Determining the 3-substituted Coumarins inhibitory potential against the HslV protease of E. coli.

OBJECTIVE: The growing bacterial resistance towards classical antibiotics demands the development of novel approaches for the effective treatment of potentially fatal bacterial infections in humans. Proteostasis is crucial for the survival of every living cell, as several important physiological functions depend on well-regulated proteostasis. Within bacteria, the regulation of proteostasis relies on AAA+ (Adenosine 5'-triphosphatases associated with diverse cellular activities), ATPases, such as the HslVU complex (heat shock locus gene products U and V), along with other proteases. The HslVU protease/chaperon complex is thought to be the progenitor of the eukaryotic proteasome that regulates proteostasis mostly in prokaryotes. This study aimed to determine the inhibitory potential of 3-substituted coumarin derivatives against Escherichia coli heat shock locus V (HslV) protease. MATERIALS AND METHODS: In this study, twenty-three derivatives of 3-substituted coumarin were assessed for their inhibitory potential against E. coli HslV protease using both in-vitro and in-silico techniques. RESULTS: Among all the tested compounds, US-I-64, US-I-66, US-I-67, and US-I-68 displayed notable inhibitory potential against the HslV protease, showing IC50 (half maximal inhibitory concentration) values ranging from 0.2 to 0.73 µM. Additionally, the inhibitory potential of these compounds against the eukaryotic proteasome was also evaluated using a separate in-silico study. It was found that these compounds did not bind with the proteasomal active site, suggesting no apparent side effects of these lead molecules. CONCLUSIONS: These identified HslV protease inhibitors can be used for the development of novel and safer anti-bacterial drugs.

Inhibitory potential of triazines and hydrazinyl thiazole substituted chromones against the HslVU protease/chaperone complex, a novel drug target.

OBJECTIVE: Proteostasis is an important process occurring in all living cells and is highly indispensable for cell survival. The HslVU protease/chaperone complex's critical role in regulating proteostasis to maintain a healthy cellular proteome and its presence in pathogenic microbes made it an important drug target. This study aimed to identify small molecular inhibitors of the HslV protease. MATERIALS AND METHODS: Herein, a library of small molecules belonging to the triazine and chromone families has been evaluated for their inhibitory potential against the E. coli HslV protease using both in silico and in vitro techniques. RESULTS: Four compounds, i.e., SHS-II-123a, SHS-II-147a, US-IV-89, and US-IV-92, were identified as potential inhibitors of the HslV protease having IC50 values in the range of 0.1 to 0.32 µM. Additionally, these compounds' drug-likeness and ADMET profiles indicated their compatibility to be considered safer drug candidates. CONCLUSIONS: To the best of our knowledge, this is the first report on small molecules having inhibitory effects on the HslVU complex. These identified compounds can be efficiently subjected to further investigations to develop novel and safer antimicrobial agents.

Impaired differentiation of small airway basal stem/progenitor cells in people living with HIV.

With highly active anti-retroviral therapy (HAART), higher incidence of airway abnormalities is common in the HIV population consistent with the concept of accelerated lung "aging". Our previous findings demonstrated that HIV induces human airway basal cells (BC) into destructive and inflammatory phenotypes. Since BC function as stem/progenitor cells of the small airway epithelium (SAE), responsible for self-renewal and differentiation of SAE, we hypothesized that BC from people living with HIV (PLWH) may have altered differentiation capacity that contribute to premature aging. The data demonstrates that BC from PLWH have impaired capacity to differentiate in vitro and senescent phenotypes including shortened telomeres, increased expression of ß-galactosidase and cell cycle inhibitors, and mitochondrial dysfunction. In vitro studies demonstrated that BC senescence is partly due to adverse effects of HAART on BC. These findings provide an explanation for higher incidence of airway dysfunction and accelerated lung aging observed in PLWH.

Author Correction: Inhibitory potential of triazines and hydrazinyl thiazole substituted chromones against the HslVU protease/chaperone complex, a novel drug target.

