The Discovery of New Inhibitors of Insulin-Regulated Aminopeptidase by a High-Throughput Screening of 400,000 Drug-like Compounds.

With the ambition to identify novel chemical starting points that can be further optimized into small drug-like inhibitors of insulin-regulated aminopeptidase (IRAP) and serve as potential future cognitive enhancers in the clinic, we conducted an ultra-high-throughput screening campaign of a chemically diverse compound library of approximately 400,000 drug-like small molecules. Three biochemical and one biophysical assays were developed to enable large-scale screening and hit triaging. The screening funnel, designed to be compatible with high-density microplates, was established with two enzyme inhibition assays employing either fluorescent or absorbance readouts. As IRAP is a zinc-dependent enzyme, the remaining active compounds were further evaluated in the primary assay, albeit with the addition of zinc ions. Rescreening with zinc confirmed the inhibitory activity for most compounds, emphasizing a zinc-independent mechanism of action. Additionally, target engagement was confirmed using a complementary biophysical thermal shift assay where compounds causing positive/negative thermal shifts were considered genuine binders. Triaging based on biochemical activity, target engagement, and drug-likeness resulted in the selection of 50 qualified hits, of which the IC50 of 32 compounds was below 3.5 µM. Despite hydroxamic acid dominance, diverse chemotypes with biochemical activity and target engagement were discovered, including non-hydroxamic acid compounds. The most potent compound (QHL1) was resynthesized with a confirmed inhibitory IC50 of 320 nM. Amongst these compounds, 20 new compound structure classes were identified, providing many new starting points for the development of unique IRAP inhibitors. Detailed characterization and optimization of lead compounds, considering both hydroxamic acids and other diverse structures, are in progress for further exploration.

A dual-target SPR screening system for simultaneous ligand discovery of SARS-CoV-2 spike protein and its receptor ACE2 from Chinese herbs.

Traditional Chinese Medicine (TCM) is a supremely valuable resource for the development of drug discovery. Few methods are capable of hunting for potential molecule ligands from TCM towards more than one single protein target. In this study, a novel dual-target surface plasmon resonance (SPR) biosensor was developed to perform targeted compound screening of two key proteins involved in the cellular invasion process of the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2): the spike (S) protein receptor binding domain (RBD) and the angiotensin-converting enzyme 2 (ACE2). The screening and identification of active compounds from six Chinese herbs were conducted taking into consideration the multi-component and multi-target nature of Traditional Chinese Medicine (TCM). Puerarin from Radix Puerariae Lobatae was discovered to exhibit specific binding affinity to both S protein RBD and ACE2. The results highlight the efficiency of the dual-target SPR system in drug screening and provide a novel approach for exploring the targeted mechanisms of active components from Chinese herbs for disease treatment.

Antiviral screening of natural, anti-inflammatory compound library against African swine fever virus.

BACKGROUND: African swine fever virus (ASFV) is a major threat to pig production and the lack of effective vaccines underscores the need to develop robust antiviral countermeasures. Pathologically, a significant elevation in pro-inflammatory cytokine production is associated with ASFV infection in pigs and there is high interest in identifying dual-acting natural compounds that exhibit antiviral and anti-inflammatory activities. METHODS: Using the laboratory-adapted ASFV BA71V strain, we screened a library of 297 natural, anti-inflammatory compounds to identify promising candidates that protected Vero cells against virus-induced cytopathic effect (CPE). Virus yield reduction, virucidal, and cell cytotoxicity experiments were performed on positive hits and two lead compounds were further characterized in dose-dependent assays along with time-of-addition, time-of-removal, virus entry, and viral protein synthesis assays. The antiviral effects of the two lead compounds on mitigating virulent ASFV infection in porcine macrophages (PAMs) were also tested using similar methods, and the ability to inhibit pro-inflammatory cytokine production during virulent ASFV infection was assessed by enzyme-linked immunosorbent assay (ELISA). RESULTS: The screen identified five compounds that inhibited ASFV-induced CPE by greater than 50% and virus yield reduction experiments showed that two of these compounds, tetrandrine and berbamine, exhibited particularly high levels of anti-ASFV activity. Mechanistic analysis confirmed that both compounds potently inhibited early stages of ASFV infection and that the compounds also inhibited infection of PAMs by the virulent ASFV Arm/07 isolate. Importantly, during ASFV infection in PAM cells, both compounds markedly reduced the production of pro-inflammatory cytokines involved in disease pathogenesis while tetrandrine had a greater and more sustained anti-inflammatory effect than berbamine. CONCLUSIONS: Together, these findings support that dual-acting natural compounds with antiviral and anti-inflammatory properties hold promise as preventative and therapeutic agents to combat ASFV infection by simultaneously inhibiting viral replication and reducing virus-induced cytokine production.

