Hypoxia and its effect on the cellular system.

Eukaryotic cells utilize oxygen for different functions of cell organelles owing to cellular survival. A balanced oxygen homeostasis is an essential requirement to maintain the regulation of normal cellular systems. Any changes in the oxygen level are stressful and can alter the expression of different homeostasis regulatory genes and proteins. Lack of oxygen or hypoxia results in oxidative stress and formation of hypoxia inducible factors (HIF) and reactive oxygen species (ROS). Substantial cellular damages due to hypoxia have been reported to play a major role in various pathological conditions. There are different studies which demonstrated that the functions of cellular system are disrupted by hypoxia. Currently, study on cellular effects following hypoxia is an important field of research as it not only helps to decipher different signaling pathway modulation, but also helps to explore novel therapeutic strategies. On the basis of the beneficial effect of hypoxia preconditioning of cellular organelles, many therapeutic investigations are ongoing as a promising disease management strategy in near future. Hence, the present review discusses about the effects of hypoxia on different cellular organelles, mechanisms and their involvement in the progression of different diseases.

In-situ Gels for Brain Delivery: Breaching the Barriers.

The blood-brain barrier (BBB) regulates blood and chemical exchange in the central nervous system. It is made up of brain parenchyma capillary endothelial cells. It separates the interstitial cerebrospinal fluid from the circulation and limits brain drug entry. Peptides, antibodies, and even tiny hydrophilic biomolecules cannot flow across the BBB due to their semi-permeability. It protects the brain from poisons, chemicals, and pathogens, and blood cells penetrate brain tissue. BBB-facilitated carrier molecules allow selective permeability of nutrients such as D-glucose, L-lactic acid, L-phenylalanine, L-arginine, and hormones, especially steroid hormones. Brain barriers prevent drug molecules from entering, making medication delivery difficult. Drugs can reach specific brain regions through the nasal cavity, making it a preferred route. The in-situ gels are mucoadhesive, which extends their stay in the nasal cavity, allows them to penetrate deep and makes them a dependable way of transporting numerous medications, including peptides and proteins, straight into the central nervous system. This approach holds great potential for neurological therapy as they deliver drugs directly to the central nervous system, with less interference and better drug release control. The brain affects daily life by processing sensory stimuli, controlling movement and behaviour, and sustaining mental, emotional, and cognitive functioning. Unlike systemic routes, the nasal mucosa is extensively vascularized and directly contacts olfactory sensory neurons. Compared to the systemic circulation, this improves brain bioavailability of medications. Drugs can be delivered to the brain using in-situ gel formulations safely and efficiently, with a greater therapeutic impact than with traditional techniques.

Vaccines in Breast Cancer: Challenges and Breakthroughs.

Breast cancer is a problem for women's health globally. Early detection techniques come in a variety of forms ranging from local to systemic and from non-invasive to invasive. The treatment of cancer has always been challenging despite the availability of a wide range of therapeutics. This is either due to the variable behaviour and heterogeneity of the proliferating cells and/or the individual's response towards the treatment applied. However, advancements in cancer biology and scientific technology have changed the course of the cancer treatment approach. This current review briefly encompasses the diagnostics, the latest and most recent breakthrough strategies and challenges, and the limitations in fighting breast cancer, emphasising the development of breast cancer vaccines. It also includes the filed/granted patents referring to the same aspects.

In-line treatments and clinical initiatives to fight against COVID-19 outbreak.

In December 2019, when the whole world is waiting for Christmas and New Year, the physicians of Wuhan, China, are astounded by clusters of patients suffering from pneumonia from unknown causes. The pathogen isolated from the respiratory epithelium of the patients is similar to previously known coronaviruses with some distinct features. The disease was initially called nCoV-2019 or SARS-nCoV-2 and later termed as COVID-19 by WHO. The infection is rapidly propagating from the day of emergence, spread throughout the globe and now became a pandemic which challenged the competencies of developed nations in terms of health care management. As per WHO report, 216 countries are affected with SARS-CoV-19 by August 5, 2020 with 18, 142, 718 confirmed cases and 691,013 deaths reports. Such huge mortality and morbidity rates are truly threatening and calls for some aggressive and effective measures to slow down the disease transmission. The scientists are constantly engaged in finding a potential solution to diagnose and treat the pandemic. Various FDA approved drugs with the previous history of antiviral potency are repurposed for COVID-19 treatment. Different drugs and vaccines are under clinical trials and some rapid and effective diagnostic tools are also under development. In this review, we have highlighted the current epidemiology through infographics, disease transmission and progression, clinical features and diagnosis and possible therapeutic approaches for COVID-19. The article mainly focused on the development and possible application of various FDA approved drugs, including chloroquine, remdesivir, favipiravir, nefamostate mesylate, penciclovir, nitazoxanide, ribavirin etc., vaccines under development and various registered clinical trials exploring different therapeutic measures for the treatment of COVID-19. This information will definitely help the researchers to understand the in-line scientific progress by various clinical agencies and regulatory bodies against COVID-19.

