Pyrrole: A Decisive Scaffold for the Development of Therapeutic Agents and Structure-Activity Relationship.

An overview of pyrroles as distinct scaffolds with therapeutic potential and the significance of pyrrole derivatives for drug development are provided in this article. It lists instances of naturally occurring pyrrole-containing compounds and describes the sources of pyrroles in nature, including plants and microbes. It also explains the many conventional and modern synthetic methods used to produce pyrroles. The key topics are the biological characteristics, pharmacological behavior, and functional alterations displayed by pyrrole derivatives. It also details how pyrroles are used to treat infectious diseases. It describes infectious disorders resistant to standard treatments and discusses the function of compounds containing pyrroles in combating infectious diseases. Furthermore, the review covers the uses of pyrrole derivatives in treating non-infectious diseases and resistance mechanisms in non-infectious illnesses like cancer, diabetes, and Alzheimer's and Parkinson's diseases. The important discoveries and probable avenues for pyrrole research are finally summarized, along with their significance for medicinal chemists and drug development. A reference from the last two decades is included in this review.

Design, Synthesis, and Anti-Breast Cancer Potential of Imidazole-Pyridine Hybrid Molecules In Vitro and Ehrlich Ascites Carcinoma Growth Inhibitory Activity Assessment In Vivo.

Breast cancer remains a challenging medical issue and is a high priority for biomedical research despite significant advancements in cancer research and therapy. The current study aims to determine the anticancer activity of a group of imidazole-pyridine-based scaffolds against a variety of breast cancer cell lines differing in their receptor expression (estrogen receptor (ER), progesterone receptor (PR), and HER-2). A series of 10 molecules (coded 5a-5j) were synthesized through multicomponent and alkylation reactions. FTIR, MS, 1H, and 13C NMR spectral analyses confirmed the structures and purity of the synthesized molecules. Subsequently, these molecules were tested for their ability to inhibit the viability of cell lines representing carcinoma of the breast, viz., MDA-MB-468 (ER-, PR-, and HER-), BT-474 (ER+, PR+, and HER+), T-47D (ER+, PR+, and HER-), and MCF-7 (ER+, PR+, and HER-) in vitro. Among these 10 molecules, 5a, 5c, 5d, and 5e exhibited better potency, as evidenced by IC50 < 50 µM at 24 h of treatment against BT-474 and MDA-MB-468 cell lines. However, except for 5d, the IC50 value is much higher than 50 µM when tested against T47D and MCF-7 cell lines at 24h. Extended treatment for 48 h reduced the effect of these molecules, as an increase in IC50 was observed. In mice, intraperitoneal administration of 5e retarded the Ehrlich ascites carcinoma (EAC) growth without causing any organ toxicity at the doses tested. In summary, we report the synthesis scheme and key structural requirements for a new series of imidazole-pyridine molecules for in vitro inhibition of the feasibility of breast cancer cells and in vivo inhibition of EAC tumors.

Sulfonated Polyether Ketone Membranes Embedded with Nalidixic Acid-An Emerging Controlled Drug Releaser.

The effective administration of medication has advanced over decades, but the medical community still faces significant demand. Burst release and inadequate assimilation are major drawbacks that affect wound healing efficiency, leading to therapy failure. The widespread application of polymers in biomedical research is significant. The polyether ether ketone (PEEK) family is known for its biocompatibility, inertness, and semi-crystalline thermoplastic properties. In our present studies, we have chosen a member of this family, polyether ketone (PEK), to explore its role as a drug carrier. The PEK backbone was subjected to sulfonation to increase its hydrophilicity. The response surface methodology (RSM) was used to optimize the sulfonation process based on the time, degree of sulfonation, and temperature. The PEK polymer was sulfonated using sulfuric acid at 150 °C for 6 h; back titration was performed to quantify the degree of sulfonation, with 69% representing the maximum sulfonation. SPEK and nalidixic sodium salt were dissolved in dichloroacetic acid to create a thin membrane. The physiological and morphological properties were assessed for the SPEK membrane. The studies on drug release in distilled water and a simulated body fluid over the course of 24 h revealed a controlled, gradual increase in the release rate, correlating with a mathematical model and demonstrating the zero-order nature of the drug release. Hemolysis on the SPEK membrane revealed lower toxicity. The SPEK membrane's biocompatibility was established using in vitro cytotoxicity tests on the Vero (IC50: 137.85 g/mL) cell lines. These results confirm that the SPEK membranes are suitable for sustained drug release.

Local government institutions in Ghana: Core partners in health and safety performance in the construction industry.