Correction to: European Review for Medical and Pharmacological Sciences 2022; 26 (22): 8567-8575. DOI: 10.26355/eurrev_202211_30392-PMID: 36459037-published online on November 30, 2022. After publication, the authors applied some corrections to the text: - Dr. U. Salar's affiliation has been corrected as follows: Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, Karachi, Pakistan. - The values in the row "Binding energy with HsIV (Kcal/mol)" Table I have been corrected as follows: from -8.4 into -9.0; from -8.6 into -9.2; from -8.0 into -8.5 from -8.3 into -8.7. There are amendments to this paper. The Publisher apologizes for any inconvenience this may cause. https://www.europeanreview.org/article/30392.

HIV induces airway basal progenitor cells to adopt an inflammatory phenotype.

Despite the introduction of anti-retroviral therapy, chronic HIV infection is associated with an increased incidence of other comorbidities such as COPD. Based on the knowledge that binding of HIV to human airway basal stem/progenitor cells (BC) induces a destructive phenotype by increased MMP-9 expression through MAPK signaling pathways, we hypothesized that HIV induces the BC to express inflammatory mediators that contribute to the pathogenesis of emphysema. Our data demonstrate that airway BC isolated from HAART-treated HIV+ nonsmokers spontaneously release inflammatory mediators IL-8, IL-1ß, ICAM-1 and GM-CSF. Similarly, exposure of normal BC to HIV in vitro up-regulates expression of the same inflammatory mediators. These HIV-BC derived mediators induce migration of alveolar macrophages (AM) and neutrophils and stimulate AM proliferation. This HIV-induced inflammatory phenotype likely contributes to lung inflammation in HIV+ individuals and provides explanation for the increased incidence of COPD in HIV+ individuals.

Unusual Cystic Fibrosis Transmembrane Conductance Regulator Mutations and Liver Disease: A Case Series and Review of the Literature.

Cystic fibrosis (CF) is caused by a mutation in the CF transmembrane conductance regulator (CFTR) gene, deranging the activity of chloride channels on the epithelial cell surface. Herein we describe end-stage liver disease in 3 infants with rare CFTR gene mutations; 2 of them were heterozygous. Case 1 was a premature male infant with negative CF screening at birth who developed a small bowel obstruction in the neonatal period requiring an ileostomy, with subsequent cholestatic liver disease and portal hypertension. In addition, he was noted to have frequent respiratory infections prompting a sweat test, which was positive. Genetic testing revealed that he was heterozygous for P.1177F. He then underwent a successful liver transplant. Case 2 was a female infant who developed progressive cholestasis with poor weight gain and was found to have neonatal hepatitis on liver biopsy. A sweat test was negative and genetic testing revealed she was heterozygous for CFTR and PEX26 gene mutations. She subsequently developed pneumatosis involving the cecum that was treated conservatively, followed by a successful liver transplant. Case 3 was a male infant who developed progressive liver disease, with liver biopsy showing neonatal hepatitis. He was extensively investigated but had a negative sweat test on repeated studies. Genetic testing revealed that the patient was heterozygous P.K186N-variant in the AKRID1 gene and homozygous P.R75Q-variant in the CFTR gene. Unfortunately, he succumbed to an acute upper gastrointestinal hemorrhage. Rare and unusual CFTR mutations, even in the heterozygous form, may be a feature in otherwise undiagnosed end-stage liver disease of infancy.

Patellofemoral morphology and alignment: reference values and dose-response patterns for the relation to MRI features of patellofemoral osteoarthritis.

OBJECTIVE: We aimed to (1) determine reference values for trochlear morphology and patellofemoral (PF) alignment in adults without magnetic resonance imaging (MRI)-defined PF full thickness cartilage damage or knee pain; and (2) evaluate dose-response patterns for these measures with prevalent MRI-defined PF structural damage and/or knee pain. DESIGN: The Framingham Community Cohort is a population-based sample of ambulatory adults aged ≥50 years. We evaluated six morphology and alignment measures using MRI (n = 985), and reported reference values (mean ± 2SD) in a subsample without MRI-defined PF full thickness cartilage damage or knee pain (n = 563). With restricted cubic spline Poisson regression, we evaluated dose-response patterns of each of the six measures with prevalent MRI-defined PF structural damage or joint pain. Our primary outcome was full thickness cartilage damage. RESULTS: For dose-response curves, prevalence ratios (PR) increased monotonically for all measures except patellar tilt, which rose with both lateral and medial tilt. Associations were generally strongest in the lateral PF compartment. PR for the strongest predictors of full thickness cartilage damage reached clinical relevance (PR > 1.5) at sulcus angle (SA) ≥135.0°; patellar tilt angle at ≤1.0° and ≥15.0°; and bisect offset ≥57.0%. Lateral trochlear inclination (LTI) achieved PR > 1.5 at ≤23.0° for full thickness cartilage damage with pain. CONCLUSIONS: SA, patellar tilt, and bisect offset were most strongly associated with full thickness cartilage damage. LTI, patellar tilt and bisect offset had stronger associations with the addition of pain. These findings contribute to better identifying a subset of patients who may benefit from mechanically based interventions.

