market exclusivity (8.4 years) compared to imported drugs (5.7 years). Market exclusivity varied from 3.6 years for antineoplastic and immunomodulating agents to 6.8 years for drugs for the alimentary tract and metabolism. If the proposed 6-year regulatory exclusivity is implemented, the market exclusivity duration for new drugs is anticipated to double. It is essential for the government to carefully weigh the impact of such policies on balancing innovation incentives and ensuring drug affordability. [ABSTRACT FROM AUTHOR]

The COVID-19, AIDS, influenza, and other infectious viral diseases have a significant impact on human health, and new antiviral drugs are continuously emerging to combat these diseases. Herein, aiming at anti-SARS-CoV-2, anti-HIV, and anti-influenza virus, the latest research progress of small-molecule drugs is reported in this paper. The discovery process, mechanism of action, synthesis process, and structure--activity relationship research of each drug are systematically expounded to promote antiviral drug research and development. [ABSTRACT FROM AUTHOR]

The estrogen receptor (ER) is a classical receptor protein that plays a crucial role in mediating multiple signaling pathways in various target organs. It has been shown that ER-targeting therapies inhibit breast cancer cell proliferation, enhance neuronal protection, and promote osteoclast formation. Several drugs have been designed to specifically target ER in ER-positive (ER+) breast cancer, including selective estrogen receptor modulators (SERM) such as Tamoxifen. However, the emergence of drug resistance in ER+ breast cancer and the potential side effects on the endometrium which has high ER expression has posed significant challenges in clinical practice. Recently, novel ER-targeted drugs, namely, selective estrogen receptor degrader (SERD) and selective estrogen receptor covalent antagonist (SERCA) have shown promise in addressing these concerns. This paper provides a comprehensive review of the structural functions of ER and highlights recent advancements in SERD and SERCA-related small molecule drugs, especially focusing on their structural optimization strategies and future optimization directions. Additionally, the therapeutic potential and challenges of novel SERDs and SERCAs in breast cancer and other ER-related diseases have been discussed. [ABSTRACT FROM AUTHOR]

Rheumatoid arthritis (RA) is a type of chronic autoimmune and inflammatory disease. In the pathological process of RA, the alteration of fibroblast-like synoviocyte (FLS) and its related factors is the main influence in the clinic and fundamental research. In RA, FLS exhibits a uniquely aggressive phenotype, leading to synovial hyperplasia, destruction of the cartilage and bone, and a pro-inflammatory environment in the synovial tissue for perpetuation and progression. Evidently, it is a highly promising way to target the pathological function of FLS for new anti-RA drugs. Based on this, we summed up the pathological mechanism of RA-FLS and reviewed the recent progress of small molecule drugs, including the synthetic small molecule compounds and natural products targeting RA-FLS. In the end, there were some views for further action. Compared with MAPK and NF-κB signaling pathways, the JAK/STAT signaling pathway has great potential for research as targets. A small number of synthetic small molecule compounds have entered the clinic to treat RA and are often used in combination with other drugs. Meanwhile, most natural products are currently in the experimental stage, not the clinical trial stage, such as triptolide. There is an urgent need to unremittingly develop new agents for RA. [ABSTRACT FROM AUTHOR]

Copyright of University Chemistry is the property of Peking University, College of Chemistry & Molecular Engineering and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

The "do not eat me" signaling pathway is extremely active in tumor cells, providing a means for these cells to elude macrophage phagocytosis and escape immune surveillance. Representative markers of this pathway, such as CD47 and CD24, are highly expressed in numerous tumors. The interaction of SIRPα with CD47 reduces the accumulation of non-myosin ⅡA on the cell membrane. The combination of CD24 and Siglec10 ultimately leads to the recruitment of SHP-1 or SHP-2 to reduce signal transduction. Both of them weaken the ability of macrophages to engulf tumor cells. Blocking the mutual recognition between CD47-SIRPα or CD24-Siglec10 using large molecular proteins or small molecular drugs represents a promising avenue for tumor immunotherapy. Doing so can inhibit signal transduction and enhance macrophage clearance rates of cancer cells. In this paper, we summarize the characteristics of the drugs that affect the "do not eat me" signaling pathway via classical large molecular proteins and small molecule drugs, which target the CD47-SIRPα and CD24-Siglec10 signaling pathways, which target the CD47-SIRPα and CD24-Siglec10 signaling pathways. We expect it will offer insight into the development of new drugs centered on blocking the "do not eat me" signaling pathway. [ABSTRACT FROM AUTHOR]

Malignant gliomas are known to be one of the most difficult diseases to diagnose and treat because of the infiltrative growth pattern, rapid progression, and poor prognosis. Many antitumor drugs are not ideal for the treatment of gliomas due to the blood-brain barrier. Temozolomide (TMZ) is a DNA alkylating agent that can cross the blood-brain barrier. As the only first-line chemotherapeutic drug for malignant gliomas at present, TMZ is widely utilized to provide a survival benefit; however, some patients are inherently insensitive to TMZ. In addition, patients could develop acquired resistance during TMZ treatment, which limits antitumor efficacy. To clarify the mechanism underlying TMZ resistance, numerous studies have provided multilevel solutions, such as improving the effective concentration of TMZ in tumors and developing novel small molecule drugs. This review discusses the in-depth mechanisms underlying TMZ drug resistance, thus aiming to provide possibilities for the establishment of personalized therapeutic strategies against malignant gliomas and the accelerated development and transformation of new targeted drugs. [ABSTRACT FROM AUTHOR]

Sphingosine-1-phosphate (S1P) is a sphingolipid mediator that exerts a variety of biological functions, including immune, cardiovascular, and neurological regulation as well as tumor promotion, through high-affinity G protein-coupled receptors (S1P1-5). It has been reported that circulating S1P levels remain higher in patients with psoriasis than in healthy individuals and that circulating S1P levels do not decrease after anti-TNF-α treatment in those patients. The S1P-S1PR signaling system plays an important role in inhibiting keratinocyte proliferation, regulating lymphocyte migration, and promoting angiogenesis, thus contributing to the regulation of psoriasis pathogenesis. Here, we review the mechanisms by which S1P-S1PR signaling affects the development of psoriasis and the available clinical/preclinical evidence for targeting S1P-S1PR in psoriasis. S1P-S1PR signaling mechanisms may partially explain the link between psoriasis and its comorbidities. Although the detailed mechanisms remain to be elucidated, S1P may be a new target for future psoriasis remission. [ABSTRACT FROM AUTHOR]

