Clinical Drugs Research Articles

Analysis of Ophthalmology Drug Clinical Trial Institutions in China: Challenges and Opportunities Under the Registration System

Objective: To analyze the status of ophthalmology drug clinical trial institutions in China following the implementation of the registration system and provide a reference for their development. Methods: An analysis was conducted using data from the Drug Clinical Trial Institution Registration Management Information Platform and the Drug Clinical Trial Registration and Information Publicity Platform of the National Medical Products Administration. The search period was up to April 19, 2024. Results: As of April 19, 2024, 314 ophthalmology-specific institutions were registered nationwide, comprising 274 comprehensive medical institutions and 40 specialized ophthalmology institutions, representing a 245% increase compared to the qualification certification phase. There were 965 major researchers in ophthalmology, accounting for 6.3% of the total number of researchers across all registered ophthalmology institutions. These institutions were predominantly located in economically developed areas such as Guangdong, Zhejiang, and Jiangsu Provinces, with the top five provinces and cities comprising 39.8% of the total registered institutions. Beijing had the highest number of major researchers (126), with their distribution positively correlated with the geographic spread of registered institutions. Furthermore, as of April 19, 2024, there were 216 clinical drugs related to eye diseases, with the top three provinces conducting 77.8% of national clinical trial projects. The number of institutions was directly proportional to the volume of clinical trials conducted. Conclusion: The implementation of the registration system has facilitated the release of ophthalmic medical resources. However, regional disparities remain in the number of ophthalmology-specific institutions, the availability of major investigators, and the distribution of clinical trial projects.

Polyketides and alkaloids from the fungus Aspergillus Fumigatus YB4-17 and ent-Fumiquinazoline J induce apoptosis, paraptosis in human hepatoma HepG2 cells

Hepatocellular carcinoma (HCC) is one of the most common malignancies. The currently available clinical drugs for HCC frequently cause serious side effects and the treatment outcomes are unsatisfactory. It is urgent to develop effective drugs with high selectivity and low adverse effects for HCC. Metabolites produced by microorganisms have shown great potential in the development of therapeutic agents for HCC. In our study, the EtOAc extract of the strain Aspergillus fumigatus YB4-17 exhibited significant cytotoxicity towards the HCC HepG2 cells at 10 μg/mL. Various column chromatographic separations of the extract afforded seven polyketides (1–7), including a new diphenyl ether derivative (1), along with fourteen known alkaloids (8–21). The structure elucidation was conducted via NMR spectroscopic data and MS data analysis. The absolute configuration of compound 11 was confirmed by comparing experimental and calculated electronic circular dichroism spectrum for the first time. The biological evaluation of these metabolites revealed that compound 11 selectively inhibited the proliferation of HCC HepG2 cells with negligible toxicity to normal cells. Mechanism study indicated that compound 11 induced apoptosis and paraptosis in HepG2 cells, providing a novel therapeutic perspective for the treatment of hepatocellular carcinoma.

Injectable Hierarchical Bioactive Hydrogels with Fibroblast Growth Factor 21/Edaravone/Caffeic Acid Asynchronous Delivery for Treating Parkinson's Disease.

Parkinson's disease (PD) is one of the most common long-term neurodegenerative disorders, with multiple comorbid psychiatric and behavioral abnormalities. The combination of clinical drugs targeting different symptoms with smart hydrogels to achieve asynchronous releases is highly translational and challenging. Here, a hierarchical bioactive hydrogel (OACDP) is designed with asynchronous release based on PD pathology. The hydrogel with caffeic acid-grafted polymer main chain is crosslinked using a micellar nanocrosslinker, with sufficient modulus (≈167Pa), antioxidant activity (>50%), injectability (30-gauge syringe needle), and shape-adaptability. Each of the three drugs (caffeic acid, fibroblast growth factor 21, and Edaravone) is separately engaged in different micro- or nanostructures of the hydrogel and released with asynchronous kinetics of first-order release, zero-order release, or matching Korsmeyer-Peppas model. The triple-loaded hydrogel is injected into the brains of PD rats, showing behavioral improvement. Histological analysis revealed that the triple-loaded OACDP hydrogels are effective in achieving immediate neuroprotection, i.e., reduction the loss of tyrosine hydroxylase in substantia nigra compacta and striatum (retained ≈10-fold versus control), decreasing oxidative stress, reducing astrocyte and microglia activation, and stimulating the AMPK/PGC-1α axis to regulate the mitochondrial function, providing a multi-dimensional PD therapy. The asynchronous release of OACDP hydrogel provides a new conception for PD treatment and other neurodegenerative diseases.

