The Dilemma of Insulin Delivery into the Brain: A Comprehensive Review.

Insulin is a peptide hormone that is essential for regulating body homeostasis. Furthermore, it is involved in various neurological functions such as memory, behaviors, and cognition. The ubiquitous distribution of insulin receptors on various brain cells, such as neurons, microglia, astrocytes, and oligodendrocytes, and their differential localization across various brain regions, including the hippocampus, hypothalamus, and olfactory bulb, collectively underscore the crucial involvement of insulin in the modulation of cerebral functions. Along with ageing, in some pathological conditions such as diabetes and brain insulin resistance, the need for exogenous insulin is felt to compensate for insulin deficiency. In these cases, the biggest obstacle to the delivery of insulin to the brain is the blood-brain barrier (a physical barrier consisting of endothelial cells with tight junctions), which prevents the direct entry of most substances possessing high molecular weight, like insulin, into the brain. Therefore, different delivery methods have been proposed by researchers for insulin delivery that directly or indirectly cause the transfer of insulin to the brain. Some of these methods lack high efficiency and cause many side effects for the patient. In this regard, many new technologies have come to the aid of researchers and have introduced more effective delivery strategies, including the use of nanocarriers. Despite the promising outcomes demonstrated in the experimental models, the utilization of these techniques in human studies remains at a nascent stage and necessitates further comprehensive investigation. This review article aims to examine the diverse methods of insulin administration to the brain by gathering extensive information on insulin and its obstacles to brain delivery.

The role of bixin as antioxidant, anti-inflammatory, anticancer, and skin protecting natural product extracted from Bixa orellana L.

Since long, medicinal plants or herbs are being used in different traditional treatment systems as therapeutic agents to treat a variety of illnesses. Bixa orellana L., an medicinal plant (family: Bixaceae), is an Ayurvedic herb used to treat dyslipidemia, diarrhoea, and hepatitis since ancient times. B. orellana L., seeds contain an orange-red coloured component known as bixin (C25H30O4), which constitutes 80% of the extract.Chemically, bixin is a natural apocarotenoid, biosynthesized through the oxidative degradation of C40 carotenoids. Bixin helps to regulate the Nrf2/MyD88/TLR4 and TGF-1/PPAR-/Smad3 pathways, which further give it antifibrosis, antioxidant, and anti-inflammatory properties. This current review article presents a comprehensive review of bixin as an anti-inflammatory, antioxidant, anticancer,and skin protecting natural product. In addition, the biosynthesis and molecular target of bixin, along with bixin extraction techniques, are also presented.

Lagerstroemia speciosa Ameliorated Blood Pressure in LNAME Induced Hypertension in Experimental Rats through NO/cGMP and Oxidative Stress Modulation.

Cardiovascular disease is the primary reason for chronic heart diseases and mortality worldwide. Hypertension (HTN) is the utmost dominant risk factor for the evolution of several diseases. Herbal medicines, traditional medicinal herbs, and their extracts are widely utilized to treat and monitor HTN. Herbal components have been shown to help relax arteries and lower oxidative stress. The current study assesses the probable role of herbal plant extract Lagerstroemia speciosa (LS) in the LNAME induced HTN in rats. LNAME (50 mg/100 mL) in drinkable water was given to rats for five weeks. There was a significant upsurge in LNAME-treated hypertensive rats' blood pressure (BP). On treatment with LS, it ameliorates blood pressure. Further, LS also improved body weight, reduced heart weight, and heart hypertrophy. The NO/cGMP concentration was lowered along with a substantial upsurge in the level of glutathione and a decline in MDA level. The LS extract also reduced the inflammatory cytokine markers in the systemic circulation. In conclusion, thus, the extract of LS treatment can efficiently alleviate the BP, oxidative stress markers, and inflammation and improve NO/cGMP concentration in LNAME induced HTN in rats.

Screening, molecular simulation & in silico kinetics of virtually designed covid-19 main protease inhibitors.