Background: High-throughput screening (HTS) of small molecule drug libraries has greatly facilitated the discovery of new cancer drugs. However, most phenotypic screening platforms used in the field of oncology are based solely on cancer cell populations and do not allow for the identification of immunomodulatory agents. Methods: We developed a phenotypic screening platform based on a miniaturized co-culture system with human colorectal cancer- and immune cells, providing a model that recapitulates part of the tumor immune microenvironment (TIME) complexity while simultaneously being compatible with a simple image-based readout. Using this platform, we screened 1,280 small molecule drugs, all approved by the Food and Drug Administration (FDA), and identified statins as enhancers of immune cell-induced cancer cell death. Results: The lipophilic statin pitavastatin had the most potent anti-cancer effect. Further analysis demonstrated that pitavastatin treatment induced a pro-inflammatory cytokine profile as well as an overall pro-inflammatory gene expression profile in our tumor-immune model. Conclusion: Our study provides an in vitro phenotypic screening approach for the identification of immunomodulatory agents and thus addresses a critical gap in the field of immuno-oncology. Our pilot screen identified statins, a drug family gaining increasing interest as repurposing candidates for cancer treatment, as enhancers of immune cell-induced cancer cell death. We speculate that the clinical benefits described for cancer patients receiving statins are not simply caused by a direct effect on the cancer cells but rather are dependent on the combined effect exerted on both cancer and immune cells. [ABSTRACT FROM AUTHOR]

Copyright of Practical Pharmacy & Clinical Remedies is the property of Editorial Department of Practical Pharmacy & Clinical Remedies and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

The unique physicochemical properties of DNA molecules allow them to be used as self‐assembling motifs for the construction of DNA nanostructures with the merits of shape designability, precise addressability, structural dynamic stimuli‐responsiveness, and superb biocompatibility. After loading therapeutical payloads, current DNA nanostructures were able to deliver them to diseased tissues and cells in a targeted manner, and release them responsively, as well as increase the cellular uptake of the payloads. In this review, we investigate the utility of typical DNA nanostructures in the development of the state‐of‐the‐art drug delivery systems, highlighting the key technological aspects in the transportation of payloads of different chemical categories, i. e. small molecules, oligonucleotides and peptides/proteins. Meanwhile, their implementation in various therapeutic modalities was surveyed, including chemotherapy, immunotherapy, gene therapy, protein therapy, photothermal and photodynamic therapy. And finally, possible challenges and future perspective are discussed for further developments. [ABSTRACT FROM AUTHOR]

Increasing evidence has proved that microbiota is not only the target of small molecule drugs but also an underexplored resource for developing small molecule drugs. Meanwhile, microbiota as a critical modulator of the immune system impacts the efficacy and toxicity of cancer immunotherapy. Harnessing microbiota or developing microbiota-derived medications provide novel therapeutic strategies to overcome resistance to cancer immunotherapy and immune-related adverse events (irAEs). In this review, we elucidate how microbiota and their metabolites impact anti-tumor immunity and immunotherapy efficacy and highlight the potential of microbiota and their metabolites as a resource for small molecule drug discovery. We further overview the current landscape of clinical trials evaluating the potential effect of microbiota and their metabolites on immunotherapy outcomes, presenting future trends in the field of microbiota-based therapies. Microbiota-based therapies are promising therapeutic options to promote therapeutic efficacy and diminish the toxicity of immunotherapy. [ABSTRACT FROM AUTHOR]

Drug hypersensitivity reactions induced by small molecule drugs encompass a broad spectrum of adverse drug reactions with heterogeneous clinical presentations and mechanisms. These reactions are classified into allergic drug hypersensitivity reactions and non-allergic drug hypersensitivity reactions. At present, the hapten theory, pharmacological interaction with immune receptors (p-i) concept, altered peptide repertoire model, and altered T-cell receptor (TCR) repertoire model have been proposed to explain how small molecule drugs or their metabolites induce allergic drug hypersensitivity reactions. Meanwhile, direct activation of mast cells, provoking the complement system, stimulating or inhibiting inflammatory reaction-related enzymes, accumulating bradykinin, and/or triggering vascular hyperpermeability are considered as the main factors causing non-allergic drug hypersensitivity reactions. To date, many investigations have been performed to explore the underlying mechanisms involved in drug hypersensitivity reactions and to search for predictive and preventive methods in both clinical and non-clinical trials. However, validated methods for predicting and diagnosing hypersensitivity reactions to small molecule drugs and deeper insight into the relevant underlying mechanisms are still limited. [ABSTRACT FROM AUTHOR]

Oral administration is the most preferred route for drug administration in clinic. However, due to unsatisfactory physicochemical properties of drugs and various physiological barriers, the oral bioavailability of most poorly water-soluble and macromolecules drugs is low and the therapeutic effect is unsatisfactory. Ionic liquids (ILs), molten salts with unique properties, show amazing potential for oral delivery. In addition to being able to form active pharmaceutical ingredients based ILs (API-ILs) to overcome drug solubility and polymorphism issues, ILs have also been used to enhance the solubility of poorly soluble drugs, enhance drug stability in the gastrointestinal environment, improve drug permeability in intestinal mucus, and facilitate drug penetration across the intestinal epithelial barrier. Furthermore, ILs were attempted as formulation components to develop novel oral drug delivery systems. This review focus on the application progress of ILs in oral drug delivery and the mechanisms. The challenges and perspectives of the development of ILs-based oral delivery systems are also discussed. This article reviews the latest advances of ionic liquids for oral drug delivery, focusing on the application and related mechanisms of ionic liquids in improving the drug physicochemical properties and enhancing drug delivery across physiological barriers. [ABSTRACT FROM AUTHOR]