HIV Reprograms Human Airway Basal Stem/Progenitor Cells to Acquire a Tissue-Destructive Phenotype.

While highly active anti-retroviral therapy has dramatically improved the survival of HIV-infected individuals, there is an increased risk for other co-morbidities, such as COPD, manifesting as emphysema. Given that emphysema originates around the airways and that human airway basal cells (BCs) are adult airway stem/progenitor cells, we hypothesized that HIV reprograms BCs to a distinct phenotype that contributes to the development of emphysema. Our data indicate that HIV binds to but does not replicate in BCs. HIV binding to BCs induces them to acquire an invasive phenotype, mediated by upregulation of MMP-9 expression through activation of MAPK signaling pathways. This HIV-induced "destructive" phenotype may contribute to degradation of extracellular matrix and tissue damage relevant to the development of emphysema commonly seen in HIV+ individuals.

Interseason variability of a functional movement test, the 9+ screening battery, in professional male football players.

BACKGROUND: The Nine Plus screening battery test (9+) is a functional movement test intended to identify limitations in fundamental movement patterns predisposing athletes to injury. However, the interseason variability is unknown. AIM: To examine the variability of the 9+ test between 2 consecutive seasons in professional male football players. METHODS: Asymptomatic Qatar Star League players (n=220) completed the 9+ at the beginning of the 2013 and 2014 seasons. Time-loss injuries in training and matches were obtained from the Aspetar Injury and Illness Surveillance Program. No intervention was initiated between test occasions. RESULTS: A significant increase in the mean total score of 1.6 points (95% CI 1.0 to 2.2, p<0.001) was found from season 1 (22.2±4.1 (SD)) to season 2 (23.8±3.3). The variability was large, as shown by an intraclass correlation coefficient (ICC) of 0.24 (95% CI 0.11 to 0.36) and a minimal detectable change (MDC) of 8.7 points. Of the 220 players, 136 (61.8%) suffered a time-loss injury between the 2 tests. There was an improvement in mean total scores in the injured (+2.0±0.4 (SE), p<0.001) group but not in the uninjured group (+0.9±0.5, p=0.089). The variability from season 1 to season 2 was large both in the injured (ICC 0.25, 0.09 to 0.40, MDC 8.3) and uninjured (ICC 0.24, 0.02 to 0.43, MDC 9.1) groups. CONCLUSIONS: The 9+ demonstrated substantial intraindividual variability in the total score between 2 consecutive seasons, irrespective of injury. A change above 8 points is necessary to represent a real change in the 9+ test between seasons.

Consensus statement on the methodology of injury and illness surveillance in FINA (aquatic sports).

BACKGROUND: Injury and illness surveillance in the aquatic disciplines has been conducted during the FINA World Championships and Olympic Games. The development of an aquatic-specific injury and illness surveillance system will improve the quality of the data collected and the development of preventive measures. Our ultimate objective is to enhance aquatic athlete health and performance. OBJECTIVE: The objective was to refine the injury and illness surveillance protocols to develop aquatic-specific definitions of injury and illness; define aquatic-specific injury location and causation; better describe overuse injuries; regard pre-existing and recurrent injuries; more accurately define aquatic athlete exposures and develop a protocol to capture out-of-competition aquatic athlete health parameters. METHODS: FINA compiled an Injury and Illness Surveillance Expert Working Group comprised of international experts to review the scientific literature in the field. A consensus meeting was convened to provide an opportunity for debate, following which recommendations were collated. RESULTS: Aquatic-specific injury and illness surveillance protocols covering both the in-competition and out-of-competition time periods were developed. Definitions for all relevant variables were outlined, and documentation forms for athletes and for clinicians were proposed. Recommendations for the implementation of an injury and illness surveillance system for FINA are presented. CONCLUSION: The FINA consensus authors recommend ongoing in-competition and out-of-competition surveillance to determine injury and illness trends over time. The implementation of the definitions and methodology outlined in this paper will improve the accuracy and value of injury and illness surveillance, and provide important information for injury prevention.