Coronavirus (covid-19) infection is considered to be deadliest ever pandemic experienced by the human being. It has very badly affected the socio-economic health of human and stuck the scientific community to think and rethink about its complete eradication. But due to no effective treatment or unavailability of vaccine the health professional could not show any significant improvement to control the pandemic. The situation needs newer molecule, vaccine or effective treatment to control covid-19 infection. Different target in viruses has been explored and proteases enzymes were found to be therapeutically effective target for the design of potential anti-covid-19 molecule as it plays the vital role in viral replication and assembly. Structure-based drug design was employed to discover the small molecule of anti-covid-19. Here we considered the small library of naturally occurring polyphenolic compounds and molecular docking, Molecular dynamics (MD) simulations, free binding energy calculation and in-silico ADME calculations to identify the newer HITs. Based upon their score the two molecules were identified as promising candidate. The docking scores were found to be -7.643 and -7.065 for the HIT1 and HIT-2 respectively. In MD simulations study the RMSD values were found to be 4.3 Å & 4.9 Å respectively. To validate these results MM-GBSA was performed and their binding free energies were computationally determined. The prime energy values of identified HITs (-13412.45 & -13441.8 kJ/mole) were found to be very close proximity to reference molecule (-13493.05 kJ/mole). Then in-silico ADME calculations were performed to calculate the drug likeliness identified HITs. BY considering all the values comparative to reference molecule and obtained in-silico pharmacokinetic properties of identified HITs we can suggest that HIT-1 and HIT-2 would be the most promising molecules that can inhibit the main protease enzyme of covid-19. These two molecules would become the potential drug candidate for the treatment of covid-19 infections.

An in-silico investigation of potential natural polyphenols for the targeting of COVID main protease inhibitor.

The deadliest recent pandemic outbreak of COVID-19 disease has severely damaged the socio-economic health of the people globally. Due to unavailability of any effective vaccine or treatment the human beings are still struggling to overcome the pandemic condition. In an attempt to discover anti-COVID molecule, we used in-silico approach and reported 160 natural polyphenols to identify the most promising druggable HITs that can further used for drug discovery process. The co-crystallized structure COVID protease enzyme (PDB id 6LU7) was used. HTVS, MD simulation, binding energy calculations and in-silico ADME calculation were done and analyzed. Depending upon the scores three compounds galangin, nalsudaldain and rhamnezine were identified and the docking score were found to be -7.704, -6.51, -4.212 respectively. These docked complexes were further subjected to MD simulation runs over a 100 ns time and the RMSD and RMSF values were determined. The RMSD values of three compounds were found to be 2.9 Å, 7.6 Å & 9.5 Å respectively and the lowest RMSF values suggested the steady stability of ligand-protein complexes. The binding free energies (ΔG) of compounds with protein were found to be -49.8, -56.45, -62.87 kJ/mole. Moreover, in-silico ADME calculations indicated the drug likeliness properties of these molecules. By considering all these in-silico results the identified HITs would be the most probable anti-COVID drug molecules that can be further taken in wet lab and can act as lead for development of newer inhibitor of COVID-19 main protease enzyme.

In Vitro Evaluation of Antibacterial, Antioxidant, and Antidiabetic Activities and Glucose Uptake through 2-NBDG by Hep-2 Liver Cancer Cells Treated with Green Synthesized Silver Nanoparticles.

The alarming rise in diabetes owing to drug resistance necessitates the implementation of prompt countermeasures in the treatment module of diabetes. Due to their unique physicochemical features, silver nanoparticles may have potential applications in the medical and pharmaceutical industries. Silver nanoparticles (AgNPs) were synthesized from the culture filtrate of Salmonella enterica (ATCC-14028). UV-Vis spectrophotometry, FTIR, SEM, and energy dispersive X-rays were used in the characterization of the nanoparticles. Transmission electron microscopy (TEM) revealed that AgNPs are spherical and highly scattered and vary in size from 7.18 nm to 13.24 nm. AgNP stability and protein loss were confirmed by thermogravimetric analysis (TGA) at different temperatures. The AgNPs had excellent antibacterial activity and a strong synergistic effect against methicillin-resistant bacteria Staphylococcus aureus (MRSA) ATCC-4330 and Streptococcus epidermis (MRSE) ATCC-51625. The DPPH experiment revealed that the AgNPs had high antioxidant activity. The antidiabetic assay revealed that these AgNPs had an IC50 for alpha-amylase of 428.60 µg/ml and an IC50 for alpha-glucosidase of 562.02 µg/ml. Flow cytometry analysis of Hep-2 cells treated with AgNPs (40 µg/ml) revealed higher expression of 2-NBDG glucose absorption (uptake) compared to control metformin. These AgNPs have promising antidiabetic properties and could be used in pharmaceuticals and biomedical industries.