Application of chitosan modified nanocarriers in breast cancer.

As per the WHO, every year around 2.1 million women are detected with breast cancer. It is one of the most invasive cancer in women and second most among all, contributing around 15% of death worldwide. The available anticancer therapies including chemo, radio, and hormone therapy are associated with a high load of reversible and irreversible adverse effects, limited therapeutic efficacy, and low chances of quality survival. To minimize the side effects, improving therapeutic potency and patient compliance promising targeted therapies are highly desirable. In this sequence, various nanocarriers and target modified systems have been explored by researchers throughout the world. Among these chitosan-based nanocarriers offers one of the most interesting, flexible, and biocompatible systems. The unique characteristics of chitosan like surface flexibility, biocompatibility, hydrophilicity, non-toxic and cost-effective behavior assist to overcome the inadequacy of existing therapy. The present review throws light on the successes, failures, and current status of chitosan modified novel techniques for tumor targeting of bioactives. It also emphasizes the molecular classification of breast cancer and current clinical development of novel therapies. The review compiles most relevant works of the past 10 years focusing on the application of chitosan-based nanocarrier against breast cancer.

Integration of System Biology Tools to Investigate Huperzine A as an Anti-Alzheimer Agent.

Aim: The present study aimed to investigate huperzine A as an anti-Alzheimer agent based on the principle that a single compound can regulate multiple proteins and associated pathways, using system biology tools. Methodology: The simplified molecular-input line-entry system of huperzine A was retrieved from the PubChem database, and its targets were predicted using SwissTargetPrediction. These targets were matched with the proteins deposited in DisGeNET for Alzheimer disease and enriched in STRING to identify the probably regulated pathways, cellular components, biological processes, and molecular function. Furthermore, huperzine A was docked against acetylcholinesterase using AutoDock Vina, and simulations were performed with the Gromacs package to take into account the dynamics of the system and its effect on the stability and function of the ligands. Results: A total of 100 targets were predicted to be targeted by huperzine A, of which 42 were regulated at a minimum probability of 0.05. Similarly, 101 Kyoto Encyclopedia of Genes and Genomes pathways were triggered, in which neuroactive ligand-receptor interactions scored the least false discovery rate. Also, huperzine A was predicted to modulate 54 cellular components, 120 molecular functions, and 873 biological processes. Furthermore, huperzine A possessed a binding affinity of -8.7 kcal/mol with AChE and interacted within the active site of AChE via H-bonds and hydrophobic interactions.

Design and optimization of curcumin loaded nano lipid carrier system using Box-Behnken design.

Herbal antioxidant like curcumin holds great potential to treat neurodegenerative disease like Alzheimer's disease. However, its therapeutic potency is obstructed due to rapid metabolism, poor solubility, GI susceptibility, enzymatic degradation and lower bioavailability. Thus, the present work aimed to design and optimize curcumin-loaded NLC (CNL) with higher drug entrapment, prolonged release and better stability. CNL was prepared by modified melt emulsification method followed by ultrasonication. The formulation was optimized by 3 factor 3 level Box-Behnken design using solid: liquid lipid, surfactant concentration and ultrasonication time as independent variable while particle size, entrapment efficiency and % drug release as dependant variable. The design suggested 3.092 solid:liquid lipid, 2.131% surfactant and 4.757 min ultrasonication fit best to get the optimized formulation. The size of the optimized CNL was noted 124.37 ± 55.81 nm, which is in the acceptable range for brain delivery. SEM results also comply with this size range (near 150 nm) and demonstrated almost spherical and uniform particles with porous and uneven surface structures. PDI, zeta potential, entrapment efficiency and % drug release were observed as 0.201 ± 0.00, - 17.2 ± 2.35 mV, 93.62 ± 0.68% and 92.73 ± 0.06%, respectively. The NLC demonstrated initial burst release with subsequent prolonged release of drug for 48 h. Weibull kinetic equation with 0.9958 R2, minimum AIC and maximum MSC value was found best fit to explain the release behavior. The ß exponent and diffusional coefficient (n) indicated combined release mechanism with Fickian diffusion as drug release mechanism. Formulation was also found stable at different storage condition.

