Discovery and optimization of (2-naphthylthio)acetic acid derivative as selective Bfl-1 inhibitor.

Bcl-2 anti-apoptotic protein family suppresses cell death by deploying a surface groove to capture the critical BH3 α-helix of pro-apoptotic members. Bfl-1 is a relatively understudied member of this family, though it has been implicated in the pathogenesis and chemoresistance of a variety of human cancers. Reported small molecular Bfl-1 inhibitors encountered the issue of either lack in potency or poor selectivity against its most homologous member Mcl-1. In order to tackle this issue, compound library was screened and a hit compound UMI-77 was identified. We modified its chemical structure to remove the characteristic of PAINS (pan-assay interference compounds), demonstrated the real binding affinity and achieved selectivity against Mcl-1 under the guidance of computational modeling. After optimization 15 was obtained as leading compound to block Bfl-1/BIM interaction in vitro with more than 10-fold selectivity over Mcl-1. We believe 15 is of great value for the exploration of Bfl-1 biological function and its potential as therapeutic target.

Menstrual pain in Australian adolescent girls and its impact on regular activities: a population-based cohort analysis based on Longitudinal Study of Australian Children survey data.

OBJECTIVES: To determine the proportion of Australian adolescent girls who experience menstrual pain (dysmenorrhea); to assess associations of dysmenorrhea and period pain severity with adolescents missing regular activities because of their periods. STUDY DESIGN: Prospective, population-based cohort study; analysis of Longitudinal Study of Australian Children (LSAC) survey data. SETTING, PARTICIPANTS: Female adolescents in the nationally representative cross-sequential sample of Australian children recruited in 2004 for the Kinder cohort (aged 4-5 years at enrolment). Survey data from waves 6 (mean age 14 years), wave 7 (16 years) and wave 8 (18 years) were analysed. MAIN OUTCOME MEASURES: Severity of period pain during the preceding three months (very, quite, a little, or not at all painful); number of activity types missed because of periods; relationship between missing activities and period pain severity. RESULTS: Of the 1835 participating female members of the LSAC Kinder cohort at waves 6 to 8, 1600 (87%) responded to questions about menstruation during at least one of waves 6 to 8 of data collection. At wave 6 (14 years), 227 of 644 respondents (35%) reported dysmenorrhea, 675 of 1341 (50%) at wave 6 (16 years), and 518 of 1115 (46%) at wave 8 (18 years). Of the 366 participants who reported period pain severity at all three waves, 137 reported no dysmenorrhea at all three waves (37%), 66 reported dysmenorrhea at all three waves (18%), 89 reported increasing period pain over time (24%), and 38 reported declining pain (10%). At wave 6, 223 of 647 participants reported missing at least one activity because of their periods (34%), 454 of 1341 at wave 7 (34%), and 344 of 1111 at wave 8 (31%). Of the participants who experienced very painful periods, 72% (wave 6), 63% (wave 7), and 65% (wave 8) missed at least one activity type because of their periods, as did 45% (wave 6), 36% (wave 7), and 40% (wave 8) of those who experienced quite painful periods. CONCLUSIONS: A large proportion of adolescent girls in Australia experience period pain that affects their engagement in regular activities, including school attendance. Recognising adolescent period pain is important not only for enhancing their immediate quality of life with appropriate support and interventions, but also as part of early screening for chronic health conditions such as endometriosis.

The effect of lung-recruitment maneuver on postoperative shoulder pain in patients undergoing laparoscopic cholecystectomy: a randomized controlled trial.

PURPOSE: Lung-recruitment maneuvers (LRM) have been shown to reduce postoperative pain after laparoscopic surgery. This study aimed to investigate the association of LRM with the incidence of shoulder pain after laparoscopic cholecystectomy. METHODS: A randomized controlled study was conducted with 110 patients undergoing elective laparoscopic cholecystectomy from July 2022 to March 2023. Participants were randomized to receive either routine exsufflation or LRM at pneumoperitoneum release. The postoperative shoulder pain and abdominal pain were assessed at 1, 4, 6, 12, and 24 h after surgery using a numeric rating scale. Analgesic consumption and postoperative nausea or vomiting (PONV) were evaluated during the first 24 h after surgery. RESULTS: The incidence of shoulder pain during the first 24 h after surgery was significantly lower in the LRM group compared to the control group (26.9 vs. 59.3%; P = 0.001). The median [interquartile range] score of worst shoulder pain was significantly lower compared to the control group (3 [2-3] vs 4 [3-5.5]; P = 0.003). Participants in the LRM group showed reduced abdominal pain at rest at 4 and 24 h after surgery, and experienced significantly lower intensities of abdominal pain during mobilization at all time points over 24 h after surgery. There were no significant differences in opioid consumption or the incidence of PONV between the groups. CONCLUSIONS: LRM reduces both the incidence and intensity of shoulder pain during 24 h after laparoscopic cholecystectomy. Additionally, LRM was associated with reduced intensity of abdominal pain during mobilization over the study period.

