Type 2 diabetes mellitus (T2D) is a metabolic disorder that knows no boundaries and is spread across the globe. It is one of the most widely spread metabolic disorder, which has now been described as a ‘lifestyle’ disease. According to the recent study conducted by International Diabetes Federation, the number of diabetic patients will rise from 463 million to 700 million by the year 2045. Conventional therapies often fail to define clear parameters and did not provide early detection in case of diabetes and pre-diabetes. Due to the limitations associated with these therapies, inclination of research is now focused on developing methods or exploring pathways which can overcome these hurdles. Considering these factors, protein tyrosine phosphatase is considered as a promising molecular level legitimate therapeutic target and is known to negatively regulate leptin and insulin signaling pathways. It has shown to be effective in the management of diabetes mellitus in various in vitro and in vivo studies. Various PTP-1B inhibitors have been studied which had shown promising results in the management of diabetes mellitus and associated complications as well. These inhibitors act by increasing insulin sensitivity by inhibiting PTP-1B mediated insulin pathway. In this article we will review the underlying mechanism of protein tyrosine phosphatase and its inhibitors by various PTP 1-B inhibitors for the management of diabetes mellitus and will further throw some light on the challenges and development of these inhibitors.
Alzheimer’s is a type of dementia that affects the affected person’s thinking, memory, and behavior. It is a multifactorial disease, developed by the breakdown of the neurotransmitter acetylcholine via acetylcholinesterase (AChE). The present study was designed to evaluate potential inhibitors of acetylcholinesterase that could be used as a therapeutic agent against Alzheimer’s disease (AD). For this course, synthetic compounds of the Schiff bases class of 2-mercaptobenzimidazole hydrazone derivatives ( 9–14 ) were determined to be potent acetylcholinesterase inhibitors with IC 50 values varying between 37.64 ± 0.2 and 74.76 ± 0.3 μM. The kinetic studies showed that these are non-competitive inhibitors of AChE. Molecular docking studies revealed that all compounds accommodate well in the active site and are stabilized by hydrophobic interactions and hydrogen bonding. Molecular dynamics (MD) simulations of selected potent inhibitors confirm their stability in the active site of the enzyme. Moreover, all compounds showed antispasmodic and Ca ²⁺ antagonistic activities. Among the selected compounds of 2-mercaptobenzimidazole hydrazone derivatives, compound 11 exhibited the highest activity on spontaneous and K ⁺ -induced contractions, followed by compound 13 . Therefore, the Ca ²⁺ antagonistic, AChE inhibition potential, and safety profile of these compounds in the human neutrophil viability assay make them potential drug candidates against AD in the future.
The 2019 outbreak of corona virus disease began from Wuhan (China), transforming into a leading pandemic, posing an immense threat to the global population. The WHO coined the term nCOVID-19 for the disease on 11th February, 2020 and the International Committee of Taxonomy of Viruses named it SARS-CoV-2, on account of its similarity with SARS-CoV-1 of 2003. The infection is associated with fever, cough, pneumonia, lung damage, and ARDS along with clinical implications of lung opacities. Brief understanding of the entry target of virus, i.e., ACE2 receptors has enabled numerous treatment options as discussed in this review. The manuscript provides a holistic picture of treatment options in COVID-19, such as non-specific anti-viral drugs, immunosuppressive agents, anti-inflammatory candidates, anti-HCV, nucleotide inhibitors, antibodies and anti-parasitic, RNA-dependent RNA polymerase inhibitors, anti-retroviral, vitamins and hormones, JAK inhibitors, and blood plasma therapy. The text targets to enlist the investigations conducted on all the above categories of drugs, with respect to the COVID-19 pandemic, to accelerate their significance in hindering the disease progression. The data collected primarily targets recently published articles and most recent records of clinical trials, focusing on the last 10-year database. The current review provides a comprehensive view on the critical need of finding a suitable treatment for the currently prevalent COVID-19 disease, and an opportunity for the researchers to investigate the varying possibilities to find and optimized treatment approach to mitigate and ameliorate the chaos created by the pandemic worldwide.
