A review of the physiological effects of microgravity and innovative formulation for space travelers.

During the space travel mission, astronauts' physiological and psychological behavior will alter, and they will start consuming terrestrial drug products. However, factors such as microgravity, radiation exposure, temperature, humidity, strong vibrations, space debris, and other issues encountered, the drug product undergo instability This instability combined with physiological changes will affect the shelf life and diminish the pharmacokinetic and pharmacodynamic profile of the drug product. Consequently, the physicochemical changes will produce a toxic degradation product and a lesser potency dosage form which may result in reduced or no therapeutic action, so the astronaut consumes an additional dose to remain healthy. On long-duration missions like Mars, the drug product cannot be replaced, and the astronaut may relay on the available medications. Sometimes, radiation-induced impurities in the drug product will cause severe problems for the astronaut. So, this review article highlights the current state of various space-related factors affecting the drug product and provides a comprehensive summary of the physiological changes which primarly focus on absorption, distribution, metabolism, and excretion (ADME). Along with that, we insist some of the strategies like novel formulations, space medicine manufacturing from plants, and 3D printed medicine for astronauts in longer-duration missions. Such developments are anticipated to significantly contribute to new developments with applications in both human space exploration and on terrestrial healthcare.

Enhancing the oral bioavailability of fisetin: polysaccharide-based self nano-emulsifying spheroids for colon-targeted delivery.

Fisetin (FS) is a flavonoid that possesses antioxidant and anti-inflammatory properties against ulcerative colitis. FS shows poor dissolution rate and permeability. An attempt has been made to develop colon-targeted solid self-nanoemulsifying drug delivery systems (S-SNEDDS) of FS. Initially, liquid (L) SNEDDS were prepared by loading FS into isotropic mixture of L-SNEDDS was prepared using Labrafil M 1944 CS, Transcutol P, and Tween 80. These L-SNEDDS were further converted into solid (S) SNEDDS by mixing the isotropic mixture with 1:1:1 ratio of guar gum (GG), xanthan gum (XG) and pectin (PC) [GG:XG:PC (1:1:1)]. Aerosil-200 (A-200) was added to enhance their flow characteristics. Further, they were converted into spheroids by extrusion-spheronization technique. The solid-state characterization of S-SNEDDS was done by SEM, DSC, and PXRD, which revealed that the crystalline form of FS was converted into the amorphous form. In the dissolution study, S-SNEDDS spheroids [GG:XG:PC (1:1:1)] exhibited less than 20% drug release within the first 5 h, followed by rapid release of the drug between the 5th and 10th h, indicating its release at colonic site. The site-specific delivery of FS to colon via FS-S-SNEDDS spheroids was confirmed by conducting pharmacokinetic studies on rats. Wherein, results showed delay in absorption of FS loaded in spheroids up to 5 h and achievement of Cmax at 7h, whereas L-SNEDDS showed rapid absorption of FS. Furthermore, FS-L-SNEDDS and FS-S-SNEDDS spheroids [GG:XG:PC (1:1:1)] increased oral bioavailability of FS by 6.86-fold and 4.44-fold, respectively, as compared to unprocessed FS.

Exploring ncRNA-mediated regulation of EGFR signalling in glioblastoma: From mechanisms to therapeutics.

Glioblastoma (GBM) is the most prevalent and deadly primary brain tumor type, with a discouragingly low survival rate and few effective treatments. An important function of the EGFR signalling pathway in the development of GBM is to affect tumor proliferation, persistence, and treatment resistance. Advances in molecular biology in the last several years have shown how important ncRNAs are for controlling a wide range of biological activities, including cancer progression and development. NcRNAs have become important post-transcriptional regulators of gene expression, and they may affect the EGFR pathway by either directly targeting EGFR or by modifying important transcription factors and downstream signalling molecules. The EGFR pathway is aberrantly activated in response to the dysregulation of certain ncRNAs, which has been linked to GBM carcinogenesis, treatment resistance, and unfavourable patient outcomes. We review the literature on miRNAs, circRNAs and lncRNAs that are implicated in the regulation of EGFR signalling in GBM, discussing their mechanisms of action, interactions with the signalling pathway, and implications for GBM therapy. Furthermore, we explore the potential of ncRNA-based strategies to overcome resistance to EGFR-targeted therapies, including the use of ncRNA mimics or inhibitors to modulate the activity of key regulators within the pathway.