The experiences of men in prison who do not receive visits from family or friends: A qualitative systematic review.

BACKGROUND: Visits present an opportunity for prisoners to preserve family ties and reduce isolation, but not all receive visits from family or friends whilst incarcerated. AIMS: To locate, appraise and synthesise qualitative data on the experiences of adult male prisoners (aged 18 years+) who do not receive prison visits from family or friends. METHODS: Nine electronic databases were searched from the date of their inception until March 2023. The quality of included studies was assessed using the Critical Appraisal Skills Programme checklist for qualitative studies, and data from the studies were synthesised using the thematic synthesis method. RESULTS: Eighteen studies from seven countries (the USA, the UK [England, Northern Ireland & Scotland], Canada, Netherlands and the Philippines) were eligible for inclusion. Three main themes emerged: (1) reasons for not receiving visits, (2) harmful effects of not receiving visits and (3) the value of volunteer visitor programmes. Practical problems were cited as interfering with visiting opportunities, but also some prisoners or families chose not to meet in prison. Loneliness and depression were extensively described as effects of not receiving visits. Qualities associated with volunteer visitors included raised self-esteem, improved mood and personal growth. CONCLUSION: Narratives of the experiences of adult men in prison without visits from family or friends suggest that not only the practical difficulties of imprisonment affect visiting; barriers that prisoners themselves impose would merit further exploration, as would family and relationship dynamics during incarceration and the emotional impact of prison visits, for both prisoners and their families. There are suggestions of therapeutic as well as humanitarian benefits from volunteer visiting programmes. There is a gap in the literature about any specific effect on rebuilding family relationships.

"Growing pains" in children and adolescents as an early symptom of migraine: A prospective study.

BACKGROUND: Children and adolescents may experience pain in the lower limbs, predominantly at the end of the day or during the night, without any relation to organic disease. These pains are often called "growing pains" (GP) by pediatricians and orthopedists. They are commonly attributed to rapid growth. OBJECTIVE: The aim of this study was to review and characterize GP in children and adolescents as a precursor/comorbidity with migraine. METHODS: The study was of a cross-sectional, prospective, longitudinal cohort, with group comparison. A sample of 100 children/adolescents born to mothers with migraine seen at a headache clinic was recruited in a random order chosen by lot, maintaining the ratio of 1:1 for the group with GP and the controls. Both groups were followed for a period of 5 years. RESULTS: After 5 years of follow-up, 78 patients completed the study, of which 42 were from the GP group and 36 were from the control group. Headache fulfilling the International Classification of Headache Disorders, 3rd edition diagnostic criteria for migraine without aura or probable migraine occurred in 32/42 (76%) of patients with GP and in 8/36 (22%) of controls (p < 0.001). In the sample that initially had "growing pains," these pains persisted in 6/42 (14%) and appeared in 14/36 (39%) of those who were previously asymptomatic (p = 0.026). CONCLUSIONS: Pain in the lower limbs of children and adolescents, commonly referred to as GP by pediatricians and orthopedists, may reflect a precursor or comorbidity with migraine.

Musculoskeletal pains among amateur and professional athletes of five disciplines in Senegal: a preliminary study.