Stimuli-responsive In situ gelling system for nose-to-brain drug delivery.

The diagnosis and treatment of neurological ailments always remain an utmost challenge for research fraternity due to the presence of BBB. The intranasal route appeared as an attractive and alternative route for brain targeting of therapeutics without the intrusion of BBB and GI exposure. This route directly and effectively delivers the therapeutics to different regions of the brain via olfactory and trigeminal nerve pathways. However, shorter drug retention time and mucociliary clearance curtail the efficiency of the intranasal route. The in situ mucoadhesive gel overthrow the limitations of direct nose-to-brain delivery by not only enhancing nasal residence time but also minimizing the mucociliary clearance and enzymatic degradation. This delivery system further improves the nasal absorption as well as bioavailability of drugs in the brain. The in situ mucoadhesive gel is a controlled and sustained release system that facilitates the absorption of various proteins, peptides and other larger lipophilic and hydrophilic moieties. Owing to multiple benefits, in situ gelling system has been widely explored to target the brain via nasal route. However, very few review works are reported which explains the application of in situ nasal gel for brain delivery of CNS acting moieties. Hence, in this piece of work, we have initially discussed the global statistics of neurological disorders reported by WHO and other reputed organizations, nasal anatomy, mechanism and challenges of nose-to-brain drug delivery. The work mainly focused on the use of different stimuli-responsive polymers, specifically thermoresponsive, pH-responsive, and ion triggered systems for the development of an effective and controlled dosage form, i.e., in situ nasal gel for brain targeting of bioactives. We have also highlighted the origin, structure, nature and phase transition behavior of the smart polymers found suitable for nasal administration, including poloxamer, chitosan, EHEC, xyloglucan, Carbopol, gellan gum and DGG along with their application in the treatment of neurological disorders. The article is aimed to gather all the information of the past 10 years related to the development and application of stimuli-responsive in situ nasal gel for brain drug delivery.

Insulin mediated novel therapies for the treatment of Alzheimer's disease.

Alzheimer's disease, a progressive neurodegenerative disorder, is one of the leading causes of death in the USA, along with cancer and cardiac disorders. AD is characterized by various neurological factors like amyloid plaques, tau hyperphosphorylation, mitochondrial dysfunction, acetylcholine deficiency, etc. Together, impaired insulin signaling in the brain is also observed as essential factor to be considered in AD pathophysiology. Hence, currently researchers focused on studying the effect of brain insulin metabolism and relation of diabetes with AD. Based on the investigations, AD is also considered as type 3 or brain diabetes. Besides the traditional view of correlating AD with aging, a better understanding of various pathological factors and effects of other physical ailments is necessary to develop a promising therapeutic approach. There is a vast scope of studying the relation of systemic insulin level, insulin signaling, its neuroprotective potency and effect of diabetes on AD progression. The present work describes worldwide status of AD and its relation with diabetes mellitus and insulin metabolism; pathophysiology of AD; different metabolic pathways associating insulin metabolism with AD; insulin receptor and signaling in the brain; glucose metabolism; insulin resistance; and various preclinical and clinical studies reported insulin-based therapies to treat AD via systemic route and through direct intranasal delivery to the brain.

Recent strategies and advances in the fabrication of nano lipid carriers and their application towards brain targeting.