Synaptotagmin-11 deficiency mediates schizophrenia-like behaviors in mice via dopamine over-transmission

Schizophrenia is a severe neuropsychiatric disease, but the initiation mechanisms are unclear. Although antipsychotics are effective against positive symptoms, therapeutic interventions for negative symptoms are limited due to the lack of pathophysiological mechanisms. Here we identify synaptotagmin-11 (Syt11) as a potential genetic risk factor and dopamine over-transmission as a mechanism in the development of schizophrenia. Syt11 expression is reduced in individuals with schizophrenia but restored following the treatment with antipsychotics. Syt11 deficiency in dopamine neurons in early adolescence, but not in adults, leads to persistent social deficits and other schizophrenia-like behaviors by mediating dopamine over-transmission in mice. Accordingly, dopamine neuron over-excitation before late adolescence induces persistent schizophrenia-associated behavioral deficits, along with the structural and functional alternations in the mPFC. Notably, local intervention of D2R with clinical drugs presynaptically or postsynaptically exhibits both acute and long-lasting therapeutic effects on social deficits in schizophrenia mice models. These findings not only define Syt11 as a risk factor and DA over-transmission as a potential risk factor initiating schizophrenia, but also propose two D2R-targeting strategies for the comprehensive and long-term recovery of schizophrenia-associated social withdrawal.

Sequential Delivery of Cardioactive Drugs via Microcapped Microneedle Patches for Improved Heart Function in Post Myocardial Infarction Rats

After myocardial infarction, the heart undergoes adverse remodeling characterized by a series of pathological changes, including inflammation, apoptosis, fibrosis, and hypertrophy. In addition to cardiac catheter-based re-establishment of blood flow, patients typically receive multiple medications that aim to address these different mechanisms underlying left ventricular remodeling. The current study aims to establish a versatile multi-drug delivery platform for the controlled and sequential delivery of multiple therapeutic agents in a single treatment. Toward this goal, we generated a microcapped microneedle patch carrying methylprednisolone, interleukin-10, and vascular endothelial growth factor. In vitro characterization demonstrated a time-sequenced release pattern of these drug: methylprednisolone for the first 3 days, interleukin-10 from day 1 to 15, and vascular endothelial growth factor from day 3 to 25. The therapeutic effects of the microneedle patch were evaluated in a rat model of acute myocardial infarction induced by permanent ligation of left anterior descending coronary artery. Heart function was measured using trans-thoracic echocardiography. Heart inflammation, apoptosis, hypertrophy and angiogenesis were evaluated using histology. Our data indicated that, at 28 days after patch transplantation, animals receiving the microneedle patch with sequential release of these three agents showed reduced inflammation, apoptosis and cardiac hypertrophy compared to the animals receiving control patch without sequential release of these agents, which is associated with the improved angiogenesis and heart function. In conclusion, the microneedle patch can be utilized to deliver multiple therapeutic agents in a controlled and sequential manner that aligns with the pathological phases following myocardial infarction. STATEMENT OF SIGNIFICANCE: The post-myocardial infarction heart remodeling is characterized by a series of pathological events including acute inflammation, apoptosis, fibrosis, cardiac hypertrophy, and depressed heart function. In current clinical practice, multiple procedures and drugs given at different time points are necessary to combat these series of pathological events. In this study, we developed a novel microcapped microneedle patch for the controlled sequential delivery of triple cardioprotective drugs aiming to combat acute inflammation and cardiac hypertrophy, and promote angiogenesis. This study presents a comprehensive therapeutic approach, with the microneedle patch addressing multifaceted pathological processes during post-myocardial infarction left ventricular remodeling. This cardiac drug delivery system has the potential to improve patient treatment by delivering drugs in alignment with the series of time-dependent pathological phases following myocardial infarction, ultimately improving clinical outcomes.

Advances in Factors Affecting ALDH2 Activity and its Mechanisms.