Development of new UV-vis spectroscopic microwave-assisted method for determination of glucose in pharmaceutical samples.

A new UV-Visible spectroscopic method assisted with microwave for the determination of glucose in pharmaceutical formulations was developed. In this study glucose solutions were oxidized by ammonium molybdate in the presence of microwave energy and reacted with aniline to produce a colored solution. Optimum conditions of the reaction including wavelength, temperature, and pH of the medium and relative concentration ratio of the reactants were investigated. It was found that the optimal wavelength for the reaction is 610 nm, the optimal reaction time is 80s, the optimal reaction temperature is 160°C, the optimal reaction pH is 4, and the optimal concentration ratio aniline/ammonium molybdate solution was found to be 1:1. The limits of detection and quantification of the method are 0.82 and 2.75 ppm for glucose solution, respectively. The use of microwaves improved the speed of the method while the use of aniline improved the sensitivity of the method by shifting the wavelength.

Cognitive status is a determinant of health resource utilization among individuals with a history of falls: a 12-month prospective cohort study.

SUMMARY: Falls are a costly public health problem worldwide. The literature is devoid of prospective data that identifies factors among fallers that significantly drive health care resource utilization. We found that cognitive function--specifically, executive functions--and cognitive status are significant determinants of health resource utilization among older fallers. INTRODUCTION: Although falls are costly, there are no prospective data examining factors among fallers that drive health care resource utilization. We identified key determinants of health resource utilization (HRU) at 6 and 12 months among older adults with a history of falls. Specifically, with the increasing recognition that cognitive impairment is associated with increased falls risk, we investigated cognition as a potential driver of health resource utilization. METHODS: This 12-month prospective cohort study at the Vancouver Falls Prevention Clinic (n = 319) included participants with a history of at least one fall in the previous 12 months. Based on their cognitive status, participants were divided into two groups: (1) no mild cognitive impairment (MCI) and (2) MCI. We constructed two linear regression models with HRU at 6 and 12 months as the dependent variables for each model, respectively. Predictors relating to mobility, global cognition, executive functions, and cognitive status (MCI versus no MCI) were examined. Age, sex, comorbidities, depression status, and activities of daily living were included regardless of statistical significance. RESULTS: Global cognition, comorbidities, working memory, and cognitive status (MCI versus no MCI ascertained using the Montreal Cognitive Assessment (MoCA)) were significant determinants of total HRU at 6 months. The number of medical comorbidities and global cognition were significant determinants of total HRU at 12 months. CONCLUSION: MCI status was a determinant of HRU at 6 months among older adults with a history of falls. As such, efforts to minimize health care resource use related to falls, it is important to tailor future interventions to be effective for people with MCI who fall. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01022866.

Developing trends in the intestinal transplant waitlist.

The United Network for Organ Sharing database was examined for trends in the intestinal transplant (ITx) waitlist from 1993 to 2012, dividing into listings for isolated ITx versus liver-intestine transplant (L-ITx). Registrants added to the waitlist increased from 59/year in 1993 to 317/year in 2006, then declined to 124/year in 2012; Spline modeling showed a significant change in the trend in 2006, p < 0.001. The largest group of registrants, <1 year of age, determined the trend for the entire population; other pediatric age groups remained stable, adult registrants increased until 2012. The largest proportion of new registrants were for L-ITx, compared to isolated ITx; the change in the trend in 2006 for L-ITx was highly significant, p < 0.001, but not isolated ITx, p = 0.270. New registrants for L-ITx, <1 year of age, had the greatest increase and decrease. New registrants for isolated ITx remained constant in all pediatric age groups. Waitlist mortality increased to a peak around 2002, highest for L-ITx, in patients <1 year of age and adults. Deaths among all pediatric age groups awaiting L-ITx have decreased; adult L-ITx deaths have dropped less dramatically. Improved care of infants with intestinal failure has led to reduced referrals for L-ITx.