Summary: COVID‐19 has spread swiftly throughout the world posing a global health emergency. The significant numbers of deaths attributed to this pandemic have researchers battling to understand this new, dangerous virus. Researchers are looking to find possible treatment regimens and develop effective therapies. This study aims to provide an overview of published scientific information on potential treatments, emphasizing angiotensin‐converting enzyme II (ACE2) inhibitors as one of the most important drug targets. SARS‐CoV‐2 receptor‐binding domain (RBD); as a viral attachment or entry inhibitor against SARS‐CoV‐2, human recombinant soluble ACE2; as a genetically modified soluble form of ACE2 to compete with membrane‐bound ACE2, and microRNAs (miRNAs); as a negative regulator of the expression of ACE2/TMPRSS2 to inhibit SARS‐CoV2 entry into cells, are the potential therapeutic approaches discussed thoroughly in this article. This review provides the groundwork for the ongoing development of therapeutic agents and effective treatments against SARS‐COV‐2. [ABSTRACT FROM AUTHOR]

Small molecules are rising as a new generation of immune checkpoints' inhibitors, with compounds targeting the human Programmed death-ligand 1 (hPD-L1) protein are pioneering this area of research. Promising examples include the recently disclosed compounds from Bristol-Myers-Squibb (BMS). These molecules bind specifically to hPD-L1 through a unique mode of action. They induce dimerization between two hPD-L1 monomers through the hPD-1 binding interface in each monomer, thereby inhibiting the PD-1/PD-L1 axis. While the recently reported crystal structures of such small molecules bound to hPD-L1 reveal valuable insights regarding their molecular interactions, there is still limited information about the dynamics driving this unusual complex formation. The current study provides an in-depth computational structural analysis to study the interactions of five small molecule compounds in complex with hPD-L1. By employing a combination of molecular dynamic simulations, binding energy calculations and computational solvent mapping techniques, our analyses quantified the dynamic roles of different hydrophilic and lipophilic residues at the surface of hPD-L1 in mediating these interactions. Furthermore, ligand-based analyses, including Free-Wilson 2D-QSAR was conducted to quantify the impact of R-group substitutions at different sites of the phenoxy-methyl biphenyl core. Our results emphasize the importance of a terminal phenyl ring that must be present in any hPD-L1 small molecule inhibitor. This phenyl moiety overlaps with a very unfavorable hydration site, which can explain the ability of such small molecules to trigger hPD-L1 dimerization. [ABSTRACT FROM AUTHOR]

Introduction: Evidence demonstrates that N6-methyladenosine (m6A) modification plays an increasingly important role in the development of tumors. The aim of this study is to explore the expression of m6A-related regulators in lung adenocarcinoma, identify the effect of altered key factors modified by m6A on the prognosis of patients with lung adenocarcinoma. Methods: A comprehensive analysis of m6A-related gene expressions in patients with lung adenocarcinoma based on The Cancer Genome Atlas database (TCGA) and the CBioPortal database. A prognostic risk score was established based on a linear combination of 4 key gene expression levels using the regression coefficients of the multivariate Cox regression models. Immunohistochemical staining analysis was performed to validate the relationship between the protein expression level of m6A regulators and the prognosis of patients retrospectively. The possible mechanism and prospective therapeutic targets of these key m6A molecules were explored by the M6A2Target database and the CMAP database. Results: Mutation pattern analysis revealed that 32% of 656 patients had genetic alterations. Four genes (writer: methyltransferase like 3 [METTL3] and three readers: insulin like growth factor 2 mRNA binding protein 2 [IGF2BP2], heterogeneous nuclear ribonucleoprotein C [HNRNPC], and heterogeneous nuclear ribonucleoprotein A2/B1 [HNRNPA2B1]) were selected to construct a survival risk prediction model and the results of immunohistochemical staining showed that the expression of these four m6A genes was significantly different between lung adenocarcinoma tissues and normal lung tissues (p <.01). The possible downstream genes and prospective therapeutic targets of these four m6A key molecules were discovered. Conclusion: These four m6A RNA methylation regulators may be effective prognostic and diagnostic factors which can provide auxiliary diagnosis and prognosis of lung adenocarcinoma. [ABSTRACT FROM AUTHOR]

Alternative splicing (AS) is significantly related to tumor development as well as a patient's clinical characteristics. This study was designed to systematically analyze the survival-associated AS signatures in Lung adenocarcinoma (LUAD). Among 30,735 AS events in 9,635 genes, we found that there were 1,429 AS in 1,125 genes which were conspicuously related to the overall survival of LUAD patients. Then, according to the seven types of AS events, we established AS signatures and constructed a new combined prognostic model. The Kaplan-Meier curve results showed that seven types of AS signatures and the combined prognostic model could divide patients into distinct prognoses. The ROC curve shows that all eight AS signatures had powerful predictive properties with different AUCs ranging from 0.708 to 0.849. Additionally, the elevated risk scores were positively related to higher TNM stage and metastasis. Interestingly, AS events and splicing factors (SFs) network shed light on a meaningful connection between prognostic AS genes and corresponding SFs. Moreover, we found that the combined prognostic model signature has a higher predictive ability than the mRNA signature. Furthermore, tumors at high risk might evade immune recognition by decreasing the expression of antigen presentation genes. Finally, we predicted the three most significant small molecule drugs to inhibit LUAD. Among them, NVP-AUY922 had the lowest IC50 value and might become a potential drug to prolong a patient's survival. In conclusion, our study established a potential prognostic signature for LUAD patients, revealed a splicing network between AS and SFs and possible immune escape mechanism, and provided several small-molecule drugs to inhibit tumorigenesis. [ABSTRACT FROM AUTHOR]

A reliable, rapid, and effective bioanalytical method is essential for the determination of the pharmacokinetic, pharmacodynamic, and toxicokinetic parameters that inform the safety and efficacy profile of investigational drugs. The overall goal of bioanalytical method development is to elucidate the procedure and operating conditions under which a method can sufficiently extract, qualify, and/or quantify the analyte(s) of interest and/or their metabolites for the intended purpose. Given the difference in the physicochemical properties of small and large molecule drugs, different strategies need to be adopted for the development of an effective and efficient bioanalytical method. Herein, we provide an overview of different sample preparation strategies, analytical platforms, as well as procedures for achieving high throughput for bioanalysis of small and large molecule drugs. [ABSTRACT FROM AUTHOR]