The potential contribution of district assemblies to improving health and safety in Ghana's construction industry has not been investigated. This paper attempts to identify the local government responsibilities that could influence health and safety performance in the construction industry and to develop a confirmatory factor model based on these responsibilities. The paper adopted a positivist philosophy and a deductive methodology. A literature search was conducted to identify the local government factors that could potentially impact health and safety performance in the Ghanaian construction industry. These factors were adapted and designed into a questionnaire, and the generated questionnaires were distributed to respondents for their feedback. It was identified using the relative importance index that "the development of sanctions for violating occupational health and safety statutory obligations," "the institution of local government occupational health and safety approval and certification for new projects," and "the creation of occupational health and safety departments and committees that are adequately resourced to assist the Department of Factories Inspectorate" were the three most important roles that district assemblies could play as partners to improve health and safety in the construction industry. Conversely, the multivariate analysis identified the evaluation of the safety policies and risk management plans of contractors and suppliers as the most important role local government institutions could play in improving health and safety in the construction industry. The result of the study suggests that local government efforts, when given the needed attention and support, could advance health and safety in the industry. The practical implication of the study is that it identifies the roles of district assemblies that could enhance health and safety in Ghana's construction industry. All district assemblies should consider implementing these health and safety initiatives in their districts and ensuring they are regularly enforced and evaluated.

Evolution and Clinical Advances of Platelet-Rich Fibrin in Musculoskeletal Regeneration.

Over the past few decades, various forms of platelet concentrates have evolved with significant clinical utility. The newer generation products, including leukocyte-platelet-rich fibrin (L-PRF) and advanced platelet-rich fibrin (A-PRF), have shown superior biological properties in musculoskeletal regeneration than the first-generation concentrates, such as platelet-rich plasma (PRP) and plasma rich in growth factors. These newer platelet concentrates have a complete matrix of physiological fibrin that acts as a scaffold with a three-dimensional (3D) architecture. Further, it facilitates intercellular signaling and migration, thereby promoting angiogenic, chondrogenic, and osteogenic activities. A-PRF with higher leukocyte inclusion possesses antimicrobial activity than the first generations. Due to the presence of enormous amounts of growth factors and anti-inflammatory cytokines that are released, A-PRF has the potential to replicate the various physiological and immunological factors of wound healing. In addition, there are more neutrophils, monocytes, and macrophages, all of which secrete essential chemotactic molecules. As a result, both L-PRF and A-PRF are used in the management of musculoskeletal conditions, such as chondral injuries, tendinopathies, tissue regeneration, and other sports-related injuries. In addition to this, its applications have been expanded to include the fields of reconstructive cosmetic surgery, wound healing in diabetic patients, and maxillofacial surgeries.

Design of an Antibiotic-Releasing Polymer: Physicochemical Characterization and Drug Release Patterns.

Conventional drug delivery has its share of shortcomings, especially its rapid drug release with a relatively short duration of therapeutic drug concentrations, even in topical applications. Prolonged drug release can be effectively achieved by modifying the carrier in a drug delivery system. Among the several candidates for carriers studied over the years, poly (ether ether ketone), a biocompatible thermoplastic, was chosen as a suitable carrier. Its inherent hydrophobicity was overcome by controlled sulfonation, which introduced polar sulfonate groups onto the polymer backbone. Optimization of the sulfonation process was completed by the variation of the duration, temperature of the sulfonation, and concentration of sulfuric acid. The sulfonation was confirmed by EDS and the degree of sulfonation was determined by an NMR analysis (61.6% and 98.9%). Various physical properties such as morphology, mechanical strength, and thermal stability were studied using scanning electron microscopy, tensile testing, and thermogravimetric analysis. Cytotoxicity tests were performed on the SPEEK samples to study the variation in biocompatibility against a Vero cell line. The drug release kinetics of ciprofloxacin (CP) and nalidixic acid sodium salt (NA)-loaded membranes were studied in deionized water as well as SBF and compared against the absorbance of standardized solutions of the drug. The data were then used to determine the diffusion, distribution, and permeability coefficients. Various mathematical models were used to fit the obtained data to establish the order and mechanism of drug release. Studies revealed that drug release occurs by diffusion and follows zero-order kinetics.

Developing a schedule integrated automated safety planning tool for residential construction projects.

Construction safety culture can be greatly improved if safety planning is done hand-in-hand with project planning. This article investigates the integration of construction scheduling with construction safety planning by developing an automated safety planning add-in (ASPA) for Microsoft Project. A risk assessment database was developed that analysed the frequency and severity of hazards associated with construction tasks and the risk level of each hazard was calculated. The developed ASPA compares the ongoing construction activity in the schedule with the safety database, and an automated safety report is produced as a spreadsheet containing details of task name, risk priority, task start and end dates, and hazard and safety regulations related to the tasks. The schedule integrated ASPA was then tested for efficacy by implementing in a real-time project. The ASPA facilitated the safety engineers to plan daily activities by prior envisaging of hazards and safety regulations through schedule-based report generation.