Aldehyde dehydrogenase 2 (ALDH2) is a mitochondrial enzyme primarily involved in the detoxification of alcohol-derived aldehyde and endogenous toxic aldehydes. It exhibits widespread expression across various organs and exerts a broad and significant impact on diverse acute cardiovascular diseases, including acute coronary syndrome, acute aortic dissection, hypoxic pulmonary hypertension, and heart failure. The ALDH2 rs671 variant represents the most prevalent genetic variant in East Asian populations, with carriage rates ranging from 30 to 50% among the Chinese population. Given its widespread presence in the body, the wide range of diseases it affects, and its high rate of variation, it can serve as a crucial tool for the precise prevention and treatment of acute cardiovascular diseases, while offering individualized medication guidance. This review aims to provide a comprehensive overview of the latest advancements in factors affecting ALDH2 activity, encompassing post-transcriptional modifications, modulators of ALDH2, and relevant clinical drugs.

Triterpenoids from Ganoderma lucidum inhibit cytochrome P450 enzymes interfering with the metabolic process of specific clinical drugs.

Ganoderma lucidum (G. lucidum), which possesses various biological effects, has been widely used as traditional medicine and functional food in Asian countries, especially China. In consideration of its various biological effects on human healthcare, G. lucidum was usually used in combination with other drugs. However, the potential drug-drug interaction induced by G. lucidum through cytochrome P450 enzymes (CYPs) remain unknown. Using the in vivo activity assay of CYPs, the inhibitory effects of G. lucidum and its constituents could be evaluated. The interference of G. lucidum on the metabolic processes of clinical drugs could be investigated. The chemical constituents of G. lucidum could be identified using LC-MS. The interaction between bioactive compounds and CYPs could be proposed through in silico docking analysis and molecular dynamics. The dichloromethane extract of G. lucidum could inhibit various CYP450 subtypes in vitro and interfere with the pharmacokinetics of four drugs in rats. Triterpenoids were identified as the main constituents of the dichloromethane extract by Q-TOF-MSn in preliminary analyses. Then, a triterpenoid library containing 66 compounds was established to evaluate their inhibitory effects against CYP 1A2, 2D6, 3A4, 2A6, 2B6, 2C9, and 2C19. CYP 1A2 was inhibited by most lanostane triterpenoids, indicating a strong affinity for these compounds. Among triterpenoids, compound 25 displayed a broad inhibitory effect against CYPs, except for CYP 3A4, 2D6, 2C9, and 2C19. Finally, compounds 6 and 25 exhibited interference with the metabolism of 16 drugs through the inhibition of CYPs in vitro. In silico molecular docking analyses for assaying the interaction between compound 25 and CYPs indicated that the hydrogen bonds formed between the hydroxyl groups and amino acid residues. G. lucidum displayed broad inhibitory effects on CYPs, with triterpenoids as the main bioactive constituents, which may induce potential drug-drug interaction. This information should be helpful for the rational use of G. lucidum in promoting human health.

Research progress in stem cell technology in Alzheimer's disease

Abstract. Dementia in the elderly is a neurodegenerative disease that affects approximately 50-75% of people worldwide. Patients with Alzheimers will gradually experience a decline in intelligence and cognitive function, and Alzheimers is also the most common form of Alzheimers disease. At present, there have been many advances in the causes and treatment of Alzheimers disease, but they also face great difficulties. There is no effective treatment for senile dementia yet, and the main clinical drugs are to alleviate symptoms, delay onset, and reduce the impact of the disease on daily life. However, stem cell technology has made great progress this year, and stem cells have shown tremendous potential in the treatment of many diseases. Many studies have been conducted on the use of stem cells in the treatment of Alzheimers and Alzheimers disease, and some of the results have shown good therapeutic effects. The application of mesenchymal stem cells in the treatment of Alzheimers disease has been partially preclinical. However, most of the plans for treating dementia in the elderly through stem cell therapy are still in the experimental stage, and there is currently a lack of standardized treatment. There are potential risks and technical difficulties in promotion and implementation that need to be further explored. Further research is needed on the risks, processes, and technical difficulties of stem cell therapy. This article will systematically discuss the symptoms and pathogenesis of senile dementia, and analyze the current use of stem cells in the treatment of senile dementia. This article will contribute to peoples understanding of dementia in the elderly and promote related research.

DbAMP 3.0: updated resource of antimicrobial activity and structural annotation of peptides in the post-pandemic era.