The Comprehensive Economic and Trade Agreement between Canada and the European Union provides for an extension of Canadian patents for prescription drugs by up to 2 years. One of the arguments advanced for longer patent time is to compensate companies for the length of the overall drug development time (the time between patent application and market approval). This study investigates overall development time in Canada for different groups of drugs approved between January 1, 2009 and December 31, 2018 and how many of these drugs are eligible for up to 2 years of patent term extension. Based on a list of patents and dates of market approval, the change in overall development time for all drugs was calculated along with whether there were differences in development time between different groups of drugs. Using Canadian patent filing dates, overall development time for all drugs went from a mean of 2240 days (95% CI: 1832, 2648) in 2009 to 4197 days (95% CI: 3728, 4665) in 2018 (analysis of variance [ANOVA], P < .0001). Using first global patent filing dates, overall development time went from a mean of 4481 days (95% CI: 3053, 5908) in 2009 to 6298 days (95% CI: 4839, 7756) in 2018 (ANOVA, P = .0118). There was a statistically significant difference in the overall development mean time between small molecule drugs (3553, 95% CI: 3361, 3746) and biologics (3903, 95% CI: 3595, 4212), (t test, P = .0487) when using Canadian patent filing dates but not when first global patent filing dates were used. There was no statistically significant change in overall development time among drugs that were substantial, moderate or little to none additional therapeutic value compared to existing drugs. Out of 238 drugs, 218 (91.6%) would have been eligible for patent term extension with 195 (80.7%) eligible for the full 2 years. Patent term extension does not appear to be justified based on changes in overall development time, except possibly in the case of biologics. There are also trade offs in terms of increased expenditures that need to be considered if patent terms are lengthened. [ABSTRACT FROM AUTHOR]

In the past two decades, three highly pathogenic human coronaviruses severe acute respiratory syndrome coronavirus (SARS‐CoV), Middle East respiratory syndrome coronavirus, and, recently, SARS‐CoV‐2, have caused pandemics of severe acute respiratory diseases with alarming morbidity and mortality. Due to the lack of specific anti‐CoV therapies, the ongoing pandemic of coronavirus disease 2019 (COVID‐19) poses a great challenge to clinical management and highlights an urgent need for effective interventions. Drug repurposing is a rapid and feasible strategy to identify effective drugs for combating this deadly infection. In this review, we summarize the therapeutic CoV targets, focus on the existing small molecule drugs that have the potential to be repurposed for existing and emerging CoV infections of the future, and discuss the clinical progress of developing small molecule drugs for COVID‐19. [ABSTRACT FROM AUTHOR]

When a drug enters an organism, interactions between the drug and proteins in the organism play a vital role in the storage, transport and metabolism of the drug and also affect its nonspecific toxicity, targeting and pharmacodynamic activity. However, monitoring the interaction process is a great challenge in the research of the absorption, transport and metabolic processes of drugs. In this study, we used reflectometric interference spectroscopy (RIfS) and silica colloidal crystal (SCC) film as a sensing platform to detect the binding affinity between human serum albumin (HSA) and indomethacin. SCC films composed of three silica nanospheres with different diameters were fabricated using the vertical evaporation method. HSA was immobilized covalently on SCCfilm using a very simple approach, and optical thickness was used as a parameter to evaluate the process of drug absorption and desorption. Finally, the optimal SCC film was selected, and three drugs other than indomethacin (i.e., warfarin, salicylic acid and quinine) were used for the validation of this sensing platform. The results verified that SCC film using RIfS is a simple and real-time sensing platform for detecting the affinity between HSA and drugs, which may be widely used in drug development and clinical testing in the future. [ABSTRACT FROM AUTHOR]

Background: Head and neck squamous cell carcinoma (HNSCC) is a common tumor worldwide with poor prognosis. The pathogenesis of human papillomavirus (HPV)-positive and HPV-negative HNSCCs differs. However, few studies have considered the HPV status when identifying biomarkers for HNSCC. Thus, the identification of biomarkers for HPV-positive and HPV-negative HNSCCs is urgently needed. Methods: Three microarray datasets from Gene Expression Omnibus (GEO) were analyzed, and the differentially expressed genes (DEGs) were obtained. Then, functional enrichment pathway analysis was performed and protein–protein interaction (PPI) networks were constructed. The expression of hub genes at both the mRNA and protein level was determined in Oncomine, The Cancer Genome Atlas (TCGA) and the Human Protein Atlas (HPA). In addition, survival analysis of the patient stratified by HPV status and the expression levels of key genes were performed based on TCGA data. The role of AREG, STAG3, CAV1 and C19orf57 in cancer were analyzed through Gene set enrichment analysis (GSEA). The top ten small molecule drugs were identified and the therapeutic value of zonisamide, NVP-AUY922, PP-2 and fostamatinib was further evaluated in six HPV-negative HNSCC cell lines. Finally, the therapeutic value of NVP-AUY922 was tested in vivo based on three HPV-negative HNSCC models, and statistical analysis was performed. Results: In total, 47 DEGs were obtained, 11 of which were identified as hub genes. Biological process analysis indicated that the hub genes were associated with the G1/S transition of the mitotic cell cycle. Survival analysis uncovered that the prognostic value of AREG, STAG3, C19orf57 and CAV1 differed between HPV-positive and HPV-negative patients. Gene set enrichment analysis (GSEA) showed the role of AREG, STAG3 and CAV1 in dysregulated pathways of tumor. Ten small molecules were identified as potential drugs specifically for HPV-positive or HPV-negative patients; three—NVP-AUY922, fostamatinib and PP-2—greatly inhibited the proliferation of six HPV-negative HNSCC cell lines in vitro, and NVP-AUY922 inhibited three HPV-negative HNSCC xenografts in vivo. Conclusions: In conclusion, AREG, STAG3, C19orf57 and CAV1 are key prognostic factors and potential therapeutic targets in HPV-negative HNSCC. NVP-AUY922, fostamatinib and PP-2 may be effective drugs for HPV-negative HNSCC. [ABSTRACT FROM AUTHOR]