Acute and sub-acute oral toxicity Lagerstroemia speciosa in Sprague-Dawley rats.

Through the boost of the natural medicinal market, individuals began to use a variety of organic materials in the marketed herbal preparation. Lagerstroemia speciosa (LS) leaves are known as banaba. People have been using a decoction of LS leaves as antidiabetic. The study aimed to investigate the acute and sub-acute oral toxicity of LS in Sprague-Dawley rats. The acute toxicity was determined by a single oral dose of LS (2000 mg/kg). Therein animal behaviour and mortality rate were observed for 14 days. The LS (200 mg/kg) was given for 28 days daily in the sub-acute study. The body weight, organ weight, food, water intake, biochemical, haematological parameters, and histopathology were studied. The findings of this study showed no mortality or morbidity was found in acute and sub-acute toxicity studies in rats. Additionally, no significant variations were found in the respective weight of organ, haematological and biochemical parameters of treated groups with reference to the control group. Moreover, no visible histological changes were detected in the liver of treated groups with reference to the control. In conclusion, the oral administration of LS did not fabricate any major toxic effect in rats. No toxic consequences were reported during acute and sub-acute toxicity investigations. Overall, LS is a safe, natural bio-actives as studied. Further investigations of cytotoxicity and genotoxicity of the above drug(s) or their combinations may be executed for appreciative safety.

Design & discovery of small molecule COVID-19 inhibitor via dual approach based virtual screening and molecular simulation studies.

The emerged COVID-19 (SARS corona virus) pandemic leads to severe or fatal respiratory tract infections affecting millions of people worldwide since its outbreak. The situation needs the newer molecule to control the infections as the pandemic had very badly affected the health and socioeconomic conditions of human being. CoV-2 main protease is considered to be key enzyme by targeting which we can design or develop the drug candidate. The active fitting and binding of any molecule depends upon the shape and electrostatic properties of ligand complementary to the receptor site. In this study ZINC13 database, a drug like subset (13,195,609 molecules) was subjected to shape and electrostic based virtual screening (VROCS & EON software) and followed by molecular modelling studies using docking and molecular dynamics simulation. Further the drug ability of identified candidate was predicted by the SiteMap analysis. The best shape and electrostatic similarities were observed between ZINC19973962 and reference molecule. The Tamintoshape and Tanimotoelectrostatic was found to be 0.667 and 0.022 respectively. The molecule also displayed the identical binding pattern with docking score -7.964 and this interaction was further validated by the molecular dynamics simulations. The RMSD & RMSF values were found to be 1.5 Å and1.8 Å respectively suggesting the stability of complex and very low fluctuation in ligand-protein complex over the entire MD simulation run. SiteMap analysis showed the identical Dscore of reference and identified HIT that indicated the molecule ZINC19973962 would be the promising druggable candidate against COVID main protease enzyme and can be used as lead molecule for the development of anti-COVID molecule.

Borderline microscopic organism and lockdown impacted across the borders-global shakers.

Viruses are the potential cause of several diseases including novel corona virus-19, flu, small pox, chicken pox, acquired immunodeficiency syndrome, severe acute respiratory syndrome etc. The objectives of this review article are to summarize the reasons behind the epidemics caused by several emerging viruses and bacteria, how to control the infection and preventive strategies. We have explained the causes of epidemics along with their preventive measures, the impact of lockdown on the health of people and the economy of a country. Several reports have revealed the transmission of infection during epidemic from the contact of an infected person to the public that can be prevented by implementing the lockdown by the government of a country. Though lockdown has been considered as one of the significant parameters to control the diseases, however, it has some negative consequences on the health of people as they can be more prone to other ailments like obesity, diabetes, cardiac problems etc. and drastic decline in the economy of a country. Therefore, the transmission of diseases can be prevented by warning the people about the severity of diseases, avoiding their public transportation, keeping themselves isolated, strictly following the guidelines of lockdown and encouraging regular exercise.