Neo-Coronavirus (NeoCoV) is a novel Betacoronavirus (β-CoVs or Beta-CoVs) discovered in bat specimens in South Africa during 2011. The viral sequence is highly similar to Middle East Respiratory Syndrome, particularly that of structural proteins. Thus, scientists have emphasized the threat posed by NeoCoV associated with human angiotensin-converting enzyme 2 (ACE2) usage, which could lead to a high death rate and faster transmission rate in humans. The development of a NeoCoV vaccine could provide a promising option for the future control of the virus in case of human infection. In silico predictions can decrease the number of experiments required, making the immunoinformatics approaches cost-effective and convenient. Herein, with the aid of immunoinformatics and reverse vaccinology, we aimed to formulate a multi-epitope vaccine that may be used to prevent and treat NeoCoV infection. Based on the NeoCoV proteins, B-cell, cytotoxic T lymphocyte (CTL), and helper T lymphocyte (HTL) epitopes were shortlisted. Four vaccines (Neo-1–4) were devised by fusing shortlisted epitopes with appropriate adjuvants and linkers. The secondary and three-dimensional structures of final vaccines were then predicted. The binding interactions of these potential vaccines with toll-like immune receptors (TLR-2, TLR-3, and TLR-4) and major histocompatibility complex molecules (MHC-I and II) reveal that they properly fit into the receptors’ binding domains. Besides, Neo-1 and Neo-4 vaccines exhibited better docking energies of -101.08 kcal/mol and -114.47 kcal/mol, respectively, with TLR-3 as compared to other vaccine constructs. The constructed vaccines are highly antigenic, non-allergenic, soluble, non-toxic, and topologically assessable with good physiochemical characteristics. Codon optimization and in-silico cloning confirmed efficient expression of the designed vaccines in Escherichia coli strain K12. In-silico immune simulation indicated that Neo-1 and Neo-4 vaccines could induce a strong immune response against NeoCoV. Lastly, the binding stability and strong binding affinity of Neo-1 and Neo-4 with TLR-3 receptor were validated using molecular dynamics simulations and free energy calculations (Molecular Mechanics/Generalized Born Surface Area method). The final vaccines require experimental validation to establish their safety and effectiveness in preventing NeoCoV infections.
Aim: The present study aimed to explore the sensitizing capability of the anticancer agents, gemcitabine (GEM) and oxaliplatin (OXA), encapsulated in a novel SLN (GEM:OXA-SLN) against the ovarian cancer cell lines. Methods: A novel SLN, prepared using hot homogenization by mixing phosphatidylcholine, cholesterol, tween 80 and oleic acid, was characterized using Transmission Electron Microscope and zetasizer. The anticancer activities and the underlying molecular mechanisms of GEM:OXA-SLN were investigated. Results: The average z-diameter of the homogeneous spherical GEM:OXA-SLN was (70.33 ± 0.70) nm with zeta potential (-7.69 ± 0.61) mV. GEM:OXA-SLN significantly inhibited the viability of ovarian cancer cells in a dose-dependent manner within 24 h. It also triggered the induction of autophagy cellular death, suppression of multidrug resistance efflux pump and inhibition of heat shock protein (Hsp90). Conclusion: The encapsulation of GEM and OXA in SLN improved the efficacy of the drugs and diminished the ovarian cancer cell's resistance.
N-linked protein glycosylation is an essential co-and posttranslational protein modification that occurs in all three domains of life; the assembly of N-glycans follows a complex sequence of events spanning the (Endoplasmic Reticulum) ER and the Golgi apparatus. It has a significant impact on both physicochemical properties and biological functions. It plays a significant role in protein folding and quality control, glycoprotein interaction, signal transduction, viral attachment, and immune response to infection. Glycoengineering of protein employed for improving protein properties and plays a vital role in the production of recombinant glycoproteins and struggles to humanize recombinant therapeutic proteins. It considers an alternative platform for biopharmaceuticals production. Many immune proteins and antibodies are glycosylated. Pathogen’s glycoproteins play vital roles during the infection cycle and their expression of specific oligosaccharides via the N-glycosylation pathway to evade detection by the host immune system. This review focuses on the aspects of N-glycosylation processing, glycoengineering approaches, their role in viral attachment, and immune responses to infection.
A potent α-glucosidase anthracene derivative (eupholaricanone, 1), along with three known compounds lupeol (2) and lupeol acetate (3), and lup 20(29)-ene (4) was isolated as a natural product from ethyl acetate fraction of Euphorbia larica. The structure of the compound was elucidated by 1D (¹H- and ¹³C) and 2D (HSQC, HMBC, COSY and NOESY) nuclear magnetic resonance (NMR) spectroscopy and mass (QTOF-LCMS) spectrometry, and crystal structure was determined by single-crystal X-ray diffraction analysis. In vitro, compound 1 displayed potent α-glucosidase inhibitory activity with 91.60% inhibition and IC50 value of 45.91 ± 0.61 µM. Furthermore, in silico structural bioinformatics tool was employed to predict the binding pattern of compound 1 in the active site of α-glucosidase where compound demonstrated excellent binding interactions with Arg213 and His351 and exhibited higher docking score than the substrate molecule. Our experimental findings and docking results indicate that this anthracene derivative could serve as a lead compound upon optimization.