Background: Head and neck squamous cell carcinoma (HNSCC) is a common tumor worldwide with poor prognosis. The pathogenesis of human papillomavirus (HPV)-positive and HPV-negative HNSCCs differs. However, few studies have considered the HPV status when identifying biomarkers for HNSCC. Thus, the identification of biomarkers for HPV-positive and HPV-negative HNSCCs is urgently needed. Methods: Three microarray datasets from Gene Expression Omnibus (GEO) were analyzed, and the differentially expressed genes (DEGs) were obtained. Then, functional enrichment pathway analysis was performed and protein–protein interaction (PPI) networks were constructed. The expression of hub genes at both the mRNA and protein level was determined in Oncomine, The Cancer Genome Atlas (TCGA) and the Human Protein Atlas (HPA). In addition, survival analysis of the patient stratified by HPV status and the expression levels of key genes were performed based on TCGA data. The role of AREG, STAG3, CAV1 and C19orf57 in cancer were analyzed through Gene set enrichment analysis (GSEA). The top ten small molecule drugs were identified and the therapeutic value of zonisamide, NVP-AUY922, PP-2 and fostamatinib was further evaluated in six HPV-negative HNSCC cell lines. Finally, the therapeutic value of NVP-AUY922 was tested in vivo based on three HPV-negative HNSCC models, and statistical analysis was performed. Results: In total, 47 DEGs were obtained, 11 of which were identified as hub genes. Biological process analysis indicated that the hub genes were associated with the G1/S transition of the mitotic cell cycle. Survival analysis uncovered that the prognostic value of AREG, STAG3, C19orf57 and CAV1 differed between HPV-positive and HPV-negative patients. Gene set enrichment analysis (GSEA) showed the role of AREG, STAG3 and CAV1 in dysregulated pathways of tumor. Ten small molecules were identified as potential drugs specifically for HPV-positive or HPV-negative patients; three—NVP-AUY922, fostamatinib and PP-2—greatly inhibited the proliferation of six HPV-negative HNSCC cell lines in vitro, and NVP-AUY922 inhibited three HPV-negative HNSCC xenografts in vivo. Conclusions: In conclusion, AREG, STAG3, C19orf57 and CAV1 are key prognostic factors and potential therapeutic targets in HPV-negative HNSCC. NVP-AUY922, fostamatinib and PP-2 may be effective drugs for HPV-negative HNSCC. [ABSTRACT FROM AUTHOR]

Copyright of Forum Reumatologiczne is the property of VM Medica-VM Group (Via Medica) and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Inflammatory bowel diseases (IBDs) are immune-mediated chronic inflammatory disorders of the gastrointestinal tract whose pathogenesis is not yet fully understood. Despite the advent of biological agents, there are still unmet needs for IBD patients, due to suboptimal rate of sustained remission achieved. Small molecule drugs (SMDs), the next generation of selective drugs in IBD, show promising results in ongoing trials. We describe the pharmacodynamics and pharmacokinetic features of novel SMDs and their main differences with biologic agents. Small molecule drugs are a promising class of drugs for the treatment of ulcerative colitis and Crohn's disease with good results in inducing and maintaining remission. Hence, over the next few years physicians will have numerous options of small molecule drugs for the treatment of patients with IBD. This group of drugs are potentially easier to use over biological agents due to pharmacokinetic features such as oral administration, short half-life, high volume of distribution, and lack of immunogenicity. On the other hand, drug–drug interactions can happen with small-molecule drugs, principally due to competitive metabolic and clearance mechanisms. [ABSTRACT FROM AUTHOR]

Clear cell renal cell carcinoma (ccRCC) is one of the most common histological subtypes of renal cancer, with a poor prognosis. Our study aimed to identify a biomarker that is significantly associated with ccRCC prognosis and novel immunotherapeutic targets, as well as some novel molecular drugs for ccRCC. Based on the overlap of The Cancer Genome Atlas (TCGA)-Kidney Renal Clear Cell Carcinoma (KIRC) data and the ImmPort database, we obtained 1,292 immune-related genes (IRGs) and constructed a weighed co-expression network based on the IRGs. A total of 39 hub genes were screened out in three modules. CTLA4, which had the highest connectivity degree among the screened genes in a protein–protein interaction network (degree = 24), was selected. Internal validation based on the GEPIA database revealed that patients with a higher expression of CTLA4 had a significantly shorter overall survival time and disease-free survival time. Expression of CTLA4 was also closely correlated with local recurrence, pathologic stage, and immune infiltration level. External validation based on the Oncomine database and merged microarray-acquired dataset validated the mRNA expression level of hub genes. Gene-set enrichment analysis revealed that six KEGG signaling pathways, which were significantly associated with CTLA4, were enriched on immune-related pathways. Further analysis according to the TIMER database demonstrated that CTLA4 expression was positively related to dendritic cells (cor = 0.446, P = 1.32E-23) and negatively associated with tumor purity (cor = −0.267, P = 5.51E-09). Finally, we screened out 293 differentially expressed genes by integrating six datasets from the GEO database. The Connectivity Map (CMap) analysis revealed the strong potential of three small molecule drugs (monensin, quercetin, and fenbufen) for ccRCC treatment. In conclusion, CTLA4 was identified and validated in prognosis of ccRCC. CTLA4 may be a new prognostic biomarker and immunotherapeutic target for ccRCC. Monensin, quercetin, and fenbufen may be novel choices for ccRCC treatment. [ABSTRACT FROM AUTHOR]

Crohn's disease (CD) and ulcerative colitis (UC), the main forms of inflammatory bowel disease (IBD) in human beings, are chronic relapsing-remitting disorders of the gastrointestinal tract, which usually require lifelong therapies. For many years, IBD have been managed with corticosteroids, aminosalicylates and immunosuppressants (ie, thiopurines). The advent of biologic therapies (anti-TNF-α agents) has significantly improved the outcome of IBD patients in terms of prolonged clinical remission, corticosteroid sparing, achievement of mucosal healing and prevention of disease-related complications. Nevertheless, primary failure or loss of response to biologics occur in about 50% of patients treated with these drugs. Therefore, the need for new effective treatments for such patients has critically emerged as an urgent priority. With this regard, several small-molecule drugs (SMDs) targeting lymphocyte trafficking (ie, sphingosine-1-phosphate receptor modulators) and the JAK/STAT pathway (eg, tofacitinib) have been recently developed and tested in IBD. In particular, JAK inhibitors are oral compounds characterized by short half-life, low antigenicity and the ability to dampen several pro-inflammatory pathways simultaneously. Tofacitinib, a pan-JAK inhibitor, has shown good efficacy and safety in UC clinical trials and has been recently approved for the treatment of UC patients. In this review, we analyze the main evidence supporting the use of JAK inhibitors in UC and explore the unanswered questions about the use of this class of drug in UC. [ABSTRACT FROM AUTHOR]