Opening avenues for treatment of neurodegenerative disease using post-biotics: Breakthroughs and bottlenecks in clinical translation.

Recent studies have indicated the significant involvement of the gut microbiome in both human physiology and pathology. Additionally, therapeutic interventions based on microbiome approaches have been employed to enhance overall health and address various diseases including aging and neurodegenerative disease (ND). Researchers have explored potential links between these areas, investigating the potential pathogenic or therapeutic effects of intestinal microbiota in diseases. This article provides a summary of established interactions between the gut microbiome and ND. Post-biotic is believed to mediate its neuroprotection by elevating the level of dopamine and reducing the level of α-synuclein in substantia nigra, protecting the loss of dopaminergic neurons, reducing the aggregation of NFT, reducing the deposition of amyloid ß peptide plagues and ameliorating motor deficits. Moreover, mediates its neuroprotective activity by inhibiting the inflammatory response (decreasing the expression of TNFα, iNOS expression, free radical formation, overexpression of HIF-1α), apoptosis (i.e. active caspase-3, TNF-α, maintains the level of Bax/Bcl-2 ratio) and promoting BDNF secretion. It is also reported to have good antioxidant activity. This review offers an overview of the latest findings from both preclinical and clinical trials concerning the use of post-biotics in ND.

Development of Moringa oleifera as functional food targeting NRF2 signaling: antioxidant and anti-inflammatory activity in experimental model systems.

Pharmacological activation of nuclear factor erythroid 2 related factor 2 (NRF2) provides protection against several environmental diseases by inhibiting oxidative and inflammatory injury. Besides high in protein and minerals, Moringa oleifera leaves contain several bioactive compounds, predominantly isothiocyanate moringin and polyphenols, which are potent inducers of NRF2. Hence, M. oleifera leaves represent a valuable food source that could be developed as a functional food for targeting NRF2 signaling. In the current study, we have developed a palatable M. oleifera leaf preparation (henceforth referred as ME-D) that showed reproducibly a high potential to activate NRF2. Treatment of BEAS-2B cells with ME-D significantly increased NRF2-regulated antioxidant genes (NQO1, HMOX1) and total GSH levels. In the presence of brusatol (a NRF2 inhibitor), ME-D-induced increase in NQO1 expression was significantly diminished. Pre-treatment of cells with ME-D mitigated reactive oxygen species, lipid peroxidation and cytotoxicity induced by pro-oxidants. Furthermore, ME-D pre-treatment markedly inhibited nitric oxide production, secretory IL-6 and TNF-α levels, and transcriptional expression of Nos2, Il-6, and Tnf-α in macrophages exposed to lipopolysaccharide. Biochemical profiling by LC-HRMS revealed glucomoringin, moringin, and several polyphenols in ME-D. Oral administration of ME-D significantly increased NRF2-regulated antioxidant genes in the small intestine, liver, and lungs. Lastly, prophylactic administration of ME-D significantly mitigated lung inflammation in mice exposed to particulate matter for 3-days or 3-months. In conclusion, we have developed a pharmacologically active standardized palatable preparation of M. oleifera leaves as a functional food to activate NRF2 signaling, which can be consumed as a beverage (hot soup) or freeze-dried powder for reducing the risk from environmental respiratory disease.

Folic Acid Functionalized Diallyl Trisulfide-Solid Lipid Nanoparticles for Targeting Triple Negative Breast Cancer.