Aspiring toward equitable benefits from genomic advances to individuals of ancestrally diverse backgrounds.

Advancements in genomic technologies have shown remarkable promise for improving health trajectories. The Human Genome Project has catalyzed the integration of genomic tools into clinical practice, such as disease risk assessment, prenatal testing and reproductive genomics, cancer diagnostics and prognostication, and therapeutic decision making. Despite the promise of genomic technologies, their full potential remains untapped without including individuals of diverse ancestries and integrating social determinants of health (SDOHs). The NHGRI launched the 2020 Strategic Vision with ten bold predictions by 2030, including "individuals from ancestrally diverse backgrounds will benefit equitably from advances in human genomics." Meeting this goal requires a holistic approach that brings together genomic advancements with careful consideration to healthcare access as well as SDOHs to ensure that translation of genetics research is inclusive, affordable, and accessible and ultimately narrows rather than widens health disparities. With this prediction in mind, this review delves into the two paramount applications of genetic testing-reproductive genomics and precision oncology. When discussing these applications of genomic advancements, we evaluate current accessibility limitations, highlight challenges in achieving representativeness, and propose paths forward to realize the ultimate goal of their equitable applications.

Leveraging shape screening and molecular dynamics simulations to optimize PARP1-Specific chemo/radio-potentiators for antitumor drug design.

PARP1 plays a pivotal role in DNA repair within the base excision pathway, making it a promising therapeutic target for cancers involving BRCA mutations. Current study is focused on the discovery of PARP inhibitors with enhanced selectivity for PARP1. Concurrent inhibition of PARP1 with PARP2 and PARP3 affects cellular functions, potentially causing DNA damage accumulation and disrupting immune responses. In step 1, a virtual library of 593 million compounds has been screened using a shape-based screening approach to narrow down the promising scaffolds. In step 2, hierarchical docking approach embedded in Schrödinger suite was employed to select compounds with good dock score, drug-likeness and MMGBSA score. Analysis supplemented with decomposition energy, molecular dynamics (MD) simulations and hydrogen bond frequency analysis, pinpointed that active site residues; H862, G863, R878, M890, Y896 and F897 are crucial for specific binding of ZINC001258189808 and ZINC000092332196 with PARP1 as compared to PARP2 and PARP3. The binding of ZINC000656130962, ZINC000762230673, ZINC001332491123, and ZINC000579446675 also revealed interaction involving two additional active site residues of PARP1, namely N767 and E988. Weaker or no interaction was observed for these residues with PARP2 and PARP3. This approach advances our understanding of PARP-1 specific inhibitors and their mechanisms of action, facilitating the development of targeted therapeutics.

Association between Socioecological Status, Nutrient Intake, and Cancer Screening Behaviors in Adults Aged 40 and Over: Insights from the Eighth Korea National Health and Nutrition Examination Survey (KNHANES, 2019).