Imaging technology, oncology, pharmacological research, cancer therapy, small molecule drugs Hence, imaging strategies are commonly applied across several research projects to evaluate the pharmacokinetics, activity, and mechanisms of cancer therapy through the use of small molecule drugs or prodrugs ([3]; [9]; [4]; [5]). Keywords: imaging technology; oncology; pharmacological research; cancer therapy; small molecule drugs EN imaging technology oncology pharmacological research cancer therapy small molecule drugs 1 3 3 07/28/21 20210723 NES 210723 Imaging technology is being recognized as an important tool for breaking through the bottleneck of drug development as it is able to provide great insights into the morphology or functionality of pharmacological models, including cell, tissue, and animal. Imaging technology includes both microscopic and macroscopic imaging scales, and encompasses fluorescence-based microscopy ([10]), Raman-based microscopy ([1]), targeted ultrasound imaging ([2]), photoacoustic imaging ([8]), SPECT, PET ([7]), and molecular MRI ([6]), among others. [Extracted from the article]

The present study aimed to identify microRNAs (miRNAs) that may be crucial for the mechanism of mesenchymal stem cell (MSC) treatment in cisplatin-induced acute kidney injury (AKI) and to investigate other potential drugs that may have a similar function. Transcriptomics (GSE85957) and miRNA expression (GSE66761) datasets were downloaded from the Gene Expression Omnibus database. Differentially expressed genes (DEGs) and differentially expressed miRNAs (DEMs) were identified using the linear models for microarray data method and mRNA targets of DEMs were predicted using the miRWalk2.0 database. The crucial DEGs were screened by constructing a protein-protein interaction (PPI) network and module analysis. Functions of target genes were analyzed using the database for annotation, visualization and integrated discovery. Small molecule drugs were predicted using the connectivity map database. As a result, 5 DEMs were identified to be shared and oppositely expressed in comparisons between AKI model and control groups, and between MSC treatment and AKI model groups. The 103 DEGs were overlapped with the target genes of 5 common DEMs, and the resulting list was used for constructing the miRNA-mRNA regulatory network, including rno-miR-210/Serpine1 and rno-miR-378/Fos. Serpine1 (degree=17) and Fos (degree=42) were predicted to be hub genes according to the topological characteristic of degree in the PPI network. Function analysis indicated Serpine1 and Fos may be inflammation-related. Furthermore, gliclazide was suggested to be a potential drug for the treatment of AKI because the enrichment score was the closest to −1 (−0.9). In conclusion, it can be speculated that gliclazide may have a similar mechanism to MSC as a potential therapeutic agent for cisplatin-induced AKI, by regulating miR-210/Serpine1 and miR-378-/Fos-mediated inflammation and cell apoptosis. [ABSTRACT FROM AUTHOR]

Over the past decade, the improvement in the understanding of the molecular mechanisms of Crohn's disease (CD) led to the development of more targeted therapies, including biologics - i.e. monoclonal antibodies that selectively block key mediators of inflammation - and novel small molecule drugs - i.e. compounds with a molecular weight <1 kDa able to diffuse through cell membranes and then fit for the oral route of administration - which will enrich the therapeutic armamentarium of CD soon. In parallel with the expansion of the medical options, the therapeutic targets to be achieved in patients with CD have changed. In particular, we moved from the simple control of symptoms to more ambitious goals which aim to permanently extinguish the inflammation, even the subclinical one. As a consequence, the role of some of the conventional drugs which have been used in CD for several years, such as 5-aminosalicylates and conventional immunosuppressants, is becoming more limited in favor of these new drugs. This profound modification of CD therapy and the intrinsic complexity of the disease are relevant to the point that the management of inflammatory bowel diseases is gradually becoming a subspecialty in the field of gastroenterology or internal medicine. [ABSTRACT FROM AUTHOR]

Chronic airway diseases such as asthma and chronic obstructive pulmonary disease (COPD), together with their comorbidities, bear a significant burden on public health. Increased appreciation of molecular networks underlying inflammatory airway disease needs to be translated into new therapies for distinct phenotypes not controlled by current treatment regimens. On the other hand, development of new safe and effective therapies for such respiratory diseases is an arduous and expensive process. Antibody‐based (biological) therapies are successful in treating certain respiratory conditions not controlled by standard therapies such as severe allergic and refractory eosinophilic severe asthma, while in other inflammatory respiratory diseases, such as COPD, biologicals are having a more limited impact. Small molecule drug (SMD)‐based therapies represent an active field in pharmaceutical research and development. SMDs expand biologicals' therapeutic targets by reaching the intracellular compartment by delivery as either an oral or topically based formulation, offering both convenience and lower costs. Aim of this review was to compare and contrast the distinct pharmacological properties and clinical applications of SMDs‐ and antibody‐based treatment strategies, their limitations and challenges, in order to highlight how they should be integrated for their optimal utilization and to fill the critical gaps in current treatment for these chronic inflammatory respiratory diseases. [ABSTRACT FROM AUTHOR]

Either osteoarthritis or sports-related injuries can lead to cartilage defects, whereas both chondrocyte self-renewal and conventional treatments face limitations. In cartilage regenerative medicine, growth factors are commonly used to induce chondrogenic differentiation of stem cells. However, application of growth factors is confined by some drawbacks. Emerging small molecules are regarded as an alternative for cartilage regeneration. A recently discovered small-molecule compound, kartogenin (KGN), has been proven to be a chondrogenic and chondroprotective agent and is more effective in inducing cartilage regeneration when compared with growth factors. KGN has been processed and applied in many forms, such as in intra-articular injection, in collaboration with growth factors, in incorporation in drug delivery systems, and in combination with scaffolds. Fortunately, progress has been achieved in KGN applications. The current review discusses the recent advances in KGN for cartilage regeneration and thus presents new concepts in cartilage repair in clinical settings. [ABSTRACT FROM AUTHOR]