Genotype CC of rs12979860 is providing protection against infection rather than assisting in treatment response for HCV genotype 3a infection.

Recent discovery of single-nucleotide polymorphisms located in the upstream region of interleukin-28B (IL28B) has shown association with interferon (IFN) treatment response especially in hepatitis C virus (HCV) genotype 1-infected patients. Pakistan, being the country with second highest prevalence of HCV with predominantly 3a genotype infection, bears a significant disease burden. The present study was conducted to evaluate the effect of rs12979860 genotypes on treatment response in HCV-3a-infected patients. This study shows that the CC genotype is providing protection against infection to HCV. But once infected, the CC genotype patients show viral persistence following IFN therapy. The TT genotype is assisting the 3a patients in viral clearance after IFN treatment. To our knowledge, this is the first study showing rs12979860 genotype association with IFN response in Pakistani HCV-3a-infected patients.

Accelerometry analysis of physical activity and sedentary behavior in older adults: a systematic review and data analysis.

Accelerometers objectively monitor physical activity and sedentary patterns and are increasingly used in the research setting. It is important to maintain consistency in data analysis and reporting, therefore, we: (1) systematically identified studies using accelerometry (ActiGraph, Pensacola, FL, USA) to measure moderate-to-vigorous physical activity (MVPA) and sedentary time in older adults, and (2) based on the review findings, we used different cut-points obtained to analyze accelerometry data from a sample of community-dwelling older women. We identified 59 articles with cut-points ranging between 574 and 3,250 counts/min for MVPA and 50 and 500 counts/min for sedentary time. Using these cut-points and data from women (mean age, 70 years), the median MVPA minutes per day ranged between 4 and 80 min while percentage of sedentary time per day ranged between 62 % and 86 %. These data highlight (1) the importance of reporting detailed information on the analysis assumptions and (2) that results can differ greatly depending on analysis parameters.

IL-6-mediated induction of matrix metalloproteinase-9 is modulated by JAK-dependent IL-10 expression in macrophages.

The mechanisms by which IL-6 contributes to the pathogenesis of chronic inflammatory diseases and cancer are not fully understood. We previously reported that cyclooxygenase-2 (Cox-2)-dependent PGE2 synthesis regulates macrophage matrix metalloproteinase (MMP)-9 expression, an endopeptidase that participates in diverse pathologic processes. In these studies, we determined whether IL-6 regulates the Cox-2→PGE2→MMP-9 pathway in murine macrophages. IL-6 coinduced Cox-2 and microsomal PGE synthase-1, and inhibited the expression of 15-hydroxyprostaglandin dehydrogenase, leading to increased levels of PGE2. In addition, IL-6 induced MMP-9 expression, suggesting that the observed proteinase expression was regulated by the synthesis of PGE2. However, inhibition of PGE2 synthesis partially suppressed IL-6-mediated induction of MMP-9. In the canonical model of IL-6-induced signaling, JAK activation triggers STAT and MAPK(erk1/2)-signaling pathways. Therefore, the ability of structurally diverse JAK inhibitors to block IL-6-induced MMP-9 expression was examined. Inhibition of JAK blocked IL-6-induced phosphorylation of STAT3, but failed to block the phosphorylation of MAPK(erk1/2), and unexpectedly enhanced MMP-9 expression. In contrast, MEK-1 inhibition blocked IL-6-induced phosphorylation of MAPK(erk1/2) and MMP-9 expression without affecting the phosphorylation of STAT3. Thus, IL-6-induced MMP-9 expression is dependent on the activation of MAPK(erk1/2) and is restrained by a JAK-dependent gene product. Using pharmacologic and genetic approaches, we identified JAK-dependent induction of IL-10 as a potent feedback mechanism controlling IL-6-induced MMP-9 expression. Together, these data reveal that IL-6 induces MMP-9 expression in macrophages via Cox-2-dependent and -independent mechanisms, and identifies a potential mechanism linking IL-6 to the pathogenesis of chronic inflammatory diseases and cancer.

