In-vitro antibacterial, antifungal and cytotoxic properties of metal-based furanyl derived sulfonamides

A new series of antibacterial and antifungal furanyl-derived sulfonamides and their cobalt (II), copper (II), nickel (II) and zinc (II) metal complexes have been synthesized, characterized and screened for their in-vitro antibacterial activity against four Gram-negative (Escherichia coli, Shigella flexneri, Pseudomonas aeruginosa and Salmonella typhi) and two Gram-positive (Bacillus subtilis and Staphylococcus aureus) bacterial strains and, for in-vitro antifungal activity against Trichophyton longifusus, Candida albicans, Aspergillus flavus, Microsporum canis, Fusarium solani and Candida glaberata. The results of these studies revealed that all compounds showed significant to moderate antibacterial activity. However, the zinc (II) complexes were found to be comparatively much more active as compared to the others. For antifungal activity generally, compounds (22) and (24) showed significant activity against Escherichia coli (a), (6) against Shigella flexeneri (b), (16) and (22) against Pseudomonas aeruginosa (c), (14) and (16) against Salmonella typhi (d), (9) against Staphylococcus aureus (e) and, (14) and (16) against Bacillus subtilis (f) fungal strains. The brine shrimp (Artemia salina) bioassay was also carried out to study their in-vitro cytotoxic properties. Only three compounds, (6), (10) and (23) displayed potent cytotoxic activity with LD50 = 1.8535 x 10(-4), 1.8173 x 10(-4) and 1.9291 x 10(-4) respectively.     

Tetraketones: a new class of tyrosinase inhibitors

Twenty-eight tetraketones (1-28) with variable substituents at C-7 were synthesized and evaluated as tyrosinase inhibitors. Remarkably compounds 25 (IC(50)=2.06 microM), 11 (IC(50)=2.09 microM), 15 (IC(50)=2.61 microM), and 27 (IC(50)=3.19 microM) were found to be the most active compounds of the series, even better than both standards kojic acid (IC(50)=16.67 microM) and L-mimosine (IC(50)=3.68 microM). This study may lead to the discovery of therapeutically potent agents against clinically very important dermatological disorders including hyperpigmentation as well as skin melanoma.     

Three-dimensional quantitative structure-activity relationship (3 D-QSAR) and docking studies on (benzothiazole-2-yl) acetonitrile derivatives as c-Jun N-terminal kinase-3 (JNK3) inhibitors

Three-dimensional quantitative structure-activity relationship (3D-QSAR) models were developed for 44 (benzothiazole-2-yl) acetonitrile derivatives, inhibiting c-Jun N-terminal kinase-3 (JNK3). It includes molecular field analysis (MFA) and receptor surface analysis (RSA). The QSAR model was developed using 34 compounds and its predictive ability was assessed using a test set of 10 compounds. The predictive 3D-QSAR models have conventional r2 values of 0.849 and 0.766 for MFA and RSA, respectively; while the cross-validated coefficient r(cv)2 values of 0.616 and 0.605 for MFA and RSA, respectively. The results of the QSAR model were further compared with a structure-based analysis using docking studies with crystal structure of JNK3. Ligands bind in the ATP pocket and the hydrogen bond with GLN155 was found to be crucial for selectivity among other kinases. The results of 3D-QSAR and docking studies validate each other and hence, the combination of both methodologies provides a powerful tool directed to the design of novel and selective JNK3 inhibitors.     