Imidazole-pyridine hybrids as potent anti-cancer agents.

In the current investigation, fifteen novel imidazole-pyridine-based molecules were synthesized and tested against cell lines of the lung (H1299) and colon (HCT116) adenocarcinomas by proliferation assay. The results demonstrated that compounds 5a, 5d, 5e, and 5f were the most active (IC50<30 µM). Based on recent literature and the current results, the glycogen synthase kinase-3ß (GSK-3ß) protein was investigated in-silico as a possible target. The molecular docking and QSAR revealed an excellent binding affinity of the selected imidazole-pyridine compounds to GSK-3ß. Notably, GSK-3ß protein levels were significantly upregulated in hepatocellular liver carcinoma (LIHCs) tissues and negatively affected patient prognosis. Consequently, the compounds were evaluated on liver cancer cell lines (HepG2, HUH-7, and PLC/PRF/5) by the MTT assay, and 5d showed the highest antitumor activity. This study offers new compounds with interesting biological activity on GSK-3ß as a target, exhibiting a potential therapeutic impact for hepatocellular carcinoma patients.

Chalcone: A Promising Bioactive Scaffold in Medicinal Chemistry.

Chalcones are a class of privileged scaffolds with high medicinal significance due to the presence of an α,ß-unsaturated ketone functionality. Numerous functional modifications of chalcones have been reported, along with their pharmacological behavior. The present review aims to summarize the structures from natural sources, synthesis methods, biological characteristics against infectious and non-infectious diseases, and uses of chalcones over the past decade, and their structure-activity relationship studies are detailed in depth. This critical review provides guidelines for the future design and synthesis of various chalcones. In addition, this could be highly supportive for medicinal chemists to develop more promising candidates for various infectious and non-infectious diseases.

Antioxidant, Anti-Tumour, and Anticoagulant Activities of Polysaccharide from Calocybe indica (APK2).

The initial structural features and in vitro biological study of crude polysaccharides from Calocybe indica (CICP) extracted by hot water followed by ethanol precipitation was investigated. High-performance gel permeation chromatography, HPLC-DAD, UV, IR and NMR spectroscopy, X-ray diffraction, scanning electron microscopy, and Congo red methods were used to determine structural features. The results revealed that CICP is a hetero-polysaccharide with a molecular weight of 9.371 × 104 Da and 2.457 × 103 Da which is composed of xylose, mannose, fucose, rhamnose, arabinose, galactose, and glucose. The antioxidant activity of CICP was evaluated using radical scavenging activity (three methods), reducing ability (three methods), metal chelating activity, and lipid peroxidation inhibition activity (two methods). It was found that the antioxidant capacity is concentration-dependent and EC50 values were found to be 1.99-3.82 mg/mL (radical scavenging activities), 0.78-2.78 mg/mL (reducing ability), 4.11 mg/mL (metal chelating activity), and 0.56-4.18 mg/mL (lipid peroxidation inhibition activity). In vitro anticoagulant assay revealed that CICP could prolong activated partial thromboplastin time (APTT), thrombin time (TT), but not prothrombin time (PT). CICP exhibited antiproliferative activity on HeLa, PC3, HT29, HepG2, and Jurkat cell lines with IC50 (µg/mL) values of 148.40, 143.60,151.00, 168.30, and 156.30, respectively. The above findings suggested that CICP could be considered a natural antioxidant and cancer preventative.

COVID-19 and diabetes: What do we know so far?

Coronavirus disease 2019 (COVID-19) management has been challenging for patients with comorbidities. Patients with diabetes and COVID-19, in particular, have shown severe symptoms and rapid progression of the disease. They also have a high mortality rate compared to the non-diabetic population. The high mortality rate is caused in people with diabetes who are in a pro-inflammatory condition; this could worsen COVID-19. In addition, people with diabetes have circulatory issues and COVID-19 infection can lead to further clotting problems. It is critical to understand the mechanisms underlying the adverse clinical outcomes in patients with diabetes and COVID-19. This review discusses various disease conditions contributing to poor prognosis in diabetic COVID-19 patients such as hyperglycemia, insulin resistance, impaired pancreatic function, and production of advanced glycation end products.

Prebiotic Potential and Value-Added Products Derived from Spirulina laxissima SV001-A Step towards Healthy Living.