Cancer screening is pivotal for early detection and improved survival rates. While socio-ecological factors are known to influence screening uptake, the role of lifestyle, dietary habits, and general health in shaping these decisions remains underexplored. Utilizing the 2019 Korea National Health and Nutrition Examination Survey (KNHANES), this study examined the myriad of factors impacting cancer screening utilization. Data from 274,872 adults aged 40 years or older were scrutinized, highlighting demographics, income, lifestyle behaviors, health-related variables, nutrient intake, and dietary quality. A combination of descriptive statistics and logistic regression helped us ascertain influential determinants. Higher educational attainment and income quartiles were positively correlated with cancer screening rates. Regular walkers, those engaged in moderate physical activity, and individuals with a previous cancer diagnosis were more likely to get screened. High-risk drinkers and smokers were less inclined towards screening. Dietary habits also influenced screening decisions. Notably, participants with healthier eating behaviors, indicated by factors such as regular breakfasts and fewer meals out, were more likely to undergo screening. Additionally, nutrient intake analysis revealed that those who had undergone screening consumed greater quantities of most nutrients, bar a few exceptions. For individuals aged 50-64, nutritional assessment indicators highlighted a higher mean adequacy ratio (MAR) and index of nutritional quality (INQ) value among those who participated in screening, suggesting better nutritional quality. This study elucidates the complex socio-ecological and nutritional landscape influencing cancer screening decisions. The results underscore the importance of a holistic approach, emphasizing lifestyle, dietary habits, and socio-economic considerations. It provides a roadmap for policymakers to craft more inclusive screening programs, ensuring equal access and promoting early detection.

In-vitro antioxidant, antimicrobial and phytochemical properties of extracts from the pulp and seeds of the African baobab fruit (Adansonia digitata L.).

Adansonia digitata, commonly known as the African Baobab plant is used widely in traditional medicine for treating of many diseases. The current study investigates the antioxidant and antimicrobial properties, and nutritional composition of the pulp and seeds from the fruit of African Baobab plant. Matured fruits were harvested and processed by separating the fruit pulp and seeds. Water, 70 % Ethanol/water mixture, and Hexane were used as solvents for extraction. Antioxidant properties of extracts in this study were investigated using the 2,2-diphenyl-1-picrylhydrazyl, hydrogen peroxidescavenging assays., Total Flavonoid Content, Total Phenolic Content, Total Tannin Content, and Total Antioxidant Capacity were also investigated. Agar Well Diffusion and Broth Dilution methods were used to estimate the antimicrobial properties of the extracts. The proximate composition of the seeds and fruit pulps was also determined. GC-MS was employed to determine the fatty acid composition. Results obtained showed the presence of Total phenolics (range 4.1-5.5 mg GAE/g), Total flavonoids (range 10.1-16.5 mg QE/g), Total Tannins (range 1.7-15.6 mg CE/g), and Antioxidants (range 2.0-14.5 mg AAE/g). The H2O2 and DPPH assays gave IC50s in the ranges of 300-1800 mg/L and 700-1600 mg/L respectively. Extract from the fruit pulp was found to inhibit the growth of a panel of 2 g-positive bacteria, 2 g-negative bacteria, and two fungi microorganisms. Fatty acids such as myristic acid, palmitic acid, and stearic acid were found to be present in oil from the seeds. Proximate components such as crude protein, crude fat, and crude fibre were found to be high. From the results, seeds and the fruit pulp of the African Baobab plant have significant antioxidant properties and can inhibit microbial growth.

An Adapted Questionnaire Tailored for Assessing the Risk of Vitamin D Deficiency in Children That Is Proving Useful in Guiding Clinical Interventions.

BACKGROUND: The identification of vitamin D (VitD) deficiency in pediatric populations is essential for preventive healthcare. We refined and tested the Evaluation of Deficiency Questionnaire (EVIDENCe-Q) for its utility in detecting VitD insufficiency among children. PATIENTS AND METHODS: We enrolled 201 pediatric patients (aged between 3 and 18 years). Clinical evaluation and serum vitamin D levels were assessed in all subjects. The EVIDENCe-Q was updated to incorporate factors influencing VitD biosynthesis, intake, assimilation, and metabolism, with scores spanning from 0 (optimal) to 36 (poor). RESULTS: We established scores for severe deficiency (<10 mg/dL) at 20, deficiency (<20 mg/dL) at 22, and insufficiency (<30 mg/dL) at 28. A score of 20 or greater was determined as the optimal cut-off for distinguishing VitD deficient from sufficient statuses, as evidenced by ROC curve analysis AUC = 0.7066; SE = 0.0841; sensitivity 100%, 95% CI 0.561-1. The most accurate alignment was seen with VitD insufficiency, defined as 25-OH-D3 < 20 ng/mL. CONCLUSIONS: This study confirms that the EVIDENCe-Q is a valid instrument for assessing the risk of vitamin D deficiency and insufficiency in children. It offers a practical approach for determining the need for clinical intervention and dietary supplementation of VitD in the pediatric population.