BACKGROUND: Musculoskeletal pains (MSPs) in sport are cause of poor performances and loss of competition in athletes. The present study aimed at determining the prevalence of MSPs with regard to sport disciplines and athletic status. METHODS: A cross-sectional study was conducted among 320 Senegalese professional and amateur athletes practicing football, basketball, rugby, tennis, athletics, and wrestling. Rates of MSPs in the past year (MSPs-12) and week (MSPs-7d) were assessed using standard questionnaires. RESULTS: Overall proportions of MSPs-12 and MSPs-7d were 70 and 74.2%, respectively. MSPs-12 were more frequently reported on shoulders (40.6%), neck (37.1%) and hips/thigh (34.4%), while MSPs-7d were predominant on hips/thigh (29.5%), shoulders (25.7%), and upper back (17.2%). Proportions of MSPs-12 and MSPs-7d varied significantly by sport disciplines, with highest values among basketball players. Again, highest MSPs-12 proportions on shoulders (29.7%, P = 0.02), wrists/hands (34.6%, P = 0.001), (40.2%, P = 0.0002), and knees (38.8%, P = 0.002) were seen among basketball players. High proportions of MSPs-7d were seen on shoulders (29.6%, P = 0.04) for tennis players, wrists/hands (29.4%, P = 0.03) for basketball and football players, and hips/thigh (38.8%, P < 0.00001) for basketball players. Football players had reduced risk of MSPs-12 by 75% on lower back (OR = 0.25; 95% CI. 0.10-0.63; P = 0.003) and by 72% on knees (OR = 0.28; 95% CI. 0.08-0. 95; P = 0.04). In contrast, tennis players were more at risk of MSPs-12 on shoulders (OR = 3.14; 95% CI. 1.14-8.68; P = 0.02), wrists/hands (OR = 5.18; 95% CI.1.40-11.13; P = 0.01), and hips/thigh (OR = 2.90; 95% CI. 1.1-8.38; P = 0.04). Professionals were protected from MSPs-12 on neck pain with a significant reduction of risk by 61% (OR = 0.39, 95% CI. 0.21-0.75, P = 0.03). CONCLUSION: MSPs are a reality among athletes and their risk is modulated by sport disciplines, athletic status and gender.

Multi-ligand molecular docking, simulation, free energy calculations and wavelet analysis of the synergistic effects between natural compounds baicalein and cubebin for the inhibition of the main protease of SARS-CoV-2.

Combination drugs have been used for several diseases for many years since they produce better therapeutic effects. However, it is still a challenge to discover candidates to form a combination drug. This study aimed to investigate whether using a comprehensive in silico approach to identify novel combination drugs from a Chinese herbal formula is an appropriate and creative strategy. We, therefore, used Toujie Quwen Granules for the main protease (Mpro) of SARS-CoV-2 as an example. We first used molecular docking to identify molecular components of the formula which may inhibit Mpro. Baicalein (HQA004) is the most favorable inhibitory ligand. We also identified a ligand from the other component, cubebin (CHA008), which may act to support the proposed HQA004 inhibitor. Molecular dynamics simulations were then performed to further elucidate the possible mechanism of inhibition by HQA004 and synergistic bioactivity conferred by CHA008. HQA004 bound strongly at the active site and that CHA008 enhanced the contacts between HQA004 and Mpro. However, CHA008 also dynamically interacted at multiple sites, and continued to enhance the stability of HQA004 despite diffusion to a distant site. We proposed that HQA004 acted as a possible inhibitor, and CHA008 served to enhance its effects via allosteric effects at two sites. Additionally, our novel wavelet analysis showed that as a result of CHA008 binding, the dynamics and structure of Mpro were observed to have more subtle changes, demonstrating that the inter-residue contacts within Mpro were disrupted by the synergistic ligand. This work highlighted the molecular mechanism of synergistic effects between different herbs as a result of allosteric crosstalk between two ligands at a protein target, as well as revealed that using the multi-ligand molecular docking, simulation, free energy calculations and wavelet analysis to discover novel combination drugs from a Chinese herbal remedy is an innovative pathway.

Application of bone metabolic parameters in the diagnosis of growing pains.