Diet-induced docosahexaenoic acid non-raft domains and lymphocyte function

Docosahexaenoic acid (DHA) is an n-3 polyunsaturated fatty acid (PUFA) that generally suppresses the function of T lymphocytes and antigen presenting cells (APCs). An emerging mechanism by which DHA modifies lymphocyte function is through changes in the organization of sphingolipid/cholesterol lipid raft membrane domains. Two contradictory models have been proposed to explain how DHA exerts its effects through changes in raft organization. The biophysical model, developed in model membranes, shows that DHA-containing phospholipids form unique non-raft membrane domains, that are organizationally distinct from lipid rafts, which serve to alter the conformation and/or lateral organization of lymphocyte proteins. In contrast, the cellular model on DHA and rafts shows that DHA suppresses lymphocyte function, in part, by directly incorporating into lipid rafts and altering protein activity. To reconcile opposing biophysical and cellular viewpoints, a major revision to existing models is presented herein. Based largely on quantitative microscopy data, it is proposed that DHA, consumed through the diet, modifies lymphocyte function, in part, through the formation of nanometer scale DHA-rich domains. These nano-scale domains disrupt the optimal raft-dependent clustering of proteins necessary for initial signaling. The data covered in this review highlights the importance of understanding how dietary n-3 PUFAs modify lymphocyte membranes, which is essential toward developing these fatty acids as therapeutic agents for treating inflammatory diseases.     

Utilization of sugarcane bagasse cellulose for producing cellulose acetates: Novel use of residual hemicellulose as plasticizer

Sugarcane bagasse was fractionated to cellulose, hemicellulose and lignin by a proprietary steam explosion process, followed by downstream purifications, developed in our laboratory. The fractionated cellulose contained ～94% cellulose, about ～5% hemicellulose, traces of lignin (～0.2%), and ～1% ash. The cellulose was acetylated under heterogeneous conditions to obtain cellulose acetates. These were extensively characterized using FTIR, TGA, DSC, GPC, HPIC, WAXRD, and viscometry. The novel feature of this study was the utilization of the hemicellulose content (5%) of bagasse cellulose as an internal plasticizer. Through kinetic experimentation, we have demonstrated that the residual hemicellulose need not be considered as an impurity; rather it can be used in acetylated form as a plasticizer as well as a biodegradable additive for cellulose acetates made from slightly impure cellulose produced from non-wood origin. Our results therefore show how lignocellulosic agricultural wastes can be utilized to produce high value plastics.     

Anticancer Potential of the Plant-Derived Saponin Gracillin: A Comprehensive Review of Mechanistic Approaches

With the increasing prevalence of cancer and the toxic side effects of synthetic drugs, natural products are being developed as promising therapeutic approaches. Gracillin is a naturally occurring triterpenoid steroidal saponin with several therapeutic activities. It is obtained as a major compound from different Dioscorea species. This review was designated to summarize the research progress on the anti-cancer activities of gracillin focusing on the underlying cellular and molecular mechanisms, as well as its pharmacokinetic features. The data were collected (up to date as of May 1, 2023) from various reliable and authentic literatures comprising PubMed, Springer Link, Scopus, Wiley Online, Web of Science, ScienceDirect, and Google Scholar. The findings demonstrated that gracillin displays promising anticancer effects through various molecular mechanisms, including anti-inflammatory effects, apoptotic cell death, induction of oxidative stress, cytotoxicity, induction of genotoxicity, cell cycle arrest, anti-proliferative effect, autophagy, inhibition of glycolysis, and blocking of cancer cell migration. Additionally, this review highlighted the pharmacokinetic features of gracillin, indicating its lower oral bioavailability. As a conclusion, it can be proposed that gracillin could serve as a hopeful chemotherapeutic agent. However, further extensive clinical research is recommended to establish its safety, efficacy, and therapeutic potential in cancer treatment.     

Measurement of Reactive Oxygen Species in the Culture Media Using Acridan Lumigen PS-3 Assay

Reactive oxygen species (ROS) are generated continuously during aerobic metabolism. ROS are highly reactive molecules and in excessive amounts, can lead to protein and DNA oxidation, protein cross-linking, and cell death. Cell-culture models provide a valuable tool in understanding the mechanisms that lead to cell death. Accumulation of ROS within cells and/or their release into the culture media are highly cell type-specific. The ability to estimate ROS levels in the culture media is an important step in understanding the mechanisms contributing to disease processes. In this paper, we describe the optimization of a simple method to estimate ROS levels in the culture media using the Acridan Lumigen PS-3 reagent provided in the Amersham ECL Plus kit (GE Healthcare, UK). We have shown that the Acridan Lumigen PS-3 assay generates ROS-specific chemiluminescence in fresh as well as media stored at −20°C, in as little as 10–20 μl of samples. The method was able to detect the dose (of stimulants)- and time (acute and chronic)-dependent changes in ROS levels in media collected from various cell types. Our results suggest that the kit reagents, PBS buffer, and various media did not contribute significantly to the overall chemiluminescence generated in the assay; however, we suggest that the unused medium specific for each cell type should be used as blanks and final readings of test samples normalized against these readings. As this method uses commonly available laboratory equipment and commercially available reagents, we believe this assay is convenient, economical, and specific in estimating ROS released extracellularly into the culture media.     