[Application status and challenges of molecular docking in development of traditional Chinese medicine].

Traditional Chinese medicine is precious treasure of ancient Chinese science and a key to unlocking the treasure trove of Chinese civilization. To elucidate the efficacy and mechanism of traditional Chinese medicines, scientists have been engaged in the research on the molecular basis and regulatory targets. Molecular docking is a computer-aided drug design method capable of visualizing the interaction between components and target proteins. With the progress in the modernization of traditional Chinese medicine and the advancement of algorithms and computing power, molecular docking has become an essential approach in the development of new traditional Chinese medicines. This article summarizes the recent research progress in molecular docking in the development of traditional Chinese medicine, aiming to provide valuable references for further screening of active components and offering insights for improving the development of new traditional Chinese medicines.

Challenges Addressing Lung Cancer Screening for Patients With Multimorbidity in Primary Care: A Qualitative Study.

PURPOSE: Many individuals who are eligible for lung cancer screening have comorbid conditions complicating their shared decision-making conversations with physicians. The goal of our study was to better understand how primary care physicians (PCPs) factor comorbidities into their evaluation of the risks and benefits of lung cancer screening and into their shared decision-making conversations with patients. METHODS: We conducted semistructured interviews by videoconference with 15 PCPs to assess the extent of shared decision-making practices and explore their understanding of the intersection of comorbidities and lung cancer screening, and how that understanding informed their clinical approach to this population. RESULTS: We identified 3 themes. The first theme was whether to discuss or not to discuss lung cancer screening. PCPs described taking additional steps for individuals with complex comorbidities to decide whether to initiate this discussion and used subjective clinical judgment to decide whether the conversation would be productive and beneficial. PCPs made mental assessments that factored in the patient's health, life expectancy, quality of life, and access to support systems. The second theme was that shared decision making is not a simple discussion. When PCPs did initiate discussions about lung cancer screening, although some believed they could provide objective information, others struggled with personal biases. The third theme was that ultimately, the decision to be screened was up to the patient. Patients had the final say, even if their decision was discordant with the PCP's advice. CONCLUSIONS: Shared decision-making conversations about lung cancer screening differed substantially from the standard for patients with complex comorbidities. Future research should include efforts to characterize the risks and benefits of LCS in patients with comorbidities to inform guidelines and clinical application.

The Role of Obesity in the Development of Preeclampsia.

PURPOSE OF REVIEW: This comprehensive review provides an in-depth exploration of the complex relationship between obesity and preeclampsia (PE) and emphasizes the clinical implications of this association. It highlights the crucial role of screening tools in assessing individual risk and determining the need for additional antenatal care among women with obesity. The review investigates various markers for identifying the risk of developing PE, while emphasizing the significance of interventions such as exercise, weight management, and a balanced diet in reducing the incidence of preeclampsia and improving outcomes for both mother and fetus. RECENT FINDINGS: Actually, there is a global pandemic of obesity, particularly among women of childbearing age and pregnant women. PE, which is characterized by maternal hypertension, proteinuria, and complications, affects 2-4% of pregnancies worldwide, posing significant risks to maternal and perinatal health. Women with obesity face an elevated risk of developing PE due to the systemic inflammation resulting from excess adiposity, which can adversely affect placental development. Adipose tissue, rich in proinflammatory cytokines and complement proteins, contributes to the pathogenesis of PE by promoting the expression of antiangiogenic factors in the mother. This review emphasizes the need for appropriate screening, interventions, and a holistic approach to reduce the incidence of preeclampsia and enhance maternal-fetal well-being, thus providing valuable insights into the multifaceted association between obesity and PE.

Hyperbilirubinemia screening and treatment in neonates born prior to 35 weeks of gestation.