Does frequency of resistance training affect tibial cortical bone density in older women? A randomized controlled trial.

SUMMARY: This randomized controlled trial evaluated the effect of resistance training frequency (0, 1, and 2 times/week) on cortical volumetric bone mineral density (vBMD) at the tibia in older women. There was no mean difference in change in tibial cortical vBMD in older women who engaged in resistance training (RT) one or two times/week compared with the control group over 12 months after adjusting for baseline values. INTRODUCTION: National guidelines recommend RT two to three times/week to optimize bone health. Our objective was to determine the effect of a 12-month intervention of three different RT frequencies on tibial volumetric cortical density (CovBMD) in healthy older women. METHODS: We randomized participants to the following groups: (1) 2×/week balance and tone group (i.e., no resistance beyond body weight, BT), (2) 1×/week RT (RT1), and (3) 2×/week RT (RT2). Treatment allocation was concealed, and measurement team and the bone data analyst were blinded to group allocation. We used peripheral quantitative computed tomography to acquire one 2.3-mm scan at the 50 % tibia, and the primary outcome was CovBMD. Data were collected at baseline, 6 and 12 months, and we used linear mixed modeling to assess the effect at 12 months. RESULTS: We assessed 147 participants; 100 women provided data at all three points. Baseline unadjusted mean (SD) tibial CovBMD (in milligrams per cubic centimeter) at the 50 % site was 1,077.4 (43.0) (BT), 1,087.8 (42.0) (RT1), and 1,058.7 (60.4) (RT2). At 12 months, there were no statistically significant differences (-0.45 to -0.17 %) between BT and RT groups for mean difference in change in tibial CovBMD for exercise interventions (BT, RT1, RT2) after adjusting for baseline tibial CovBMD. CONCLUSION: We note no mean difference in change in tibial CovBMD in older women who engaged in RT one or two times/week compared with the control group over 12 months. It is unknown if RT of 3× or 4×/week would be enough to promote a statistically significant difference in change of bone density.

Survival of cystic fibrosis patients undergoing liver and liver-lung transplantations.

BACKGROUND: We evaluated the outcome of combined liver-lung transplantation (L-LTx) in cystic fibrosis (CF) patients with liver transplantation (LTx) for CF liver disease. METHODS: The United Network for Organ Sharing (UNOS) data were analyzed from October 1987 to August 2009. RESULTS: Of 294 patients (210 children), 265 (90.1%) received an LTx and 29, an L-LTx. Patient survival was: adult LTx, 80%, 74%, and 67% at 1, 3, and 5 years, and L-LTx, 72%, 61.4%, and 61.4% (P = .7); pediatric LTx, 85%, 82%, and 74% at 1, 3, and 5 years, and L-LTx, 83%, 83%, and 83% (P = .4). Pediatric patients had a slight survival advantage over adults for LTx (P = .08). Graft survival, not affected by immunosuppression regimens, was similar to patient survival. CONCLUSIONS: The outcome of L-LTx appears similar to LTx in CF providing support for the prospect of a combined transplant.

Early postnatal lead exposure induces tau phosphorylation in the brain of young rats.

Cognitive impairment is a common feature of both lead exposure and hyperphosphorylation of tau. We, therefore, investigated whether lead exposure would induce tau hyperphosphorylation. Wistar rat pups were exposed to 0.2% lead acetate via their dams' drinking water from postnatal day 1 to 21. Lead in blood and brain were measured by atomic absorption spectrophotometry and the expression of tau, phosphorylated tau and various serine/threonine protein phosphatases (PP1, PP2A, PP2B and PP5) in the brain was analyzed by Western blot. Lead exposure significantly impaired learning and resulted in a significant reduction in the expression of tau but increased the phosphorylation of tau at Ser199/202, Thr212/Ser214 and Thr231. PP2A expression decreased, whereas, PP1 and PP5 expression increased in lead-exposed rats. These results demonstrate that early postnatal exposure to lead decrease PP2A expression and induce tau hyperphosphorylation at several serine and threonine residues. Hyperphosphorylation of tau may be a mechanism of Pb-induced deficits in learning and memory.