Trends in prevalence of chronic disease and multimorbidity in Ontario,Canada

BACKGROUND:New case-mix tools from the Canadian Institute for Health Information offer a novel way of exploring the prevalence of chronic disease and multimorbidity using diagnostic data. We took a comprehensive approach to determine whether the prevalence of chronic disease and multimorbidity has been rising in Ontario, Canada.METHODS:In this observational study, we applied case-mix methodology to a population-based cohort. We used 10 years of patient-level data (fiscal years 2008/09 to 2017/18) from multiple care settings to compute the rolling 5-year prevalence of 85 chronic diseases and multimorbidity (i.e., the co-occurrence of 2 or more diagnoses). Diseases were further classified based on type and severity. We report both crude and age- and sex-standardized trends.RESULTS:The number of patients with chronic disease increased by 11.0% over the 10-year study period to 9.8 million in 2017/18, and the number with multimorbidity increased 12.2% to 6.5 million. Overall increases from 2008/09 to 2017/18 in the crude prevalence of chronic conditions and multimorbidity were driven by population aging. After adjustments for age and sex, the prevalence of patients with ≥ 1 chronic conditions decreased from 70.2% to 69.1%, and the prevalence of multimorbidity decreased from 47.1% to 45.6%. This downward trend was concentrated in minor and moderate diseases, whereas the prevalence of many major chronic diseases rose, along with instances of extreme multimorbidity (≥ 8 conditions). Age- and sex-standardized resource intensity weights, which reflect relative expected costs associated with patient diagnostic profiles, increased 4.6%.INTERPRETATION:Evidence of an upward trend in the prevalence of chronic disease was mixed. However, the change in case mix toward more serious conditions, along with increasing patient resource intensity weights overall, may portend a future need for population health management and increased health system spending above that predicted by population aging.

Multimorbidity exists when a patient is diagnosed with 2 or more chronic diseases. Patients with multimorbidity present challenges for physicians managing their care and, as the proportion of these patients in the population increases, for health care system planning. The prevalence of multimorbidity and chronic disease has been strongly associated with primary care use, specialist consultations, number and intensity of inpatient hospital admissions and other types of care.^1–7 Among beneficiaries of fee-for-service Medicare in the United States, expenditures for those with 4 or more chronic diseases were reported to be 66 times higher than for those with none.⁸ One study found that most health spending growth (77.6%) in the US between 1987 and 2011 could be attributed to patients with 4 or more diseases.⁹Several recent studies have estimated the prevalence of chronic disease and multimorbidity in Canada.^3,10–13 Rates of multimorbidity ranged from 10% to 25%, owing to differences in classification systems used to identify chronic disease, including the choice of conditions, and variations in study population. Lack of standardization in measures of chronic disease prevalence and multimorbidity has hampered the evaluation of trends over time and across settings.Ontario provides an ideal setting to evaluate trends in the prevalence of chronic disease because patients have access to a comprehensive set of publicly funded services. The Canadian Institute for Health Information (CIHI) has created a system that maps patient diagnosis data from all health care settings to a set of 226 clinically meaningful health conditions, covering the full spectrum of acute and chronic morbidity (Jeffrey Hatcher, Canadian Institute for Health Information, Ottawa: personal communication, 2017). CIHI’s system has been independently compared with the Johns Hopkins ACG System; CIHI’s system was deemed to be more specific and less sensitive in classifying diagnoses, making it more conservative in identifying health conditions (S. Cheng, ICES, unpublished data, 2016). The purpose of this study was to evaluate trends in the prevalence of chronic disease and multimorbidity in Ontario using CIHI’s comprehensive disease classification system.