Globally, lung cancer accounts for 18% of cancer-associated mortalities. Among the subtypes, non-small cell lung cancer (NSCLC) is the most prevalent. The increased resistance and poor survival rates signify disease aggressiveness and thus require a search for an alternative anticancer molecule. Earlier, the isolated sesquiterpene, i.e., compound 3 ((E)-methyl 6-acetoxy-7-methoxy-1-(2-methylpropylidene)-1H-indene-3-carboxylate) from Polygonum barbatum, was isolated, characterized by us, and reported for preliminary anticancer activity. Therefore, based on these results, this study was designed to explore the underlying molecular mechanism of apoptosis and metastasis against NCI-H460 cells. The molecular mechanism of compound 3 inducing apoptosis and inhibiting metastasis was elucidated by analyzing mitochondrial membrane potential, DNA fragmentation, clonogenic assay, invasion assay, and expression of apoptotic (caspases 3, 6, 8, 9, and BAK) and metastatic markers (MMP 2, MMP 9, and osteopontin). Compound 3 significantly inhibited cell proliferation and induced apoptosis via the intrinsic route, i.e., the mitochondrial pathway, by disrupting mitochondrial membrane potential. The enhanced expression of caspases 6, 9, BAK, and HRK with downregulation of Bcl-2L1 and Ki67 further confirmed the involvement of the intrinsic apoptotic pathway. Moreover, compound 3 restricted the invasive nature of NCI-H460 cells evinced by reduced cell invasion in Boyden chamber invasion assay and downregulating the expression of metastatic markers, i.e., matrix metalloproteinase 2/9 and VEGF. It was also found to block osteopontin by negatively regulating its expression, a marker protein in cancer management. Conclusively, this sesquiterpene exhibited potent anticancer and antimetastatic activity and can be explored further as possible pharmacophores.
Traumatic brain injury (TBI) is an important global health concern that represents a leading cause of death and disability. It occurs due to direct impact or hit on the head caused by factors such as motor vehicles, crushes, and assaults. During the past decade, an abundance of new evidence highlighted the importance of inflammation in the secondary damage response that contributes to neurodegenerative and neurological deficits after TBI. It results in disruption of the blood–brain barrier (BBB) and initiates the release of macrophages, neutrophils, and lymphocytes at the injury site. A growing number of researchers have discovered various signalling pathways associated with the initiation and progression of inflammation. Targeting different signalling pathways (NF-κB, JAK/STAT, MAPKs, PI3K/Akt/mTOR, GSK-3, Nrf2, RhoGTPase, TGF-β1, and NLRP3) helps in the development of novel anti-inflammatory drugs in the management of TBI. Several synthetic and herbal drugs with both anti-inflammatory and neuroprotective potential showed effective results. This review summarizes different signalling pathways, associated pathologies, inflammatory mediators, pharmacological potential, current status, and challenges with anti-inflammatory drugs.
The non-porous rubbery polyurethane membranes (PUMs) have been successfully prepared from different molecular weights of polycaprolactone (PCL), 4,4,-dicyclohexylmethane (H12MDI diisocyanates) and 1,4-Butane diol (BDO), which are used in synthesis of soft and rigid segment, in gas separation. All structure of membranes were confirmed by FTIR technique that exhibits high molecular weight content of PCL conveniences the strong peak at 1710 cm⁻¹ corresponds to hydrogen bonding in urethane groups that controls the packing, morphology and crystallization in polyurethane membranes. Differential scanning calorimeter (DSC) measurement provided a lower Tg at 50 °C and Tmax at 550 °C in the heating scanning curve of PCL 750–2000, which indicated that lower energy is required to overcome the chain–chain interaction. The polyester groups in PCL structure created hydrogen bonding which increased hydrophilicity, chain mobility, flexibility and transport of gases. Atomic force microscopy confirmed the non-porous, wettability and increase roughness on membrane surface as high molecular weight of polyol increases the gas solubility and diffusivity. Excellent values of tensile strength (13.25 Mpa), elongation at break hardness (361%) and hardness (86A) were observed for higher molecular weight (2000) PUM by universal testing machine. The lower molecular PUM-1 (750 Mw) content has 46% lower CO2, CH4, N2 and O2 permeability of pure gases as compared to high PUM-4 and PUM-5 having 1600, 2000 of PCL content in polyurethane. Permeability property of gases is associated with free volume and flexibility of polymer backbone segments within the membrane, which is dominated by the chain mobility of polymeric substance. The high permeation flux and selectivity were achieved by increasing feed temperature, pressure and transient gaps. The CO2/N2 selectivity increased as compared to CO2/CH4 due to chain packing density, lower free volume and saturation of carrier efficiency.