BACKGROUND: Guidelines on when to screen for neonatal hyperbilirubinemia apply to infants born at 35 weeks or later of gestation. It is unknown whether infants born earlier would benefit from similar guidelines. Our objective was to examine hyperbilirubinemia screening and phototherapy prescription among early preterm infants during the first 6 days of life. METHODS: We reviewed the charts of 193 infants born prior to 35 weeks of gestation who were admitted to a tertiary care NICU in Southeastern Ontario in 2018-2019. Information on total serum bilirubin (TSB) measurements over each 12-hour interval during the first six days of life and the treatment decision (no treatment, initiate, continue, or stop phototherapy) was extracted. We also examined what proportion of infants were prescribed phototherapy during each 12-hour interval. RESULTS: Of 1006 TSB measurements performed over the first 6 days of life, 605 were done to determine whether phototherapy should be initiated. Treatment was prescribed in 275 instances (45%). A higher proportion of infants born prior to 28 weeks of gestation required phototherapy in the first 12 hours of life (37%) compared to those born at 28-32 weeks (20%) and 33-34 weeks (5.7%). CONCLUSIONS: Our results suggest that TSB measurements are often poorly timed to detect treatment need in infants born prior to 35 weeks of gestation. This unnecessarily increases the risk of complications from phlebotomy and is an ineffective use of health care resources. There is a need to develop guidelines to optimize hyperbilirubinemia screening among early preterm infants.

Discovery of a potent inhibitor, D-132, targeting AsfvPolX, via protein-DNA complex-guided pharmacophore screening and in vitro molecular characterizations.

The heightened transmissibility and capacity of African swine fever virus (ASFV) induce fatal diseases in domestic pigs and wild boars, posing significant economic repercussions and global threats. Despite extensive research efforts, the development of potent vaccines or treatments for ASFV remains a persistent challenge. Recently, inhibiting the AsfvPolX, a key DNA repair enzyme, emerges as a feasible strategy to disrupt viral replication and control ASFV infections. In this study, a comprehensive approach involving pharmacophore-based inhibitor screening, coupled with biochemical and biophysical analyses, were implemented to identify, characterize, and validate potential inhibitors targeting AsfvPolX. The constructed pharmacophore model, Phar-PolX-S, demonstrated efficacy in identifying a potent inhibitor, D-132 (IC50 = 2.8 ± 0.2 µM), disrupting the formation of the AsfvPolX-DNA complex. Notably, D-132 exhibited strong binding to AsfvPolX (KD = 6.9 ± 2.2 µM) through a slow-on-fast-off binding mechanism. Employing molecular modeling, it was elucidated that D-132 predominantly binds in-between the palm and finger domains of AsfvPolX, with crucial residues (R42, N48, Q98, E100, F102, and F116) identified as hotspots for structure-based inhibitor optimization. Distinctively characterized by a 1,2,5,6-tetrathiocane with modifications at the 3 and 8 positions involving ethanesulfonates, D-132 holds considerable promise as a lead compound for the development of innovative agents to combat ASFV infections.

In vitro antimicrobial and antibiofilm screening of eighteen Iranian medicinal plants.