Antimicrobial resistance is one of the most urgent global health threats, especially in the post-pandemic era. Antimicrobial peptides (AMPs) offer a promising alternative to traditional antibiotics, driving growing interest in recent years. dbAMP is a comprehensive database offering extensive annotations on AMPs, including sequence information, functional activity data, physicochemical properties and structural annotations. In this update, dbAMP has curated data from over 5200 publications, encompassing 33,065 AMPs and 2453 antimicrobial proteins from 3534 organisms. Additionally, dbAMP utilizes ESMFold to determine the three-dimensional structures of AMPs, providing over 30,000 structural annotations that facilitate structure-based functional insights for clinical drug development. Furthermore, dbAMP employs molecular docking techniques, providing over 100 docked complexes that contribute useful insights into the potential mechanisms of AMPs. The toxicity and stability of AMPs are critical factors in assessing their potential as clinical drugs. The updated dbAMP introduced an efficient tool for evaluating the hemolytic toxicity and half-life of AMPs, alongside an AMP optimization platform for designing AMPs with high antimicrobial activity, reduced toxicity and increased stability. The updated dbAMP is freely accessible at https://awi.cuhk.edu.cn/dbAMP/. Overall, dbAMP represents a comprehensive and essential resource for AMP analysis and design, poised to advance antimicrobial strategies in the post-pandemic era.

Strategic insights into the cultivation of pancreatic cancer organoids from endoscopic ultrasonography-guided biopsy tissue

BACKGROUND The frequent suboptimal efficacy of endoscopic ultrasound-guided fine-needle biopsy (EUS-FNB) to culture pancreatic cancer (PC) organoids (PCOs) poses a major challenge in the advancement of personalized medicine for advanced PC. AIM To explore how to obtain appropriate puncture tissues from EUS-FNB and optimize the strategy for efficiently constructing PCOs, providing an efficient tool for the advancement of personalized medicine. METHODS Patients who underwent EUS-FNB for the diagnosis of PC tissue were prospectively enrolled. We refined the endoscopic biopsy procedures and organoid cultivation techniques. All tissue specimens verified by on-site pathological assessment were cultured in a semi-suspended medium in a microfluidic environment. We assessed differences in PCOs cultured beyond and below five generations examining patient demographics, specimen and organoid attributes, and the sensitivity of organoids to a panel of clinical drugs through cell viability assays. RESULTS In this study, 16 patients with PC were recruited, one sample was excluded because onsite cytopathology showed no tumor cells. Successful organoid generation occurred in 93.3% (14 of 15) of the EUS-FNB specimens, with 60% (9 of 15) sustaining over five generations. Among these patients, those with a history of diabetes, familial cancer, or larger tumors exhibited enhanced PCO expandability. The key factors influencing long-term PCOs expansion included initial needle sample quality (P = 0.005), rapid initiation of organoid culture post-isolation (P ≤ 0.001), and high organoid activity (P = 0.031). Drug sensitivity analysis revealed a partial response in two patients following therapeutic intervention and surgery and stable disease in four patients, indicating a moderate correlation between organoid response and clinical outcomes. CONCLUSION Optimal initial needle sampling, rapid and precise biopsy sample processing, process isolated samples as soon as possible, and sufficient cellular material are crucial for successful cultivating PCOs. High organoid activity is an important factor in maintaining their long-term expansion, which is essential for shortening the time of drug sensitivity analysis and is the basis of PC research.

Identification of key programmed cell death genes for predicting prognosis and treatment sensitivity in colorectal cancer

Colorectal cancer (CRC) ranks third in global incidence and second in mortality. However, a comprehensive predictive model for CRC prognosis, immunotherapy response, and drug sensitivity is still lacking. Various types of programmed cell death (PCD) are crucial for cancer occurrence, progression, and treatment, indicating their potential as valuable predictors. Fourteen PCD genes were collected and subjected to dimensionality reduction using regression methods to identify key hub genes. Predictive models were constructed and validated based on bulk transcriptomes and single-cell transcriptomes. Furthermore, the tumor microenvironment, immunotherapy response, and drug sensitivity profiles among patients with CRC were explored and stratified by risk. A risk score incorporating the PCD genes FABP4, AQP8, and NAT1 was developed and validated across four independent datasets. Patients with CRC who had a high-risk score exhibited a poorer prognosis. Unsupervised clustering algorithms were used to identify two molecular subtypes of CRC with distinct features. The risk score was combined with the clinical features to create a nomogram model with superior predictive performance. Additionally, patients with high-risk scores exhibited decreased immune cell infiltration, higher stromal scores, and reduced responsiveness to immunotherapy and first-line clinical drugs compared with low-risk patients. Furthermore, the top ten non-clinical first-line drugs for treating CRC were selected based on their predicted IC50 values. Our results indicate the efficacy of the model and its potential value in predicting prognosis, response to immunotherapy, and sensitivity to different drugs in patients with CRC.