Preparation and Evaluation of Silymarin-Loaded Solid Eutectic for Enhanced Anti-Inflammatory, Hepatoprotective Effect: In Vitro-In Vivo Prospect.

Solubility of phytochemicals is a major concern for drug delivery, permeability, and their biological response. However, advancements in the novel formulation technologies have been helping to overcome these challenges. The applications of these newer technologies are easy for commercialization and high therapeutic outcomes compared to conventional formulations. Considering these facts, the present study is aimed to prepare a silymarin-loaded eutectic mixture with three different ratios of Polyvinylpyrrolidone K30 (PVP K30) and evaluating their anti-inflammatory, and hepatoprotective effects. The preliminary phytochemical and characterization of silymarin, physical mixture, and solid dispersions suggested and successfully confirmed the formation of solid dispersion of silymarin with PVP K30. It was found that the solubility of silymarin was increased by 5-fold compared to pure silymarin. Moreover, the in vitro dissolution displayed that 83% of silymarin released within 2 h with 2.8-fold increase in dissolution rate compared to pure silymarin. Also, the in vivo study suggested that the formulation significantly reduced the carbon tetrachloride- (0.8620 ± 0.05034∗∗ for 1 : 3 ratio), paracetamol- (0.7300 ± 0.01517∗∗ for 1 : 3 ratio), and ethanol- (0.8100 ± 0.04037∗∗ for 1 : 3 ratio) induced hepatotoxicity in rats. Silymarin solid dispersion was prepared using homogenization methods that have prominent anti-inflammatory effect (0.6520 ± 0.008602∗∗ with 8.33%) in carrageenan-induced rat paw model.

Elucidation of DNA binding interaction of new Cu(II)/Zn(II) complexes derived from Schiff base and L-tryptophan amino acid: a multispectroscopic and molecular docking approach.

Herein, we describe the synthesis, structural elucidation, and DNA interaction of newly synthesized Cu(II) and Zn(II) complexes, i.e., [Cu(SB)(L-trp)(H2O)2]NO3 (1) and [Zn(SB)(L-trp)(H2O)2]NO3 (2) (SB = Schiff base obtained from the reaction between o-vanillin and 2-amino-2-methylpropane-1,3-diol; L-trp = L-tryptophan). From the analysis, a six-coordinated environment around the Cu(II) or Zn(II) center is proposed. The ability of the complexes to bind with calf thymus DNA was examined by optical spectroscopy (UV-vis titrations and steady-state fluorescence emission) and viscosity measurements. The vivid experimental results revealed that complexes 1 and 2 avidly bind to DNA through surface and groove binding modes, albeit with dissimilar intrinsic binding constants (1.54 × 104 and 1.36 × 104 M-1 for 1 and 2, respectively). Both complexes can displace ethidium bromide (EB) to some extent from the intercalated EB-DNA system, resulting in fluorescence quenching. Additional experiments such as [Fe(CN)6]4--induced quenching and thermal melting confirmed the electrostatic and groove binding mode. Furthermore, molecular docking studies verified that both complexes locate in the DNA minor groove by surface binding and were stabilized through weak intermolecular forces. The binding affinity of the lowest energy docked pose was found to be -5.37 kcal/mol for complex 1 and - 5.18 kcal/mol for complex 2. The present work is expected to pave the way for the synthesis of DNA-targeting Cu(II)/Zn(II) metal complexes for the development of chemotherapeutic agents.

Inhibition of human amylin aggregation by Flavonoid Chrysin: An in-silico and in-vitro approach.

Islet amyloid polypeptide (amylin), consecrated by the pancreatic ß-cells with insulin, has a significant role to play in maintaining homeostasis of islet cell hormones. Alzheimer's disease is the predominant source of dementia. However, its etiology remains uncertain; it appears that type 2 diabetes mellitus and other prediabetic states of insulin resistance contribute to the intermittent Alzheimer's disease presence. Amylin is abnormally elevated in Type II diabetes patients, accumulated into amylin aggregates, and ultimately causes apoptosis of the ß-cells, and till date, its mechanism remains unclear. Several flavonoids have inhibitory effects on amylin amyloidosis, but its inhibition mechanisms are unknown. Screening a collection of traditional compounds revealed the flavone Chrysin, a potential lead compound. Chrysin inhibits amyloid aggregate formation according to Thioflavin T binding, turbidimetry assay. We report results of molecular interaction analysis of Chrysin with amylin which shows potent binding affinity against amylin. Pharmacokinetics and Drug likeness studies of Chrysin also suggest that it is a potential lead compound. Therefore, Chrysin prevented amylin aggregation.