Wound healing is a complex tissue regeneration process that promotes the growth of new tissue to provide the body with the necessary barrier from the outside environment. In the class of non-healing wounds, diabetic wounds, and ulcers, dressing materials that are available clinically (e.g., gels and creams) have demonstrated only a slow improvement with current available technologies. Among all available current technologies, electrospun fibers exhibit several characteristics that may provide novel replacement dressing materials for the above-mentioned wounds. Therefore, in this review, we focus on recent achievements in electrospun drug-eluting fibers for wound healing applications. In particular, we review drug release, including small molecule drugs, proteins and peptides, and gene vectors from electrospun fibers with respect to wound healing. Furthermore, we provide an overview on multifunctional dressing materials based on electrospun fibers, including those that are capable of achieving wound debridement and wound healing simultaneously as well as multi-drugs loading/types suitable for various stages of the healing process. Our review provides important and sufficient information to inform the field in development of fiber-based dressing materials for clinical treatment of non-healing wounds. [ABSTRACT FROM AUTHOR]

The Notch pathway is a cell‐cell communication system where membrane‐bound ligands interact with the extracellular region of Notch receptors to induce intracellular, downstream effects on gene expression. Aberrant Notch signaling promotes tumorigenesis, and the Notch pathway has tremendous potential for novel targeting strategies in cancer treatment. While γ‐secretase inhibitors as Notch‐inhibiting agents are already promising in clinical trials, they are highly non‐specific with adverse side‐effects. One of the underlying challenges is that two of the four known human Notch paralogs, NOTCH1 and 2, share very high structural similarity but play opposing roles in some tumorigenesis pathways. This perspective explores the feasibility of developing Notch‐specific small molecule inhibitors targeting the anti‐NOTCH2 antibody‐binding epitopes or the “S2‐Leu‐plug‐binding site” using a computer‐aided drug discovery approach. [ABSTRACT FROM AUTHOR]

In the present study, the RNA sequencing (RNA-seq) data of uterine corpus endometrial carcinoma (UCEC) samples were collected and analyzed using bioinformatics tools to identify potential genes associated with the development of UCEC. UCEC RNA-seq data were downloaded from The Cancer Genome Atlas database. Differential analysis was performed using edgeR software. A false discovery rate <0.01 and |log2(fold change)|>1 were set as the cut-off criteria to screen for differentially expressed genes (DEGs). Differential gene co-expression analysis was performed using R/EBcoexpress package in R. DEGs in the gene co-expression network were subjected to Gene Ontology analysis using the Database for Annotation, Visualization and Integration Discovery. Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis was also performed on the DEGs using KOBAS 2.0 software. The ConnectivityMap database was used to identify novel drug candidates. A total of 3,742 DEGs were identified among the 552 UCEC samples and 35 normal controls, and comprised 2,580 upregulated and 1,162 downregulated genes. A gene co-expression network consisting of 129 DEGs and 368 edges was constructed. Genes were associated with the cell cycle and the tumor protein p53 signaling pathway. Three modules were identified, in which genes were associated with the mitotic cell cycle, nuclear division and the M phase of the mitotic cell cycle. Multiple key hub genes were identified, including cell division cycle 20, cyclin B2, non-SMC condensin I complex subunit H, BUB1 mitotic checkpoint serine/threonine kinase, cell division cycle associated 8, maternal embryonic leucine zipper kinase, MYB proto-oncogene like 2, TPX2, microtubule nucleation factor and non-SMC condensin I complex subunit G. In addition, the small molecule drug esculetin was implicated in the suppression of UCEC progression. Overall, the present study identified multiple key genes in UCEC and clinically relevant small molecule agents, thereby improving our understanding of UCEC and expanding perspectives on targeted therapy for this type of cancer. [ABSTRACT FROM AUTHOR]

OIC-A006 (BMPs osteogenesis compounds), can stimulate bone marrow mesenchymal stem cells ALP, OPN, OC, Cbfal expression. To stimulate new bone formation in the body. We postulate different amounts of drug microspheres on the PLGA/β-CPT scaffold can produce the effects on performance and sustained release characteristics. In this paper, through adding different amount of carrier drug microsphere, three concentrations scaffolds which are 12.5, 18.75 and 25 μmol/L are prepared by adding different amounts of drug-loaded microspheres. Hereafter called OICM/CPT-200, OICM/CPT-300, OICM/CPT-400. We implant them in rat femur diameter 3 mm depth of 3 mm hole for eight weeks. The degradation, microsphere, delivery properties, with X-ray, micro-CT and histology are tested. Results show that the contain carrier drug microsphere scaffolds become radiopaque, and the gaps between the scaffold and radial cut ends are often invisible. This preliminary study reveals that different carrier drug microsphere has a corresponding effect the performance of stent body, OICM/CPT – 200 scaffolds induction effect is best. Illustrates that the low concentration load OIC-A006 microspheres can promote bone healing, and high concentration of OIC-A006 micro ball is played a inhibitory effect on bone healing process. [ABSTRACT FROM PUBLISHER]

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This study aimed to screen out differentially expressed genes (DEGs) and explore small molecule drugs for Tetralogy of Fallot (TOF). The gene expression profile of TOF GSE26125 was downloaded from the Gene Expression Omnibus database, including 16 idiopathic TOF samples and five healthy controls. The DEGs were identified by the Limma package in R language and underwent functional enrichment analysis via Database for Annotation, Visualization and Integrated Discovery tools. A protein-protein interaction (PPI) network of DEGs was then constructed and the significant clusters were selected for functional analysis. In addition, the DEGs were mapped to the connectivity map (CMap) database to identify potential small-molecule drugs. As a result, a total of 499 DEGs were selected between TOF and healthy controls. Meanwhile, the functional changes of DEGs related to TOF were mainly associated with cellular respiration and energy metabolism. Furthermore, in the PPI network, two clusters were identified via cluster 1 analysis. And only cluster 1 was significantly enriched into gene ontology terms, including respiratory chain, electron transport chain, and oxidation reduction. The hub gene of cluster 1 was NDUFAB1. Additionally, small molecules, such as harmine, solanine, and testosterone, may have the potential to repair the disordered metabolic pathways of TOF. [ABSTRACT FROM AUTHOR]