OBJECTIVE: The present study aimed to assess the diagnostic significance of serum bone metabolic parameters in children with growing pains (GPs). METHODS: All patients diagnosed with GP and healthy controls matched with age and gender were recruited at the outpatient clinic of Children's Hospital at Zhejiang University School of Medicine from August 2016 to August 2021. In all subjects, serum levels of calcium (Ca), phosphorus (P), procollagen type-I N-terminal (PINP), parathormone (PTH), 25-hydroxyvitamin D (25-(OH)D), osteocalcin (OC), N-terminal cross-linked telopeptides of type-I collagen (CTX), and tartrate-resistant acid phosphatase type 5b (TRACP5b) were investigated. The univariate analysis, multivariate logistic regression analysis, and receiver operating characteristic (ROC) curve were used to identify the bone metabolic parameters factors for diagnosing GP. RESULTS: We enrolled 386 children with GP and 399 healthy controls in present study. The mean age of GP group was 5.319 years, and, primarily, the subjects were preschool-age children. The gender ratio (male-to-female) was 1.27 in GP group. After adjusting for age and gender, we identified that the serum levels of Ca (p < 0.001, OR: 25.039), P (p = 0.018, OR: 2.681), PINP (p < 0.001, OR: 1.002), and PTH (p = 0.036, OR: 0.988) were independent diagnostic factors associated with GP. Area under curve (AUC) of the ROC curves was in the order: PINP (0.612) > Ca (0.599) > P (0.583) > PTH (0.541). A combination of independent diagnostic factors and multivariable logistic regression analysis provided a refined logistic regression model to improve the diagnostic potential, of which the AUC had reached 0.655. CONCLUSIONS: Serum levels of Ca, P, PINP, and PTH could be independent diagnostic factors associated with GP. The logistic model was significantly superior to bone metabolic parameters for diagnosing GP.

A randomized, double-blind, placebo-controlled trial of vitamin D supplementation with or without calcium in community-dwelling vitamin D deficient subjects.

BACKGROUND: Although vitamin D deficiency is highly prevalent in the Middle East, very few studies have attempted to measure its health impact. AIMS: We aimed to assess whether vitamin D3 and calcium, either alone or in combination, have health benefit. METHODS: In a 2 × 2 factorial design double-blind, placebo-controlled trial, Community free living adults living in the city of Al Ain, UAE were randomly assigned to receive daily 2000 IU oral vitamin D3 alone, 600 mg calcium alone, oral vitamin D3 (2000 IU per day) combined with 600 mg calcium, or a placebo for 6 months. Primary outcomes were self-rated health and bone turnover markers. RESULTS: Of the 545 randomized, 277 subjects completed 6 months follow up. 25(OH)D levels marginally increased in the two groups received vitamin D3 alone or combined with calcium compared to the decline seen in those who received calcium supplement alone or a placebo. Sub-group analysis revealed that parathyroid hormone (PTH) concentration decreased and Calcium/creatinine ratio increased significantly in the combined vitamin D and Calcium group compared to the vitamin D alone or Calcium alone in contrast to the increase seen in the placebo group [p < 0.05 for between group difference at 6 months]. There were no statistically significant differences between the supplement and placebo groups at the 6 months follow-up in body weight, body mass index (BMI), blood pressure, body pains and general health. CONCLUSION: PTH concentration decreased and calcium/creatinine ratio increased in subjects who received vitamin D and Calcium together compared to those who received vitamin D alone. TRIAL REGISTRATION: NCT02662491 , First registered on 25 January 2016 ( https://register. CLINICALTRIALS: gov/prs/app/action/SelectProtocol?sid=S00060CE&selectaction=Edit&uid=U0001M6P&ts=3&cx=scu4cb , Last update: 05 August 2019.

[The disability of patients with amputation of upper and lower extremities in The Russian Federation].

The article presents characteristics of examined disabled patients with amputations of upper and lower extremities. The purpose of the study was to investigate demand of disability status in respondents (on gender, age, disability causes, amputation level, capability of moving in home conditions).

Bacterial Cytological Profiling Identifies Rhodanine-Containing PAINS Analogs as Specific Inhibitors of Escherichia coli Thymidylate Kinase In Vivo.