Dubas bug (Ommatissus lybicus de Bergevin) infestations are frequent in several Middle Eastern and North African countries, causing havoc to date palms. The key objectives of this research were (1) to examine the prevalence of the Dubas bug geographically and (2) to identify hotspots and clusters at the local levels. Normalised difference vegetation indices, kernel density estimations, spatial autocorrelations, Getis-Ord G*, Anselin spatial indicators, ordinary regression and forest-based classification and regression algorithms were used to detect Dubas bug infestations in the Al Batinah North and Al Batinah South governorates in Oman from 2017 to 2021. Images of the region, including several sub-locations with diverse levels of infestation, were collected throughout the Dubas bug spring and autumn generations during the study period. The spring generation's kappa coefficient for identifying infestation levels was 0.97, whereas the autumn generation's kappa coefficient was 0.98. Varying infestation levels were observed over the study period, with some areas experiencing fewer or more cold spots or hotspots than others. The highest Moran's I value of 0.48, along with the highest z-score of 12.9, characterised the highly clustered pattern of infestation during the 2017 spring generation, while the lowest infestation clustering occurred during the 2019 spring generation, with the lowest Moran's I of 0.23 and the highest z-score of 7.2. Despite seasonal fluctuations, most Dubas bug hotspots were located in the southern parts of the study area. Thus, the infestations caused the greatest damage to palm tree farms in interior areas between mountains, away from the coastal plains. Dubas bugs were found in high-density clusters in the south of Sohar and Al Khaburah and in the southwest of Al Rustaq during the 2017 and 2018 spring generations. By observing statistically significant changes in infection clustering patterns, entomologists can assess the prevalence of infestation using spatial information techniques.
Many cleaning products contain chemicals that can be harmful to human health, and manufacturers do not receive Food and Drug Administration (FDA) approval whether the ingredients in the products are safe or not. The use of commercially available detergents for household cleaning on a daily basis can also have a negative impact on the environment. Hence, this study proposed the application of Bacillus salmalaya, a Gram positive, facultatively aerobic, bacilli-shaped endospore-forming bacteria that are capable of producing various enzymes suitable for cleaning. This study demonstrated the ability of B. salmalaya's cell-free supernatant to clean common household stains. The cleaning capability of supernatant was compared with two different cleaning agents, i.e., detergent and water. Cleaning images were analyzed using spot-density analysis computer program, which measures the stain's color intensity to quantify the cleaning capacity of each cleaning agent before and after cleaning. Results show that the detergent cleans the best for most stains. Interestingly, the cleaning ability of the supernatant of higher concentration does not deviate much from detergent. In soy sauce, the supernatant cleans better than detergent by 15%, whereas in ketchup and oil, the cleaning ability of the supernatant is less than detergent by 2% and 16%, respectively. However, no significant difference was observed when cleaning turmeric extract. Thus, these imply that B. salmalaya's supernatant has the potential as an eco-friendly cleaning agent and needs to be further investigated to develop a more effective formula and commercially feasible product and therefore be the key to reduce the impacts on environmental pollution.
Background Carbonic anhydrase II (CA-II) is associated with calcification, tumorigenicity, epilepsy, osteoporosis, and several other physiological or pathological processes. CA-II inhibitors can be used to reduce the intraocular pressure usually associated with glaucoma. Objective In search of potent CA-II inhibitors, a series of thiosemicarbazone derivatives (3a-u) was synthesized. Methods This series was evaluated against bovine and human carbonic anhydrase II (bCA-II and hCA-II) and their docking studies were carried out Results In the preliminary screening, most of the compounds exhibited significant inhibition of bCA-II and hCA-II. The predictive structure-activity relationship suggested that the thiosemicarbazide moiety play a key role in the inhibition of enzyme activity and substitution at R position and has a remarkable contribution to the overall activity. The kinetics studies of the most active inhibitors of bCA-II (3d, 3e, 3l, 3f, and 3p) and hCA-II (3g) were performed against bCA-II and hCA-II, respectively to investigate their mode of inhibition and dissociation constants (Ki). Conclusion Subsequently, 3e, 3f, 3l and 3p were identified as competitive inhibitors of bCA-II with Ki values of 5.02-14.70 µM, while 3d as a noncompetitive inhibitor of bCA-II (Ki = 2.5±0.015 µM), however, 3g demonstrated competitive inhibition of hCA-II with Ki value of 5.95±0.002 µM. The selectivity index reflects that the compound 3g is more selective for hCA-II. The binding modes of these compounds with bCA-II and hCA-II were investigated by structure-based molecular docking, and the docking results are in complete agreement with the experimental findings.