Background Rheumatoid arthritis ( RA) is a chronic, systemic inflammatory disorder that may affect many tissues and organs, but principally attacks flexible (synovial) joints. Aims Our aim is to explore the change of gene expression profile in patients with RA, and investigate the underlying mechanism of the pathogenesis and progression of RA. Methods We downloaded the dataset GSE2053 from Gene Expression Omnibus database and screened the differentially expressed genes by analyzing the profiles between RA and normal cells with bioinformatics methods. Furthermore, Gene Ontology ( GO) function analysis and Kyoto Encyclopedia of Genes and Genomes ( KEGG) pathway analysis were used to screen GO and the significantly changed signaling pathways in RA cells with the Database for Annotation, Visualization and Integrated Discovery ( DAVID). Results By bioinformatics methods, we obtained the metabolic pathway changed in the cells of patients with RA, and explored small molecule drugs that can restore these changes. Conclusions These results may provide a new approach for explore the pathogenesis of RA and a new breakthrough in the medical treatment of patients with RA. [ABSTRACT FROM AUTHOR]

For a significant proportion of patients with inflammatory bowel disease (IBD), primary non-response and secondary loss of response to treatment remain significant issues. Anti-tumor necrosis factor therapies have been licensed for use in IBD. Other disease-related pathways have been targeted as well, including the interleukin 12/23 axis and lymphocyte tracking. However, the need for parenteral administration and the associated costs of dispensing and monitoring all biologics remain a burden on healthcare systems and patients. Janus kinase inhibitors are small-molecule drugs that can be administered orally and are relatively inexpensive, thus offering an additional option for treating IBD. They have been shown to be effective in patients with ulcerative colitis (UC), but they are less effective in those with Crohn's disease (CD). Nonetheless, given the immune-system-based mechanism of these drugs, their safety profile remains a cause for concern. This article provides an overview of Janus kinase (JAK) inhibitors and new trends in the treatment of IBD. [ABSTRACT FROM AUTHOR]

Inflammatory bowel diseases (IBDs), mainly represented by Crohn's disease (CD) and Ulcerative Colitis (UC), are chronic disorders with an unclear pathogenesis. This incurable and iterative intestinal mucosal inflammation requires the life-long use of anti-inflammatory drugs to prevent flares or relapses, which are the major providers of complications, such as small bowel strictures and intestinal perforations. The introduction of tumor necrosis factor (TNF)-alpha inhibitors and other compounds, such as anti-IL12/23 and anti-alpha4/beta7 integrin monoclonal antibodies, has considerably improved the clinical management of IBDs. They are now the standard of care, being the first-line therapy in patients with aggressive disease and in patients with moderate to severe disease with an inadequate response to conventional therapy. However, for approximately one third of all patients, their efficacy remains insufficient by a lack or loss of response due to the formation of anti-drug antibodies or compliance difficulties with parenteral formulations. To address these issues, orally administered Small Molecules Drugs (SMDs) that use a broad range of novel pharmacological pathways, such as JAK inhibitors, sphingosine-1-phosphate receptor modulators, and phosphodiesterase 4 inhibitors, have been developed for CD and UC. This article provides an updated and complete review of the most recently authorized SMDs and SMDs in phase II/III development. [ABSTRACT FROM AUTHOR]

Simple Summary: New clinical radiology scans using trace amounts of therapeutic cancer drugs labeled with radioisotope injected into patients can provide oncologists with fundamentally unique insights about drug delivery to tumors. This new application of radiology aims to improve how cancer drugs are used, towards improving patient outcomes. The article reviews published clinical research in this important new field. Translational development of radiolabeled analogues or isotopologues of small molecule therapeutic drugs as clinical imaging biomarkers for optimizing patient outcomes in targeted cancer therapy aims to address an urgent and recurring clinical need in therapeutic cancer drug development: drug- and target-specific biomarker assays that can optimize patient selection, dosing strategy, and response assessment. Imaging the in vivo tumor pharmacokinetics and biomolecular pharmacodynamics of small molecule cancer drugs offers patient- and tumor-specific data which are not available from other pharmacometric modalities. This review article examines clinical research with a growing pharmacopoeia of investigational small molecule cancer drug tracers. [ABSTRACT FROM AUTHOR]

Inflammatory bowel disease (IBD) is a chronic and life-long disease characterized by gastrointestinal tract inflammation. It is caused by the interplay of the host's genetic predisposition and immune responses, and various environmental factors. Despite many treatment options, there is no cure for IBD. The increasing incidence and prevalence of IBD and lack of effective long-term treatment options have resulted in a substantial economic burden to the healthcare system worldwide. Biologics targeting inflammatory cytokines initiated a shift from symptomatic control towards objective treatment goals such as mucosal healing. There are seven monoclonal antibody therapies excluding their biosimilars approved by the US Food and Drug Administration for induction and maintenance of clinical remission in IBD. Adverse side effects associated with almost all currently available drugs, especially biologics, is the main challenge in IBD management. Natural products have significant potential as therapeutic agents with an increasing role in health care. Given that natural products display great structural diversity and are relatively easy to modify chemically, they represent ideal scaffolds upon which to generate novel therapeutics. This review focuses on the pathology, currently available treatment options for IBD and associated challenges, and the roles played by natural products in health care. It discusses these natural products within the current biodiscovery research agenda, including the applications of drug discovery techniques and the search for next-generation drugs to treat a plethora of inflammatory diseases, with a major focus on IBD. [ABSTRACT FROM AUTHOR]

Although RNA-binding proteins (RBPs) coordinate many key decisions during cell growth and differentiation, the dynamics of RNA–RBP interactions have not been extensively studied on a global basis. We immunoprecipitated endogenous ribonucleoprotein complexes containing HuR and PABP throughout a T-cell activation time course and identified the associated mRNA populations using microarrays. We used Gaussian mixture modeling as a discriminative model, treating RBP association as a discrete variable (target or not target), and as a generative model, treating RBP-association as a continuous variable (probability of association). We report that HuR interacts with different populations of mRNAs during T-cell activation. These populations encode functionally related proteins that are members of the Wnt pathway and proteins mediating T-cell receptor signaling pathways. Moreover, the mRNA targets of HuR were found to overlap with the targets of other posttranscriptional regulatory factors, indicating combinatorial interdependence of posttranscriptional regulatory networks and modules after activation. Applying HuR mRNA dynamics as a quantitative phenotype in the drug-gene-phenotype Connectivity Map, we identified candidate small molecule effectors of HuR and T-cell activation. We show that one of these candidates, resveratrol, exerts T-cell activation-dependent posttranscriptional effects that are rescued by HuR. Thus, we describe a strategy to systematically link an RBP and condition-specific posttranscriptional effects to small molecule drugs. [ABSTRACT FROM AUTHOR]