QbD-driven formulation development and evaluation of topical hydrogel containing ketoconazole loaded cubosomes.

The proposed study aimed to develop topical hydrogel containing ketoconazole loaded cubosomes with lower surfactant concentrations using the 'Quality by Design' (QbD) approach. Risk assessment was performed, followed by screening and optimization of formulations by 32 factorial design using Design-Expert® software. Keeping the combination of constituents similar to that of the optimized batches as predicted post conduct of 'Design of Experiment' (DoE) studies, scale-up batches were prepared. The 32 factorial design model successfully predicted the composition of the optimized formulation within the confidence limits. In vitro drug release study was performed and analyzed by various mathematical models. Ex vivo permeation study was investigated using goat ear skin. These ketoconazole loaded cubosomes showed a release pattern similar to the Korsmeyer-Peppas model experiencing Fickian diffusion having 67% cumulative ketoconazole release within 24 h. Ex vivo permeation study of hydrogel containing ketoconazole loaded cubosomes revealed a sustained release pattern through the goat ear skin with around 92.73 % release within 24 h. Scale-up studies also gave the confirmatory results for the post characterization studies, whereby the particle size of ketoconazole loaded cubosomes was 198 nm with 45% ketoconazole entrapment efficiency. This hydrogel containing ketoconazole loaded cubosomes can be used for topical drug delivery.

Approaches for prevention and environmental management of novel COVID-19.

The World Health Organization (WHO) recognized a novel coronavirus as the causative agent of a new form of pneumonia. It was subsequently named COVID-19 and reported as the source of a respiratory disease occurrence starting in December 2019 in Wuhan, Hubei Province, China. It has been affirmed a public health emergency of international significance by the World Health Organization. It is regarded as a subset of the severe acute respiratory syndrome (SARS) and the Middle East respiratory syndrome (MERS); COVID-19 is triggered by a betacoronavirus called SARS-CoV-2, which affects the lower respiratory tract and occurs in humans as pneumonia. A variety of drugs, such as remdesivir and favipiravir, are currently undergoing clinical trials to evaluate for the management of COVID-19. The effect of the pandemic as well as the epidemic that follows through the life cycles of various recycled plastic is evaluated, particularly those required for personal safety and health care. In response to the growth in COVID-19 cases worldwide, the energy and environmental impacts of these lifecycle management have risen rapidly. However, significant hazardous waste management concerns arise due to the need to assure the elimination of residual pathogens in household and medical wastes. This review article summarizes the preventive and environmental management of COVID-19.

Crystal Growth and Kinetic Behaviour of Pseudoalteromonas espejiana Assisted Biosynthesized Gold Nanoparticles.

Pseudoalteromonas espejiana (P. espejiana) is a marine bacterium known for its high resistance to alkalinity. The ability of P. espejiana to reduce Au (III) and biosynthesize gold nanoparticles (AuNPs) is found positive and was confirmed using UV-VIS, EDS, SEM, and TEM studies. Previously, many studies have been reported regarding the crystalline nature of AuNPs; therefore, this research aims at studying the crystal growth behaviour of AuNPs through DLS and TEM studies. Spherically shaped and monodispersed, AuNPs ranging between 5 to 160 nm were obtained with an average particle size of 62 nm. Also, to achieve maximum production of AuNPs, the reaction kinetic study was performed using an ICP-OES method and the effect of various parameters including pH, temperature, rpm, and concentration of substrate was analyzed. During the biosynthesis process, an appropriate phase of nucleation, crystal growth, and saturation was observed and this helped to determine the rate constants and order of reaction. The parameters such as pH profile (pH 9), temperature (30°C), agitation speed (150 rpm), and enzyme substrate ratio (2 : 3) were found to be the best fits for maximum production of low size AuNPs. This demonstrates that in initial few hours, a quick conversion of the ionic gold precursor takes place into metallic gold nuclei, trailed by crystal growth via coalescence of small nuclei. Subsequently, it can be concluded that coalescence processes drive the crystal growth process of AuNPs over a time interval and finally leads to saturation and no newer particle formation in the solution.