Study on the molecular mechanism of atopic dermatitis in mice based on skin and serum metabolomic analysis.

Atopic dermatitis (AD) is a common chronic inflammatory dermatosis. However, the exact molecular mechanism underlying the development of AD remain largely unclear. To investigate comprehensive metabolomic alterations in serum and skin tissue between 2,4-dinitrofluorobenzene (DNFB)-induced AD-like mice and healthy controls, aiming to identify the potential disease biomarkers and explore the molecular mechanisms of AD. In this study, Untargeted metabolomics analysis was used to investigate both skin and serum metabolic abnormalities of 2,4-dinitrofluorobenzene (DNFB)-induced AD-like mice. Then, the metabolic differences among the groups were determined through the application of multivariate analysis. Additionally, the selection of predictive biomarkers was accomplished using the receiver operating characteristic (ROC) module. Our findings showed that levels of 220 metabolites in the skin and 94 metabolites in the serum were different in AD-like mice that were treated with DNFB compared to control mice. Uracil, N-Acetyl-L-methionine, deoxyadenosine monophoosphate, 2-acetyl-l-alkyl-sn-glycero-3-phosphcholine, and prostaglandin D2 are considered potential biomarkers of AD as obtained by integrating skin and serum differential metabolite results. Metabolomic data analysis showed that the metabolic pathways in which skin and serum are involved together include histidine metabolism, pyrimidine metabolism, alanine, aspartate, and glutamate metabolism. Our research explained the possible molecular mechanism of AD at the metabolite level and provided potential targets for the development of clinical drugs for AD.

Netupitant Inhibits the Proliferation of Breast Cancer Cells by Targeting AGK.

Background: Currently, there is a significant lack of effective pharmacological agents for the treatment of breast cancer. Acylglycerol Kinase (AGK), a lipid kinase, has been found to be aberrantly expressed in breast cancer and is closely associated with tumor proliferation, migration, and invasion. However, no clinical anti-tumor drugs specifically targeting this kinase have been developed. Methods: siRNA was utilized to knock down the AGK gene; CCK8 and colony formation assays were employed to evaluate the in vitro proliferative capacity of tumor cells. Molecular dynamics simulations and BIL assays were conducted to analyze drug binding affinity. Annexin V/PI staining was used to assess apoptotic phenomena; subcutaneous xenograft tumor experiments in nude mice were performed to confirm the in vivo anti-tumor efficacy of the drug. Results: Netupitant exhibited stable binding affinity for AGK and interacted with amino acids within the ATP-binding region of the enzyme. The IC50 values for the SK-BR-3 and MDA-MB-231 cell lines were determined as 16.15 ± 4.25 µmol/L and 24.02 ± 4.19 µmol/L, respectively; at a concentration of 2.5 µmol/L, Netupitant effectively inhibited clonogenic capacity in breast cancer cells; furthermore, treatment with 10 µmol/L significantly induced apoptosis in these cells. Doses of 50 mg/kg and 100 mg/kg Netupitant markedly suppressed growth rates of subcutaneous xenograft tumors in nude mice while also promoting apoptotic processes. Both in vivo and in vitro studies indicated that Netupitant could inhibit the activation of the PI3K/AKT/mTOR signaling pathway. Conclusions: By targeting AGK, Netupitant inhibits its kinase activity, which leads to reduced phosphorylation levels of PTEN, thereby suppressing the activation of the PI3K/AKT/mTOR signaling pathway and ultimately resulting in apoptosis in breast cancer cells.