In last two decades, the lipid nanocarriers have been extensively investigated for their drug targeting efficiency towards the critical areas of the human body like CNS, cardiac region, tumor cells, etc. Owing to the flexibility and biocompatibility, the lipid-based nanocarriers, including nanoemulsion, liposomes, SLN, NLC etc. have gained much attention among various other nanocarrier systems for brain targeting of bioactives. Across different lipid nanocarriers, NLC remains to be the safest, stable, biocompatible and cost-effective drug carrier system with high encapsulation efficiency. Drug delivery to the brain always remains a challenging issue for scientists due to the complex structure and various barrier mechanisms surrounding the brain. The application of a suitable nanocarrier system and the use of any alternative route of drug administration like nose-to-brain drug delivery could overcome the hurdle and improves the therapeutic efficiency of CNS acting drugs thereof. NLC, a second-generation lipid nanocarrier, upsurges the drug permeation across the BBB due to its unique structural properties. The biocompatible lipid matrix and nano-size make it an ideal drug carrier for brain targeting. It offers many advantages over other drug carrier systems, including ease of manufacturing and scale-up to industrial level, higher drug targeting, high drug loading, control drug release, compatibility with a wide range of drug substances, non-toxic and non-irritant behavior. This review highlights recent progresses towards the development of NLC for brain targeting of bioactives with particular reference to its surface modifications, formulations aspects, pharmacokinetic behavior and efficacy towards the treatment of various neurological disorders like AD, PD, schizophrenia, epilepsy, brain cancer, CNS infection (viral and fungal), multiple sclerosis, cerebral ischemia, and cerebral malaria. This work describes in detail the role and application of NLC, along with its different fabrication techniques and associated limitations. Specific emphasis is given to compile a summary and graphical data on the area explored by scientists and researchers worldwide towards the treatment of neurological disorders with or without NLC. The article also highlights a brief insight into two prime approaches for brain targeting, including drug delivery across BBB and direct nose-to-brain drug delivery along with the current global status of specific neurological disorders.

Formulation Strategies of Nano Lipid Carrier for Effective Brain Targeting of Anti-AD Drugs.

NLC is a next-generation lipid nanocarrier, which holds many advantages over other colloidal lipid carrier systems like higher drug loading, better and controlled release and enhanced stability. Owing to the unique structural composition, i.e. crystallized solid and liquid lipid blend, it offers excellent biocompatibility and higher permeation across physiological membranes like BBB. Moreover, the surface of NLC can easily be modified with target-specific ligands, proteins, peptides, etc. which makes it a potential candidate for brain targeting of CNS acting drugs. NLC has found various applications for the treatment of various CNS disorders including Alzheimer's disease, Parkinson's disease, schizophrenia, epilepsy, migraine, cerebral ischemia, etc. Among these, the application of NLC towards the treatment of AD has been well-explored in the past two decades. In this piece of work, we have discussed the types of NLC, its composition, fabrication techniques, characterization, stability profile and application in the treatment of AD.

Understanding the Pharmaceutical Aspects of Dendrimers for the Delivery of Anticancer Drugs.

Dendrimers are emerging class of nanoparticles used in targeted drug delivery systems. These are radially symmetric molecules with well-defined, homogeneous, and monodisperse structures. Due to the nano size, they can easily cross the biological membrane and increase bioavailability. The surface functionalization facilitates targeting of the particular site of action, assists the high drug loading and improves the therapeutic efficiency of the drug. These properties make dendrimers advantageous over conventional drug delivery systems. This article explains the features of dendrimers along with their method of synthesis, such as divergent growth method, convergent growth method, double exponential and mixed method, hyper-core and branched method. Dendrimers are effectively used in anticancer delivery and can be targeted at the site of tumor either by active or passive targeting. There are three mechanisms by which drugs interact with dendrimers, and they are physical encapsulation, electrostatic interaction, chemical conjugation of drug molecules. Drug releases from dendrimer either by in vivo cleavage of the covalent bond between drugdendrimer complexes or by physical changes or stimulus like pH, temperature, etc.

Recent avenues in Novel Patient-Friendly Techniques for the Treatment of Diabetes.