BACKGROUND: Natural products are one of the best candidates for controlling drug-resistant pathogens, the advantages of which include low production costs and low side effects. In this study, as potential antimicrobials, the anti-bacterial and antibiofilm activities of several Iranian native medicinal plants were screened. METHODS: The antibacterial/antifungal and anti-biofilm activities of 18 medicinal plants including Reseda lutea L., Nepeta sintenisii Bunge., Stachys turcomanica Trautv., Stachys lavandulifolia Vahl, Diarthron antoninae (Pobed.) Kit Tan., Ziziphora clinopodioides Lam., Euphorbia kopetdaghi Prokh, Euphorbia serpens Kunth., Hymenocrater calycinus Benth., Scutellaria pinnatifida A.Ham., Viola tricolor L., Hypericum helianthemoides (Spach) Boiss., Hypericum scabrum L., Convolvulus lineatus L., Scabiosa rotata M.Bieb Greuter & Burdet, Delphinium semibarbatum Bien. Ex Boiss., Glycyrrhiza triphylla Fisch. & C.A.Mey., and Ziziphus jujuba Mill., against two Gram-positive bacteria, Staphylococcus aureus, Bacillus cereus, as well as two Gram-negative bacteria, Pseudomonas aeruginosa, Escherichia coli; and Candida albicans as a fungal strain, were evaluated. The minimum inhibitory concentration (MIC) and minimum bactericidal/fungicidal concentration (MBC/MFC) values of the extracts against tested microorganisms were reported and we investigated their effect on the biofilm inhibition of Pseudomonas aeruginosa PAO1, Staphylococcus epidermis, Staphylococcus aureus and Streptococcus mutans. In addition, the effect of the extracts on the eradication of the biofilms of these bacteria was evaluated. RESULTS: In this study, H. scabrum was found to exhibit potentially significant activity against Gram-positive bacteria with the MIC range of 6.25-25 µg/mL. This extract also showed a significant effect on inhibiting the biofilm of S. aureus, S. mutans, and S. epidermidis and eradicating the biofilm of S. epidermidis DSMZ 3270. In addition, Hymenocrater calycinus root extract had moderate antibacterial activity against B. cereus with the MIC and MBC 62.5 µg/mL, respectively. CONCLUSIONS: The results of this study showed that the root extracts of two plants, Hypericum scabrum and Hymenocrater calycinus, had antimicrobial and anti-biofilm effects. Based on the observed anti-biofilm effects, these two plants may be considered in future studies to find responsible antimicrobial compounds.

Screening for lung cancer with computed tomography: protocol for systematic reviews for the Canadian Task Force on Preventive Health Care.

PURPOSE: Lung cancer is the leading cause of cancer deaths in Canada, and because early cancers are often asymptomatic screening aims to prevent mortality by detecting cancer earlier when treatment is more likely to be curative. These reviews will inform updated recommendations by the Canadian Task Force on Preventive Health Care on screening for lung cancer. METHODS: We will update the review on the benefits and harms of screening with CT conducted for the task force in 2015 and perform de novo reviews on the comparative effects between (i) trial-based selection criteria and use of risk prediction models and (ii) trial-based nodule classification and different nodule classification systems and on patients' values and preferences. We will search Medline, Embase, and Cochrane Central (for questions on benefits and harms from 2015; comparative effects from 2012) and Medline, Scopus, and EconLit (for values and preferences from 2012) via peer-reviewed search strategies, clinical trial registries, and the reference lists of included studies and reviews. Two reviewers will screen all citations (including those in the previous review) and base inclusion decisions on consensus or arbitration by another reviewer. For benefits (i.e., all-cause and cancer-specific mortality and health-related quality of life) and harms (i.e., overdiagnosis, false positives, incidental findings, psychosocial harms from screening, and major complications and mortality from invasive procedures as a result of screening), we will include studies of adults in whom lung cancer is not suspected. We will include randomized controlled trials comparing CT screening with no screening or alternative screening modalities (e.g., chest radiography) or strategies (e.g., CT using different screening intervals, classification systems, and/or patient selection via risk models or biomarkers); non-randomized studies, including modeling studies, will be included for the comparative effects between trial-based and other selection criteria or nodule classification methods. For harms (except overdiagnosis) we will also include non-randomized and uncontrolled studies. For values and preferences, the study design may be any quantitative design that either directly or indirectly measures outcome preferences on outcomes pertaining to lung cancer screening. We will only include studies conducted in Very High Human Development Countries and having full texts in English or French. Data will be extracted by one reviewer with verification by another, with the exception of result data on mortality and cancer incidence (for calculating overdiagnosis) where duplicate extraction will occur. If two or more studies report on the same comparison and it is deemed suitable, we will pool continuous data using a mean difference or standardized mean difference, as applicable, and binary data using relative risks and a DerSimonian and Laird model unless events are rare (< 1%) where we will pool odds ratios using Peto's method or (if zero events) the reciprocal of the opposite treatment arm size correction. For pooling proportions, we will apply suitable transformation (logit or arcsine) depending on the proportions of events. If meta-analysis is not undertaken we will synthesize the data descriptively, considering clinical and methodological differences. For each outcome, two reviewers will independently assess within- and across-study risk of bias and rate the certainty of the evidence using GRADE (Grading of Recommendations Assessment, Development, and Evaluation), and reach consensus. DISCUSSION: Since 2015, additional trials and longer follow-ups or additional data (e.g., harms, specific patient populations) from previously published trials have been published that will improve our understanding of the benefits and harms of screening. The systematic review of values and preferences will allow fulsome insights that will inform the balance of benefits and harms. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42022378858.