Withdrawal Notice: Lipid Carriers Mediated Targeted Delivery of Neurotherapeuticals: Challenges, Role of Blood Brain Barrier and Promises of Nanotechnology Based Approaches in Neuronal Disorders

The article has been withdrawn at the request of the editor of the journal Current Drug Metabolism due to incoherent content. Bentham Science apologizes to the readers of the journal for any inconvenience this may have caused. The Bentham Editorial Policy on Article Withdrawal can be found at https://benthamscience.com/editorial-policies-main.php. Bentham Science Disclaimer: It is a condition of publication that manuscripts submitted to this journal have not been published and will not be simultaneously submitted or published elsewhere. Furthermore, any data, illustration, structure or table that has been published elsewhere must be reported, and copyright permission for reproduction must be obtained. Plagiarism is strictly forbidden, and by submitting the article for publication the authors agree that the publishers have the legal right to take appropriate action against the authors, if plagiarism or fabricated information is discovered. By submitting a manuscript, the authors agree that the copyright of their article is transferred to the publishers if and when the article is accepted for publication.

Molecular insights and novel approaches for targeting tumor metastasis.

In recent years, due to the effective drug delivery and preciseness of tumor sites or microenvironment, the targeted drug delivery approaches have gained ample attention for tumor metastasis therapy. The conventional treatment approaches for metastasis therapy have reported with immense adverse effects because they exhibited maximum probability of killing the carcinogenic cells along with healthy cells. The tumor vasculature, comprising of vasculogenic impressions and angiogenesis, greatly depends upon the growth and metastasis in the tumors. Therefore, various nanocarriers-based delivery approaches for targeting to tumor vasculature have been attempted as efficient and potential approaches for the treatment of tumor metastasis and the associated lesions. Furthermore, the targeted drug delivery approaches have found to be most apt way to overcome from all the limitations and adverse effects associated with the conventional therapies. In this review, various approaches for efficient targeting of pharmacologically active chemotherapeutics against tumor metastasis with the cohesive objectives of prognosis, tracking and therapy are summarized.

Global impacts of pre- and post-COVID-19 pandemic: Focus on socio-economic consequences.

On March 11, 2020, the novel Corona virus disease (COVID-19), was described as a pandemic by World Health Organization (WHO). Globally, the COVID-19 has not only affected the public health socially but also has rigorously affected economically. Substantial declines in income, increase in unemployment, and distractions in the transportation, amenities, and industrial sectors are amongst the major concerns of the pandemic disease extenuation. Furthermore, the governments of most of the countries underestimated the menaces of COVID-19 spread and were typically responsive for the calamities in their respective countries. As outbreak of this pandemic is not likely to wane in the nearby future, preventive actions are prerequisite to prevent infection spread, save people lives and also to save the economic affluence. In this review, based on the present knowledge and available literature, we have demonstrated the various aspects of pre-and post-COVID-19 effects over the social and economic phases worldwide. Moreover, the evidence based data have been summarized regarding threats, social influences, scientific upgrades, moral dynamics, stress and adapting in the pre- and post- COVID-19 situations.

Stability indicating liquid chromatographic method for simultaneous quantification of betamethasone valerate and tazarotene in in vitro and ex vivo studies of complex nanoformulation.

Low-potency corticosteroid betamethasone valerate and vitamin-A tazarotene are used in combination for effective treatment of psoriasis. There is no robust high-performance liquid chromatography analytical technique available for simultaneous estimation of betamethasone valerate and tazarotene in conventional and nanocarriers based formulations. A simple, accurate, robust isocratic high-performance liquid chromatography method was developed for simultaneous estimation of betamethasone valerate and tazarotene in topical pharmaceutical formulations. The developed method was validated as per the regulatory guidelines. The validated method was linear over the concentration range of 150-6000 ng/mL (r2  > 0.999) at 239 nm wavelength. Limits of detection and quantification of two analytes were 50 and 150 ng/mL, respectively. The %relative standard deviation for intraday and interday precision was less than 2%. The method was also evaluated in the presence of forced degradation conditions. The developed method was successfully applied for in vitro and ex vivo drug release studies of in-house designed nanoformulations.