In this study, we sought to determine whether an in vivo assay for studying antibiotic mechanisms of action could provide insight into the activity of compounds that may inhibit multiple targets. Thus, we conducted an activity screen of 31 structural analogs of rhodanine-containing pan-assay interference compounds (PAINS). We identified nine active molecules against Escherichia coli and classified them according to their in vivo mechanisms of action. The mechanisms of action of PAINS are generally difficult to identify due to their promiscuity. However, we leveraged bacterial cytological profiling, a fluorescence microscopy technique, to study these complex mechanisms. Ultimately, we found that although some of our molecules promiscuously inhibit multiple cellular pathways, a few molecules specifically inhibit DNA replication despite structural similarity to related PAINS. A genetic analysis of resistant mutants revealed thymidylate kinase (essential for DNA synthesis) as an intracellular target of some of these rhodanine-containing antibiotics. This finding was supported by in vitro activity assays, as well as experiments utilizing a thymidylate kinase overexpression system. The analog that demonstrated the half-maximal inhibitory concentration in vitro and MIC in vivo displayed the greatest specificity for inhibition of the DNA replication pathway, despite containing a rhodamine moiety. Although it is thought that PAINS cannot be developed as antibiotics, this work showcases novel inhibitors of E. coli thymidylate kinase. Moreover, perhaps more importantly, this work highlights the utility of bacterial cytological profiling for studying the in vivo specificity of antibiotics and demonstrates that bacterial cytological profiling can identify multiple pathways that are inhibited by an individual molecule. IMPORTANCE We demonstrate that bacterial cytological profiling is a powerful tool for directing antibiotic discovery efforts because it can be used to determine the specificity of an antibiotic's in vivo mechanism of action. By assaying analogs of PAINS, molecules that are notoriously intractable and nonspecific, we (surprisingly) identify molecules with specific activity against E. coli thymidylate kinase. This suggests that structural modifications to PAINS can confer stronger inhibition by targeting a specific cellular pathway. While in vitro inhibition assays are susceptible to false-positive results (especially from PAINS), bacterial cytological profiling provides the resolution to identify molecules with specific in vivo activity.

Markers of vitamin D metabolism and premenstrual symptoms in healthy women with regular cycles.

STUDY QUESTION: Are insufficient 25-hydroxyvitamin D (25(OH)D) concentrations, and other markers of vitamin D metabolism, associated with premenstrual symptoms in healthy women with regular menstrual cycles? SUMMARY ANSWER: 25(OH)D insufficiency was associated with specific physical premenstrual symptoms, while no associations were observed with psychological symptoms or with other markers of vitamin D metabolism. WHAT IS KNOWN ALREADY: Prior studies evaluating vitamin D and premenstrual symptoms have yielded mixed results, and it is unknown whether 25(OH)D insufficiency and other markers of vitamin D metabolism are associated with premenstrual symptoms. STUDY DESIGN, SIZE, DURATION: We used two cohorts of women with regular menstrual cycles; 1191 women aged 18-40 years in EAGeR (cross-sectional analysis of a prospective cohort within a randomized trial) and 76 women aged 18-44 years in BioCycle (prospective cohort). In EAGeR, premenstrual symptoms over the previous year were assessed at baseline, whereas in BioCycle, symptoms were assessed prospectively at multiple points over two menstrual cycles with symptoms queried over the previous week. In both cohorts, symptomatology was assessed via questionnaire regarding presence and severity of 14 physical and psychological symptoms the week before and after menses. Both studies measured 25(OH)D in serum. We also evaluated the association of additional markers of vitamin D metabolism and calcium homeostasis, including intact parathyroid hormone (iPTH), calcium (Ca), fibroblast growth factor 23 (FGF23), and 1,25 dihydroxyvitamin D (1,25(OH)2D) with premenstrual symptoms in the BioCycle cohort. PARTICIPANTS/MATERIALS, SETTING, METHODS: One cohort of women actively seeking pregnancy (Effects of Aspirin in Gestation and Reproduction (EAGeR)) and one cohort not seeking pregnancy (BioCycle) were evaluated. Log-binomial regression was used to estimate risk ratios (RR) and 95% CIs for associations between insufficient 25(OH)D (<30 ng/ml) and individual premenstrual symptoms, adjusting for age, BMI, race, smoking, income, physical activity, and season of blood draw. MAIN RESULTS AND THE ROLE OF CHANCE: 25(OH)D insufficiency was associated with increased risk of breast fullness/tenderness (EAGeR RR 1.27, 95% CI 1.03, 1.55; BioCycle RR 1.37, 95% CI 0.56, 3.32) and generalized aches and pains (EAGeR RR 1.33, 95% CI 1.01, 1.78; BioCycle 1.36, 95% CI 0.41, 4.45), though results were imprecise in the BioCycle study. No associations were observed between insufficient 25(OH)D and psychological symptoms in either cohort. In BioCycle, iPTH, Ca, FGF23, and 1,25(OH) 2D were not associated with any premenstrual symptoms. LIMITATIONS, REASONS FOR CAUTION: Results from the EAGeR study were limited by the study design, which assessed both 25(OH)D at baseline and individual premenstrual symptoms over the past year at the baseline. As such, reverse causality is a potential concern. Though premenstrual symptoms were assessed prospectively in the BioCycle cohort, the power was limited due to small sample size. However, results were fairly consistent across both studies. WIDER IMPLICATIONS OF THE FINDINGS: Serum 25(OH)D may be associated with risk and severity of specific physical premenstrual symptoms. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland (Contract nos. HHSN267200603423, HHSN267200603424, and HHSN267200603426). JG.R. and D.L.K. have been funded by the NIH Medical Research Scholars Program, a public-private partnership jointly supported by the NIH and generous contributions to the Foundation for the NIH by the Doris Duke Charitable Foundation (Grant #2014194), the American Association for Dental Research, the Colgate Palmolive Company, Genentech, and other private donors. For a complete list, visit the foundation website at http://www.fnih.org. The authors have no conflicts of interest to disclose. TRIAL REGISTRATION NUMBER: Clinicaltrials.gov NCT00467363.