Lately, microalgae-based value-added products have been gaining market value because they moderate the dependency on fossil fuel and high-value chemical products. To this end, the purpose of this study was to develop prebiotic products from the microalgae Spirulina sp. The microalgae were isolated from the fresh water and characterized at the molecular level. The dry biomass, chlorophyll content, phycocyanin, cytotoxicity and antimicrobial and antioxidant properties of the isolated strains were analyzed. Moreover, value-added products like Spirulina cake, chocolate, tea, vermicelli and Spirulina juice were made for a vulnerable population due to high nutritive value.

Convalescent serum-derived exosomes: Attractive niche as COVID-19 diagnostic tool and vehicle for mRNA delivery.

The spread of SARS-CoV-2 over the entire world is more commonly known as COVID-19. COVID-19 has impacted society in every aspect of routine life. SARS-CoV-2 infection is often misdiagnosed as influenza or seasonal upper respiratory tract viral infections. General diagnostic tools can detect the viral antigen or isotypes of antibodies. However, inter- and intraindividual variations in antibody levels can cause false negatives in antibody immunoassays. On the contrary, the false-positive test results can also occur due to either cross-reactivity of the viral antigens or some other patient-related autoimmune factors. There is need for a cogent diagnostic tool with more specificity, selectivity, and reliability. Here, we have described the potential of convalescent serum-derived exosome as a diagnostic tool for the detection of SARS-CoV-2, even in asymptomatic patients, which is a limitation for currently practiced diagnostic tests throughout the globe. In addition, its potential as a vehicle for messenger RNA (mRNA) delivery is also emphasized.

Effects of Carboxymethyl Modification on the Acidic Polysaccharides from Calocybe indica: Physicochemical Properties, Antioxidant, Antitumor and Anticoagulant Activities.

An acidic polysaccharide fraction was obtained from Calocybe indica (CIP3a) after subjecting it to hot water extraction followed by purification through DEAE-cellulose 52 and Sepaharose 6B column chromatography. The CIP3a was further modified using chloroacetic acid to yield carboxymethylated derivatives (CMCIP3a). The modified polysaccharide was characterized using various spectroscopic methods. In addition, further antioxidant, antitumor and anticoagulant activities were also investigated. The polysaccharides CIP3a and CMCIP3a were heterogeneous in nature and composed of various molar percentages of glucose, arabinose and mannose with molecular weights of 1.456 × 103 and 4.023 × 103 Da, respectively. The NMR and FT-IR data demonstrated that the carboxymethylation on the polysaccharide was successful. In comparison to CIP3a polysaccharides, the modified derivatives had lower sugar and protein contents, and higher levels of uronic acid. The in vitro antioxidant activity showed that CMCIP3a with higher molecular weight displayed an elevated ability in scavenging the DPPH radical, ABTS, superoxide, hydroxyl radical, ferric reducing power, cupric reducing power and erythrocyte hemolysis inhibition with an EC50 value of 2.49, 2.66, 4.10, 1.60, 3.48, 1.41 and 2.30 mg/mL, respectively. The MTT assay results revealed that CMCIP3a displayed a dose-dependent inhibition on five cancer cells (HT29, PC3, HeLa, Jurkat and HepG-2) in the range of 10-320 µg/mL. The APTT, PT and TT were significantly extended by CMCIP3a in relation to dosage, indicating that the anticoagulant effect of CIP was both extrinsic and intrinsic, along with a common coagulation pathway. These findings demonstrated that carboxymethylation might effectively improve the biological potential of the derivatives and offer a theoretical framework for the creation of novel natural antioxidants, low-toxicity antitumor and antithrombotic drugs.

Sulfated modification, characterization and bioactivities of an acidic polysaccharide fraction from an edible mushroom Pleurotus eous (Berk.) Sacc.

The acidic fraction (P3a) of Pleurotus eous was successfully sulfated by sulphur trioxide-pyridine complex method. The effect of sulfate modification (SP3a) on the structure, physicochemical properties and in vitro biological activity of P3 was studied. The structural characteristics were established by UV absorption, FT-IR, HPGPC and GC-MS. Biological studies were carried out, such as in vitro antioxidant, anticoagulant, anti-tumour and antibacterial activities. The sulfation process changed its physicochemical and biological characteristics. Compared with P3a, the molecular weight of SP3a is reduced. P3a and SP3a are composed of galactose, xylose, arabinose with different molar percentages. Sulfated derivatives have strong antioxidant and anticoagulant properties. Compared with P3a, SP3a showed obvious cytotoxicity to Jurkat and HeLa cells. SP3a showed a higher inhibition zone for Gram-positive and Gram-negative bacteria. This article demonstrates that sulfation is an effective way to enhance biological activity, especially SP3a is a promising candidate for bioactive macromolecules and has great potential for industrial and biomedical applications.