BACKGROUND: Diabetes is one of the most common chronic metabolic disorders which affect the quality of human life worldwide. As per the WHO report, between 1980 to 2014, the number of diabetes patients increases from 108 million to 422 million, with a global prevalence rate of 8.5% per year. Diabetes is the prime reason behind various other diseases like kidney failure, stroke, heart disorders, glaucoma, etc. It is recognized as the seventh leading cause of death throughout the world. The available therapies are painful (insulin injections) and inconvenient due to higher dosing frequency. Thus, to find out a promising and convenient treatment, extensive investigations are carried out globally by combining novel carrier system (like microparticle, microneedle, nanocarrier, microbeads etc.) and delivery devices (insulin pump, stimuli-responsive device, inhalation system, bioadhesive patch, insulin pen etc.) for more precise diagnosis and painless or less invasive treatment of disease. OBJECTIVE: The review article is made with an objective to compile information about various upcoming and existing modern technologies developed to provide greater patient compliance and reduce the undesirable side effect of the drug. These devices evade the necessity of daily insulin injection and offer a rapid onset of action, which sustained for a prolonged duration of time to achieve a better therapeutic effect. CONCLUSION: Despite numerous advantages, various commercialized approaches, like Afrezza (inhalation insulin) have been a failure in recent years. Such results call for more potential work to develop a promising system. The novel approaches range from the delivery of non-insulin blood glucose lowering agents to insulin-based therapy with minimal invasion are highly desirable.

PHD-2 activation: a novel strategy to control HIF-1α and mitochondrial stress to modulate mammary gland pathophysiology in ER+ subtype.

Estrogen receptor-positive mammary gland carcinoma and its involvement in regulation of overexpressed hypoxia-inducible factor-1α and fatty acid synthase level in hypoxia influenced cancer cells are the present molecular crosstalk of this entire study. To test the hypothesis, we have proceed our study through chemical activation of prolyl hydroxylase 2 which leads to inhibition of hypoxia-inducible factor-1α and fatty acid synthase in ER+MCF-7 cancer cell line and n-methyl-n-nitrosourea induced mammary gland carcinoma rat model. ER+MCF-7 cells were evident with array of nuclear changes when stained through acridine orange/ethidium bromide. Afterward, JC-1 staining of the cells was evident in mitochondrial depolarization. The cells were arrested in G2/M phase when analyzed with flow cytometry. The morphological analysis of rat mammary gland tissue revealed decrease in alveolar buds, restoration of histopathological features along with intra-arterial cushion. The western blotting and fold change expressions of the genes validating the anticancer efficacy of BBAPH-1 is mediated through mitochondria-mediated apoptosis pathway. BBAPH-1 also modulates the expression of prolyl hydroxylase-2 with significant curtailment of hypoxia-inducible factor-1α, fatty acid synthase expression, and their respective downstream markers. These finding suggest that the BBAP-1-mediated activation of prolyl hydroxylase-2 significantly decreased the level of hypoxia-inducible factor-1α and fatty acid synthase. BBAPH-1 also activates the mitochondria-mediated death apoptosis pathway.

Recent Expansions on Cellular Models to Uncover the Scientific Barriers Towards Drug Development for Alzheimer's Disease.

Globally, the central nervous system (CNS) disorders appear as the most critical pathological threat with no proper cure. Alzheimer's disease (AD) is one such condition frequently observed with the aged population and sometimes in youth too. Most of the research utilizes different animal models for in vivo study of AD pathophysiology and to investigate the potency of the newly developed therapy. These in vivo models undoubtably provide a powerful investigation tool to study human brain. Although, it sometime fails to mimic the exact environment and responses as the human brain owing to the distinctive genetic and anatomical features of human and rodent brain. In such condition, the in vitro cell model derived from patient specific cell or human cell lines can recapitulate the human brain environment. In addition, the frequent use of animals in research increases the cost of study and creates various ethical issues. Instead, the use of in vitro cellular models along with animal models can enhance the translational values of in vivo models and represent a better and effective mean to investigate the potency of therapeutics. This strategy also limits the excessive use of laboratory animal during the drug development process. Generally, the in vitro cell lines are cultured from AD rat brain endothelial cells, the rodent models, human astrocytes, human brain capillary endothelial cells, patient derived iPSCs (induced pluripotent stem cells) and also from the non-neuronal cells. During the literature review process, we observed that there are very few reviews available which describe the significance and characteristics of in vitro cell lines, for AD investigation. Thus, in the present review article, we have compiled the various in vitro cell lines used in AD investigation including HBMEC, BCECs, SHSY-5Y, hCMEC/D3, PC-2 cell line, bEND3 cells, HEK293, hNPCs, RBE4 cells, SK-N-MC, BMVECs, CALU-3, 7W CHO, iPSCs and cerebral organoids cell lines and different types of culture media such as SCM, EMEM, DMEM/F12, RPMI, EBM and 3D-cell culture.