Barriers to Small Molecule Drug Discovery for Systemic Amyloidosis.

Inhibition of amyloid fibril formation could benefit patients with systemic amyloidosis. In this group of diseases, deposition of amyloid fibrils derived from normally soluble proteins leads to progressive tissue damage and organ failure. Amyloid formation is a complex process, where several individual steps could be targeted. Several small molecules have been proposed as inhibitors of amyloid formation. However, the exact mechanism of action for a molecule is often not known, which impedes medicinal chemistry efforts to develop more potent molecules. Furthermore, commonly used assays are prone to artifacts that must be controlled for. Here, potential mechanisms by which small molecules could inhibit aggregation of immunoglobulin light-chain dimers, the precursor proteins for amyloid light-chain (AL) amyloidosis, are studied in assays that recapitulate different aspects of amyloidogenesis in vitro. One molecule reduced unfolding-coupled proteolysis of light chains, but no molecules inhibited aggregation of light chains or disrupted pre-formed amyloid fibrils. This work demonstrates the challenges associated with drug development for amyloidosis, but also highlights the potential to combine therapies that target different aspects of amyloidosis.

Problems that Can Occur when Assaying Extracts to Pure Compounds in Biological Systems.

For a significant number of years, scientists of many persuasions have assayed natural product materials ranging from crude extracts to pure compounds, in a multitude of assays causally related to some biological processes. However, in a very significant number of submitted papers and published articles, what may be considered as canned biological assays were used, and if a positive effect was observed, then the authors would claim that the material assayed was a potential drug lead. This also occurred with pure synthetic compounds and compounds derived from natural products by simple chemical modifications. However, what has now become quite obvious-with all such classes of materials-is that there are many promiscuous players with multiple bioactivities. These can range from relatively crude extracts, pure compounds from natural products, synthetic processes that produce natural product derivatives, and even compounds that are truly synthetic in origin. There is also a potential problem with the data from crude to purified extracts being used to claim some form of beneficial activities for such materials, to sell that particular mixture to the lay public, by very careful descriptions of its possible uses due to legal hurdles. With the advent of artificial intelligence and very large compound databases, some of which may well contain impure materials, scientists from a variety of backgrounds have begun to utilize such listings to obtain compounds for their low to high throughput biological screens, without realizing that there are very significant numbers of active compounds (eg, pan assay interference compounds and invalid metabolic panaceas), that will hit in many different screens for a variety of reasons, thus leading to significant wasted efforts and published scientific articles that have incorrect results. This commentary gives some of the history of such materials but is designed to be used as a warning to both researchers and in particular, journal editors, and reviewers, that reports of biological results that are claimed to be the result of the compounds used, need to be very carefully screened for results due to such promiscuous compounds, irrespective of their nominal source(s). All literature searches were made by the author and the background knowledge has come from more than 55 years of research in industry and governmental laboratories in both the United Kingdom and the United States, for enzyme inhibitors/activators as well as antimicrobial and antitumor lead compounds mainly from natural product sources. The conclusion that I came up with as a result is this: Caveat emptor. (Curr Ther Res Clin Exp. 2021; 82:XXX-XXX) © 2021 Elsevier HS Journals, Inc.