Moxidectin elevates Candida albicans ergosterol levels to synergize with polyenes against oral candidiasis

Candida albicans, the most common opportunistic pathogenic fungus, is also the main pathogenic organism for oral candidiasis. This condition is particularly prevalent among the elderly, children, and individuals undergoing radiotherapy or suffering from HIV. The lack of new antifungal drugs, and drug resistance coupled with the side effects of current antifungal agents have increased the challenges of clinical antifungal therapies. Polyenes, including amphotericin B and nystatin, are clinical fungicidal drugs, however, their side effects and low solubility have limited their clinical applications. Here, we identified that moxidectin, a novel approved antiparasitic agent, could synergize with both amphotericin B and nystatin to inhibit the growth and biofilm formation of Candida albicans including 60 clinical isolates. The transcriptome and RT-PCR analysis indicated that moxidectin activated the biosynthesis pathway of ergosterol, the direct target of polyenes, further being verified by the loss of the synergistic activities with polyenes against ergosterol pathway mutants, including Δ/Δerg3, Δ/Δerg11 and Δ/Δerg3 Δ/Δerg11. Moxidectin was then confirmed to elevate the ergosterol biosynthesis levels of C. albicans and enhance the binding between cells and polyenes. In a mouse oral candidiasis model, moxidectin combined with low dosages of polyenes to significantly reduce the infection area, colonization of C. albicans and the inflammatory degree of tongue mucosa. Our study originally demonstrated that moxidectin could activate the ergosterol biosynthesis then elevate the ergosterol contents to enhance the antifungal effects of polyenes against C. albicans and its infections. Moxidectin can serve as the candidate potentiator of polyenes for further clinical practice.Key points• Moxidectin synergized with polyenes against Candida albicans.• Moxidectin activated the ergosterol biosynthesis of Candida albicans.• Moxidectin combined with polyenes to effectively combat oral candidiasis in mice.

Progress in GABAA receptor agonists for insomnia disorder.

Insomnia is the most common sleep disorder in which an individual has trouble falling or staying asleep. Chronic sleep loss interferes with daily functioning and adversely affects health. The main clinical drugs for insomnia are the positive allosteric modulator of the GABA (gamma-aminobutyric acid) A receptors (GABAARs) at the benzodiazepine site with selectivity of the GABA-α1 receptor. They are divided into benzodiazepine drugs and non-benzodiazepine drugs. Most recently, the first partial positive allosteric modulator of GABAAR Dimdazenil was approved by National Medical Products Administration (NMPA) and launched in China. This review summarized the mechanism of actions of current clinical drugs for insomnia, and the clinical applications of these drugs, which may help to understand their involvement in insomnia, and to search for more selective and potent ligands to be used in the treatment of insomnia.

Pyrazole derivatives as antileishmanial agents: Biological evaluation, molecular docking study, DFT analysis and ADME prediction

Leishmaniasis is a parasitic disease that is commonly found in tropical and sub-tropical regions. Currently, there is no protective antileishmanial vaccine, and the available clinical drugs have serious side effects. On the other hand, due to the emergence of multidrug-resistant strains of the causative pathogens, the study and design of novel antileishmanial agents is urgently needed. Accordingly, fourteen previously synthesized pyrazole and pyrano [2,3-c] pyrazole derivatives (P1-P14) were evaluated for antileishmanial efficacy against the protozoan parasite, Leishmania major. Among the tested compounds, seven derivatives including P1, P3, P5, P8, P12, P13, and P14 exhibited promising antileishmanial activity with IC50 values in the range of 34.79–43.55 μg/mL, compared to the standard drug (Glucantime) with an IC50 value of 97.31 μg/mL. In the case of pyrazole derivatives, P1, P5, and P8 exhibited significant antileishmanial activity with IC50 values of 35.53, 36.79, and 37.40 μg/mL, respectively. The most potent antileishmanial activity is belong to P12 and P14, with IC50 values of 34.79 and 38.51 μg/mL, respectively. Molecular docking outputs presented that P12 and P14 formed favorable interactions with key residues in the active site of the 14-alpha demethylase enzyme, which is an important target for antileishmanial agents. Various DFT parameters were also calculated for compounds P1 and P12, which were the most and least active compounds, respectively. The outputs indicated that compound P1 was more thermodynamically stable than P12. Additionally, P1 had higher hardness and a higher energy gap, resulting in greater stability. In addition, these compounds showed satisfactory theoretical ADME properties. The present results indicate that the investigated pyrazole and pyrano [2,3-c] pyrazole derivatives can be considered as promising agents for the development of antileishmaniasis treatments.

The diverse functions of DYRK2 in response to cellular stress.