This article argues that the Sasanian government tried to reshape the hydrological order of water resources by damming rivers, digging canals and building aqueducts according to their conception of justice. Although all Iranian dynasties more or less replenished their budget with agricultural revenues, it was the Sasanian government that for the first time exalted irrigated cultivation as the cornerstone of their political economy. The hydraulic mission of the Sasanian polity was to keep a balance between water resources and workforce in their agricultural units. This mission pursued two schemes; first all water resources were reorganized through investing in a considerable number of hydraulic structures, second the agricultural working class was kept confined to the area irrigated and affected by the same supplied water, the area that is called hydro-political territory in this study. Hydro-political borders were the product of a mesh of interactions between ideology, political power, ecology and economy, which impeded social mobility and stifled different aspects of socio-economic change in Iran’s agrarian communities. This article concludes that today’s Iran has inherited the same political tradition that gives rise to hydro-political borders by reorganizing water resources based on a geopolitical disparity between different regions and the leaders’ institutional priorities.
Background: Candida auris is an emergent fungal pathogen and a global concern, mostly due to its resistance to many currently available antifungal drugs. Objective: Thus, in response to this challenge, we evaluated the in vitro activity of potential new drugs, diphenyl diselenide (PhSe)2 and nikkomycin Z (nikZ), alone and in association with currently available antifungals (azoles, echinocandins, and polyenes) against Candida auris. Methods: Clinical isolates of C. auris were tested in vitro. (PhSe)2 and nikZ activities were tested alone and in combination with amphotericin B, fluconazole, or the echinocandins, micafungin and caspofungin. Results: (PhSe)2 alone was unable to inhibit C. auris, and antagonism or indifferent effects were observed in the combination of this compound with the antifungals tested. NikZ appeared not active alone either, but frequently acted cooperatively with conventional antifungals. Conclusion: Our data show that (PhSe)2 appears to not have a good potential to be a candidate in the development of new drugs to treat C. auris, but that nikZ is worthy of further study.
Carbonyl-carbonyl (CO⋯CO) interactions are recently explored noncovalent interactions of significant interest owing to their role in the stability of biomacromolecules. Currently, substantial efforts are being made to understand the nature of these interactions. In this study, twelve phenoxy pendant isatins 1-12 have been evaluated for their α-glucosidase inhibitory potential in addition to the analysis of X-ray single crystals of 4 and 9. Both compounds 4 and 9 showed intriguing and unique self-assembled structures. The CO⋯CO and antiparallel displaced π⋯π stacking interactions are mainly involved in the formation of 1D-stair like supramolecular chains of 4 whereas antiparallel π⋯π stacking interactions drive the formation of 1D-columnar stacks of 9. These compounds not only highlight the potential of the isatin moiety in forming strong CO⋯CO and antiparallel π⋯π stacking interactions but also are interesting models to provide considerable insight into the nature of these interactions. The in vitro biological studies revealed that all twelve phenoxy pendant isatins 1-12 are highly potent inhibitors of α-glucosidase enzyme with IC50 values ranging from 5.32 ± 0.17 to 150.13 ± 0.62 μM, showing many fold more potent activity than the standard drug, acarbose (IC50 = 873.34 ± 1.67). Easy access and high α-glucosidase inhibition potential of these phenoxy pendant isatins 1-12 provide an attractive platform for finding more effective medication for controlling postprandial hyperglycemia.
The in vitro panel of technologies to address biomolecular interactions are in play, however microscale thermophoresis is continuously increasing in use to represent a key player in this arena. This review highlights the usefulness of microscale thermophoresis in the determination of molecular and biomolecular affinity interactions. This work reviews the literature from January 2016 to January 2022 about microscale thermophoresis. It gives a summarized overview about both the state-of the art and the development in the field of microscale thermophoresis. The principle of microscale thermophoresis is also described supported with self-created illustrations. Moreover, some recent advances are mentioned that showing application of the technique in investigating biomolecular interactions in different fields. Finally, advantages as well as drawbacks of the technique in comparison with other competing techniques are summarized.
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