Advancing preclinical drug evaluation through automated 3D imaging for high-throughput screening with kidney organoids.

High-throughput drug screening is crucial for advancing healthcare through drug discovery. However, a significant limitation arises from availablein vitromodels using conventional 2D cell culture, which lack the proper phenotypes and architectures observed in three-dimensional (3D) tissues. Recent advancements in stem cell biology have facilitated the generation of organoids-3D tissue constructs that mimic human organsin vitro. Kidney organoids, derived from human pluripotent stem cells, represent a significant breakthrough in disease representation. They encompass major kidney cell types organized within distinct nephron segments, surrounded by stroma and endothelial cells. This tissue allows for the assessment of structural alterations such as nephron loss, a characteristic of chronic kidney disease. Despite these advantages, the complexity of 3D structures has hindered the use of organoids for large-scale drug screening, and the drug screening pipelines utilizing these complexin vitromodels remain to be established for high-throughput screening. In this study, we address the technical limitations of kidney organoids through fully automated 3D imaging, aided by a machine-learning approach for automatic profiling of nephron segment-specific epithelial morphometry. Kidney organoids were exposed to the nephrotoxic agent cisplatin to model severe acute kidney injury. An U.S. Food and Drug Administration (FDA)-approved drug library was tested for therapeutic and nephrotoxicity screening. The fully automated pipeline of 3D image acquisition and analysis identified nephrotoxic or therapeutic drugs during cisplatin chemotherapy. The nephrotoxic potential of these drugs aligned with previousin vivoand human reports. Additionally, Imatinib, a tyrosine kinase inhibitor used in hematological malignancies, was identified as a potential preventive therapy for cisplatin-induced kidney injury. Our proof-of-concept report demonstrates that the automated screening process, using 3D morphometric assays with kidney organoids, enables high-throughput screening for nephrotoxicity and therapeutic assessment in 3D tissue constructs.

Therapeutic Potential of Traditional Oriental Medicines in Targeting Tau Pathology: Insights from Cell-free and Cell-based Screening.

BACKGROUND: Traditional Oriental Medicines (TOMs) formulated using a variety of medicinal plants have a low risk of side effects. In previous studies, five TOMs, namely Dangguijakyaksan, Hwanglyeonhaedoktang, Ukgansan, Palmijihwanghwan, and Jowiseungchungtang have been commonly used to treat patients with Alzheimer's disease. However, only a few studies have investigated the effects of these five TOMs on tau pathology. OBJECTIVE: This study aimed to examine the effect of five TOMs on various tau pathologies, including post-translational modifications, aggregation and deposition, tau-induced neurotoxicity, and tau-induced neuroinflammation. METHODS: Immunocytochemistry was used to investigate the hyperphosphorylation of tau induced by okadaic acid. In addition, the thioflavin T assay was used to assess the effects of the TOMs on the inhibition of tau K18 aggregation and the dissociation of tau K18 aggregates. Moreover, a water-soluble tetrazolium-1 assay and a quantitative reverse transcription polymerase chain reaction were used to evaluate the effects of the TOMs on tau-induced neurotoxicity and inflammatory cytokines in HT22 and BV2 cells, respectively. RESULTS: The five TOMs investigated in this study significantly reduced okadaic acid-induced tau hyperphosphorylation. Hwanglyeonhaedoktang inhibited the aggregation of tau and promoted the dissociation of tau aggregates. Dangguijakyaksan and Hwanglyeonhaedoktang attenuated tau-induced neurotoxicity in HT22 cells. In addition, Dangguijakyaksan, Hwanglyeonhaedoktang, Ukgansan, and Palmijihwanghwan reduced tauinduced pro-inflammatory cytokine levels in BV2 cells. CONCLUSION: Our results suggest that five TOMs are potential therapeutic candidates for tau pathology. In particular, Hwanglyeonhaedoktang showed the greatest efficacy among the five TOMs in cell-free and cell-based screening approaches. These findings suggest that Hwanglyeonhaedoktang is suitable for treating AD patients with tau pathology.