To maintain microenvironmental and cellular homeostasis, cells respond to multiple stresses by activating characteristic cellular mechanisms consisting of receptors, signal transducers, and effectors. Dysfunction of these mechanisms can trigger multiple human diseases as well as cancers. Dual-specificity tyrosine-regulated kinases (DYRKs) are members of the CMGC group and are evolutionarily conserved from yeast to mammals. Previous studies revealed that DYRK2 has important roles in the regulation of the cell cycle and survival in cancer cells. On the other hand, recent studies show that DYRK2 also exhibits significant functions in multiple cellular stress responses and in maintaining cellular homeostasis. Hence, the further elucidation of mechanisms underlying DYRK2's diverse responses to various stresses helps to promote the advancement of innovative clinical therapies and pharmacological drugs. This review summarizes the molecular mechanisms of DYRK2, particularly focusing on cellular stress responses.

Exploring the Potential of Anthocyanins for Repairing Photoaged Skin: A Comprehensive Review.

Long-term exposure to ultraviolet (UV) rays can result in skin photoaging, which is primarily characterized by dryness, roughness, pigmentation, and a loss of elasticity. However, the clinical drugs commonly employed to treat photoaged skin often induce adverse effects on the skin. Anthocyanins (ACNs) are water-soluble pigments occurring abundantly in various flowers, fruits, vegetables, and grains and exhibiting a range of biological activities. Studies have demonstrated that ACNs contribute to the repair of photoaged skin due to their diverse biological characteristics and minimal side effects. Evidence suggests that the stability of ACNs can be enhanced through encapsulation or combination with other substances to improve their bioavailability and permeability, ultimately augmenting their efficacy in repairing photoaged skin. A growing body of research utilizing cell lines, animal models, and clinical studies has produced compelling data demonstrating that ACNs mitigate skin photoaging by reducing oxidative stress, alleviating the inflammatory response, improving collagen synthesis, alleviating DNA damage, and inhibiting pigmentation. This review introduces sources of ACNs while systematically summarizing their application forms as well as mechanisms for repairing photoaged skin. Additionally, it explores the potential role of ACNs in developing functional foods. These findings may provide valuable insight into using ACNs as promising candidates for developing functional products aimed at repairing photoaged skin.

Elucidating Antibiotic Permeation through the Escherichia coli Outer Membrane: Insights from Molecular Dynamics.

Antibiotic resistance represents a critical public health threat, with an increasing number of Gram-negative pathogens demonstrating resistance to a broad range of clinical drugs. A primary challenge in enhancing antibiotic efficacy is overcoming the robust barrier presented by the bacterial outer membrane. Our research addresses a longstanding question: What is the rate of antibiotic permeation across the outer membrane (OM) of Gram-negative bacteria? Utilizing molecular dynamics (MD) simulations, we assess the passive permeability profiles of four commercially available antibiotics─gentamicin, novobiocin, rifampicin, and tetracycline across an asymmetric atomistic model of the Escherichia coli (E. coli) OM, employing the inhomogeneous solubility-diffusion model. Our examination of the interactions between these drugs and their environmental context during OM permeation reveals that extended hydrogen bond formation and drug-cation interactions significantly hinder the energetics of passive permeation, notably affecting novobiocin. Our MD simulations corroborate well with experimental data and reveal new implications of solvation on drug permeability, overall advancing the possible use of computational prediction of membrane permeability in future antibiotic discovery.

Green Construction of Novel 3‐(Benzo[d][1,3]dioxol‐5‐yl)‐1,8‐naphthyridin‐2‐yl)amino)quinazoline‐2,4(1H,3H)‐dione and Phenyl‐[1,2,4]triazolo[4,3‐a][1,8]naphthyridine and Their Antimicrobial Activity

ABSTRACTA straightforward and an efficient green synthetic method has been outlined for the construction of 3‐(benzo[d][1, 3] dioxol‐5‐yl)‐1,8‐naphthyridine derivatives in the presence of glacial acetic acid and Cu(OAc)2 catalyst accomplished excellent yields in short reaction time. The reaction proceeds efficiently by using a greener way under microwave conditions to elevate the quantity of pure products. The purity of all the synthesized compounds was confirmed by IR, 1H and 13CNMR, LC–MS data and also from the elemental analyses studies. The synthesized compounds 7d and 7f performed strongest antibacterial activity against pathogenic cell lines Bacillus subtilis (17.5, 20.5 mm), Escherichia coli (28.5, 30 mm), and antifungal cell lines Candida albicans (18, 22.5 mm), and Aspergillus Niger (28.5, 40.5 mm) which are compared with clinical drugs Penicillin, Grieseofulvin. We scrutinized the remaining molecules and found that their activity ranged from modest to exceptional.