Non-Carbohydrate Glycomimetics as Inhibitors of Calcium(II)-Binding Lectins.

Because of the antimicrobial resistance crisis, lectins are considered novel drug targets. Pseudomonas aeruginosa utilizes LecA and LecB in the infection process. Inhibition of both lectins with carbohydrate-derived molecules can reduce biofilm formation to restore antimicrobial susceptibility. Here, we focused on non-carbohydrate inhibitors for LecA to explore new avenues for lectin inhibition. From a screening cascade we obtained one experimentally confirmed hit, a catechol, belonging to the well-known PAINS compounds. Rigorous analyses validated electron-deficient catechols as millimolar LecA inhibitors. The first co-crystal structure of a non-carbohydrate inhibitor in complex with a bacterial lectin clearly demonstrates the catechol mimicking the binding of natural glycosides with LecA. Importantly, catechol 3 is the first non-carbohydrate lectin ligand that binds bacterial and mammalian calcium(II)-binding lectins, giving rise to this fundamentally new class of glycomimetics.

Design of Drug-Like Protein-Protein Interaction Stabilizers Guided By Chelation-Controlled Bioactive Conformation Stabilization.

Protein-protein interactions (PPIs) of 14-3-3 proteins are a model system for studying PPI stabilization. The complex natural product Fusicoccin A stabilizes many 14-3-3 PPIs but is not amenable for use in SAR studies, motivating the search for more drug-like chemical matter. However, drug-like 14-3-3 PPI stabilizers enabling such studies have remained elusive. An X-ray crystal structure of a PPI in complex with an extremely low potency stabilizer uncovered an unexpected non-protein interacting, ligand-chelated Mg2+ leading to the discovery of metal-ion-dependent 14-3-3 PPI stabilization potency. This originates from a novel chelation-controlled bioactive conformation stabilization effect. Metal chelation has been associated with pan-assay interference compounds (PAINS) and frequent hitter behavior, but chelation can evidently also lead to true potency gains and find use as a medicinal chemistry strategy to guide compound optimization. To demonstrate this, we exploited the effect to design the first potent, selective, and drug-like 14-3-3 PPI stabilizers.

In vitro and in vivo evaluation of the antimalarial MMV665831 and structural analogs.

Antimalarial candidates possessing novel mechanisms of action are needed to control drug resistant Plasmodium falciparum. We were drawn to Malaria Box compound 1 (MMV665831) by virtue of its excellent in vitro potency, and twelve analogs were prepared to probe its structure-activity relationship. Modulation of the diethyl amino group was fruitful, producing compound 25, which was twice as potent as 1 against cultured parasites. Efforts were made to modify the phenolic Mannich base functionality of 1, to prevent formation of a reactive quinone methide. Homologated analog 28 had reduced potency relative to 1, but still inhibited growth with EC50 ≤ 200 nM. Thus, the antimalarial activity of 1 does not derive from quinone methide formation. Chemical stability studies on dimethyl analog 2 showed remarkable hydrolytic stability of both the phenolic Mannich base and ethyl ester moieties, and 1 was evaluated for in vivo efficacy in P. berghei-infected mice (40 mg/kg, oral). Unfortunately, no reduction in parasitemia was seen relative to control. These results are discussed in the context of measured plasma and hepatocyte stabilities, with reference to structurally-related, orally-efficacious antimalarials.

Efficacy of phloroglucinol for the treatment of pain of gynaecologic or obstetrical origin: a systematic review of literature of randomised controlled trials.