Cannabis use and cannabis use disorders and their treatment in the Europe.

This paper introduces the special issue on cannabis use in Europe. It describes data on the prevalence of cannabis use in Europe and the more limited data on the prevalence of cannabis use disorders, one of the most common forms of drug problem treated in many countries in Europe. It summarises what research has indicated about the adverse effects of acute and chronic cannabis use and discusses potential health system responses that may reduce some of these harms. These include public education about the risks of cannabis use; screening and brief interventions in primary medical settings; and specialist treatment for cannabis use disorders. It briefly indicates the special issues that may need to be addressed in dealing with the high rates of comorbidity between cannabis use disorders, other types of drug use disorders, and common mental disorders.

[Research Status and Trend of Screening for Women's Common Diseases in China].

Objective To visualize the research status and hotspots of women's common disease screening based on CiteSpace 6.1.R6,and to provide a reference for the in-depth research in this field thereafter. Methods The relevant articles were retrieved from the China National Knowledge Infrastructure with the time interval from January 1,1992 to December 13,2022.The analysis was conducted on the number of annual publications,countries(regions),institutions,author collaboration networks,keyword co-occurrence,clustering,and bursts. Results A total of 900 papers that met the criteria were included,and the number of annual publications showed a trend of first increasing and then decreasing.The cross-institutional collaboration network was mature.The research hotspots mainly covered women's health,the prevalence of women's diseases,reproductive health,and breast diseases.The hotspots have evolved from an initial focus on reproductive health care to gynecological disease management,and eventually to reproductive health and holistic health care in women. Conclusions The attention should be kept on the screening of women's common diseases.It is advisable to synchronize the screening of women's common diseases with the screening of cervical and breast cancers to expand the screening coverage,promote early disease detection and treatment,and comprehensively safeguard women's health.

Discovery of novel IDO1/TDO2 dual inhibitors: a consensus Virtual screening approach with molecular dynamics simulations, and binding free energy analysis.

The pursuit of effective cancer immunotherapy drugs remains challenging, with overexpression of indoleamine 2,3-dioxygenase 1 (IDO1) and tryptophan 2,3-dioxygenase 2 (TDO2) allowing cancer cells to evade immune attacks. While several IDO1 inhibitors have undergone clinical testing, only three dual IDO1/TDO2 inhibitors have reached human trials. Hence, this study focuses on identifying novel IDO1/TDO2 dual inhibitors through consensus structure-based virtual screening (SBVS). ZINC15 natural products library was refined based on molecular descriptors, and the selected compounds were docked to the holo form IDO1 and TDO2 using two different software programs and ranked according to their consensus docking scores. The top-scoring compounds underwent in silico evaluations for pharmacokinetics, toxicity, CYP3A4 affinity, molecular dynamics (MD) simulations, and MM-GBSA binding free energy calculations. Five compounds (ZINC00000079405/10, ZINC00004028612/11, ZINC00013380497/12, ZINC00014613023/13, and ZINC00103579819/14) were identified as potential IDO1/TDO2 dual inhibitors due to their high consensus docking scores, key residue interactions with the enzymes, favorable pharmacokinetics, and avoidance of CYP3A4 binding. MD simulations of the top three hits with IDO1 indicated conformational changes and compactness, while MM-GBSA analysis revealed strong binding free energy for compounds 10 (ΔG: -20.13 kcal/mol) and 11 (ΔG: -16.22 kcal/mol). These virtual hits signify a promising initial step in identifying candidates as supplementary therapeutics to immune checkpoint inhibitors in cancer treatment. Their potential to deliver potent dual inhibition of IDO1/TDO2, along with safety and favorable pharmacokinetics, makes them compelling. Validation through in vitro and in vivo assays should be conducted to confirm their activity, selectivity, and preclinical potential as holo IDO1/TDO2 dual inhibitors.Communicated by Ramaswamy H. Sarma.