Schizonticidal antimalarial sesquiterpene lactones from Magnolia champaca (L.) Baill. ex Pierre: microwave-assisted extraction, HPTLC fingerprinting and computational studies.

The present study explored the schizonticidal potential of traditionally used Magnolia champaca (L.) Baill. ex. Pierre flowers, identifying constituents of interest. The extraction of phytoconstituents was carried out by microwave-assisted technique, isolated via column chromatography, and characterised by various physicochemical, spectral (IR, 1H-NMR and Mass) and chromatographic (HPTLC) techniques. Both the isolated compounds (parthenolide and costunolide diepoxide) exhibited potent schizonticidal antimalarial activity during primary screening in rodent models, with maximum parasitaemia suppression (85.18% and 83.65%, respectively) at a dose of 20 mg/kg body weight when compared to the standard drugs chloroquine and artesunate. In silico techniques were employed to identify the probable biological target and mechanism of action of these isolated compounds. Molecular docking studies also predicted the binding orientations and multi-targeted action of these compounds, in particular costunolide diepoxide with maximum affinity towards SERCA and DHFR proteins. Additionally, favourable in silico ADMET parameters were envisaged through various computational programmes.

Current Status of Stem Cell Therapies in Tissue Repair and Regeneration.

Tissue engineering is a multi-disciplinary field such as material science, life science, and bioengineering that are necessary to make artificial tissue or rejuvenate damaged tissue. Numerous tissue repair techniques and substitute now exist even though it has several shortcomings; these shortcomings give a good reason for the continuous research for more acceptable tissue-engineered substitutes. The search for and use of a suitable stem cell in tissue engineering is a promising concept. Stem cells have a distinctive capability to differentiate and self-renew that make more suitable for cell-based therapies in tissue repair and regeneration. This review article focuses on stem cell for tissue engineering and their methods of manufacture with their application in nerve, bone, skin, cartilage, bladder, cardiac, liver tissue repair and regeneration.

Amalgamation of Stem Cells with Nanotechnology: A Unique Therapeutic Approach.

In the last few years, the stem cell therapy has gained much popularity among researchers and scientists of biomedical field. It became an effective and alternative approach for the treatment of various physiological conditions (like accidental injuries, burn damage, organ failure, bone marrow transfusion, etc.) and chronic disorders (diabetes, cancer, neurodegenerative disorders, periodontal diseases, etc.). Due to the unique ability of cellular differentiation and regeneration, stem cell therapy serves as the last hope for various incurable conditions and severe damages. The amalgamation of stem cell therapy with nanotechnology brings new prospects to the stem cell research, as it improves the specificity of the treatment and controls the stem cell proliferation and differentiation. In this review article, we have discussed various nanocarrier systems such as carbon nanotubes, quantum dots, nanofibers, nanoparticles, nanodiamonds, nanoparticle scaffold, etc. utilized for the delivery of stem cell inside the body.

Recent Biomedical Applications on Stem Cell Therapy: A Brief Overview.

Stem cells are the specialized cell population with unique self-renewal ability and act as the precursor of all the body cells. Broadly, stem cells are of two types one is embryonic stem cells while the other is adult or somatic stem cells. Embryonic stem cells are the cells of zygote of the blastocyst which give rise to all kind of body cells including embryonic cells, and it can reconstruct a complete organism. While the adult stem cells have limited differentiation ability in comparison with embryonic stem cells and it proliferates into some specific kind of cells. This unique ability of the stem cell makes it a compelling biomedical and therapeutic tool. Stem cells primarily serve as regenerative medicine for particular tissue regeneration or the whole organ regeneration in any physical injury or disease condition (like diabetes, cancer, periodontal disorder, etc.), tissue grafting and plastic surgery, etc. Along with this, it is also used in various preclinical and clinical investigations, biomedical engineering and as a potential diagnostic tool (such as the development of biomarkers) for non-invasive diagnosis of severe disorders. In this review article, we have summarized the application of stem cell as regenerative medicine and in the treatment of various chronic diseases.