PURPOSE: Antispasmodics like phloroglucinol are commonly used to alleviate pain. Various authorities recommend the use of this drug for conditions such as dysmenorrhoea, threatened abortion or labour pains. The goal was to carry out a systematic review analysing the existing data concerning the efficacy of phloroglucinol to treat pain in obstetrical or gynaecologic cases. The protocol was registered in Prospero (CRD 42018094065). METHODS: The keywords "phloroglucinol" and "randomised controlled trials" were used to search Medline, Embase and the Cochrane Library. We selected randomised, controlled against placebo trials testing the effect of phloroglucinol on gynaecologic or obstetrical pain either as a primary or secondary endpoint. We excluded trials exploring pain caused by intestinal, renal, metabolic or other causes and trials that were not available for critical review in either English or French. A quantitative synthesis (meta-analysis) was planned if the included trials were sufficiently homogenous. If this were not the case, a descriptive synthesis would be presented. RESULTS: Twelve trials identified studied the effect of phloroglucinol in gynaecologic or obstetrical conditions. Only two trials corresponded to the inclusion criteria of this review, one of which was not available for critical review. CONCLUSIONS: Phloroglucinol is not well evaluated in this field. Whether for labour pains, abortion pains or benign gynaecologic pains, the results found are insufficient to promote the use of this drug in these indications.

Anti-Trypanosoma cruzi activity of costic acid isolated from Nectandra barbellata (Lauraceae) is associated with alterations in plasma membrane electric and mitochondrial membrane potentials.

As part of our continuous studies on prospecting metabolites from Brazilian plant species with pharmacologic activity against Trypanosoma cruzi, the n-hexane extract from twigs of Nectandra barbellata (Lauraceae) was subjected to a bioactivity-guided fractionation to afford the sesquiterpene costic acid. As results, costic acid induced a trypanocidal effect with IC50 of 37.8 and 7.9 µM to trypomastigotes and intracellular amastigotes, respectively. When tested in L929 cells, no cytotoxicity was detected in the highest tested concentration (CC50 > 200 µM), resulting in SI values >5 and >25 to trypomastigotes and amastigotes, respectively. Based on these promising results against T. cruzi, a mechanistic study of the parasite death was investigated. The flow cytometry analysis of costic acid-treated parasites showed depolarization of the plasma membrane electric potential. Spectrofluorimetrical analysis and transmission electron microscopy showed no evidence of plasma membrane permeability alteration of trypomastigotes, but strong ultrastructural damage, evidenced by large vacuoles. Although Ca2+ and reactive oxygen species (ROS) levels were unaltered after short time incubation with costic acid, it rapidly affected the mitochondria, leading to a depolarized potential of the membrane, reducing the ATP levels. In silico studies of costic acid showed good predictions for drug-likeness, with adherence to Lipinskís rules of five (RO5), good ADMET properties and no alerts for Pan-Assay Interference Compounds (PAINS). Therefore, costic acid demonstrated promising activity against T. cruzi parasites, with high selectivity to intracellular amastigotes. Considering the lethal action of costic acid in affecting a vital and unique organelle as the mitochondria, it could be considered a new hit compound for future drug design studies for Chagas disease.

Evaluating the effectiveness of TENS for maternal satisfaction in laboring parturients - Comparison with epidural analgesia.

BACKGROUND AND AIMS: Labor pain is one of the most severe pain that a woman experiences in her lifetime. Various methods are being used to relieve this pain and to achieve higher maternal satisfaction. One such technique is transcutaneous electrical nerve stimulation (TENS) that uses low-frequency electrotherapy. The aim of our study was to evaluate TENS by comparing it to an established labor analgesia technique, i.e., epidural analgesia in terms of maternal satisfaction. MATERIAL AND METHODS: This prospective study was conducted on 60 parturients in active stage of labor. The choice of analgesia was made by the parturient after informed consent. In group A (n = 30) TENS was used, while in group B (n = 30) epidural ropivacaine 0.125% + 2 µg/ml fentanyl was given. Continuous monitoring of maternal vitals, visual analogue score, and fetal heart rate (FHR) was done. Maternal satisfaction was scored considering pain relief, ability to move and experience of labor at the end of delivery and outcome was labeled as favorable and unfavorable. RESULTS: TENS was found to be favorable in 90% of parturients as compared to 96.6% in epidural (P 0.301). The number of highly satisfied parturients was 4 (13.3%) in TENS group and 17 (56.6%) in the epidural group (P= 0.000). Three patients in the epidural group had assisted delivery and two had cesarean section whereas all patients in TENS group delivered normally (P= 0.065). No significant difference was found in the fetal outcome. CONCLUSIONS: TENS is a good alternate choice for providing labor analgesia and may have a major role in future.