DATS (diallyl trisulfide), an anti-oxidant and cytotoxic chemical derived from the plant garlic, has been found to have potential therapeutic activity against triple-negative breast cancer (TNBC). Its hydrophobicity, short half-life, lack of target selectivity, and limited bioavailability at the tumor site limit its efficacy in treating TNBC. Overexpression of the Folate receptor on the surface of TNBC is a well-known target receptor for overcoming off-targeting, and lipid nanoparticles solve the limitations of limited bioavailability and short half-life. In order to overcome these constraints, we developed folic acid (FA)-conjugated DATS-SLNs in this research. The design of experiment (DoE) method was employed to optimize the FA-DATS-SLNs' nanoformulation, which resulted in a particle size of 168.2 ± 3.78 nm and a DATS entrapment of 71.91 ± 6.27%. The similarity index between MCF-7 and MDA-MB-231 cell lines demonstrates that FA-DATS-SLNs are more therapeutically efficacious in the treatment of aggravating TNBC. Higher cellular internalization and efficient Bcl2 protein downregulation support the hypothesis that functionalization of the FA on the surface of DATS-SLNs improves anticancer efficacy when compared with DATS and DATS-SLNs. FA-functionalized DATS-SLNs have demonstrated to be a promising therapeutic strategy for TNBC management.

WZB117 Decorated Metformin-Carboxymethyl Chitosan Nanoparticles for Targeting Breast Cancer Metabolism.

The "Warburg effect" provides a novel method for treating cancer cell metabolism. Overexpression of glucose transporter 1 (GLUT1), activation of AMP-activated protein kinase (AMPK), and downregulation of mammalian target of rapamycin (mTOR) have been identified as biomarkers of abnormal cancer cell metabolism. Metformin (MET) is an effective therapy for breast cancer (BC), but its efficacy is largely reliant on the concentration of glucose at the tumor site. We propose a WZB117 (a GLUT1 inhibitor)-OCMC (O-carboxymethyl-chitosan)-MET combo strategy for simultaneous GLUT1 and mTOR targeting for alteration of BC metabolism. WZB117 conjugated polymeric nanoparticles were 225.67 ± 11.5 nm in size, with a PDI of 0.113 ± 0.16, and an encapsulation of 72.78 6.4%. OCMC pH-dependently and selectively releases MET at the tumor site. MET targets the mTOR pathway in cancer cells, and WZB117 targets BCL2 to alter GLUT1 at the cancer site. WZB117-OCMC-MET overcomes the limitations of MET monotherapy by targeting mTOR and BCL2 synergistically. WZB117-OCMC-MET activates AMPK and suppresses mTOR in a Western blot experiment, indicating growth-inhibitory and apoptotic characteristics. AO/EB and the cell cycle enhance cellular internalization as compared to MET alone. WZB117-OCMC-MET affects cancer cells' metabolism and is a promising BC therapeutic strategy.

Brain targeted intra nasal acyclovir lipid nanoparticles; in-vitro characterization and in-vivo biodistribution studies.

Acyclovir (ACY) is an antiviral class of drugs used to treat herpes simplex virus infections such as herpes simplex encephalitis (HSE). ACY is widely distributed; Systemic exposure of ACY leads to serious adverse effects. Because of its high pH, intravenous ACY may cause phlebitis and local inflammation if extravasation occurs. This study aims to enhance acyclovir delivery to the brain via the intranasal route by formulating ACY nano lipid carriers (ACY-NLCs) to circumvent the side-effects, as mentioned earlier. ACY-NLCs were prepared by emulsification, followed by ultrasonication. A Box-Behnken statistical design with three factors, three levels and 17 runs was selected for the optimization study using Design- Expert Software. Nanoparticles were characterized for particle size, entrapment efficiency and in-vitro drug release. ACY- NLC showed biphasic release pattern i.e. an initial faster release followed by sustained release. Biodistribution study by imaging, Nanoparticles were slowly cleared and biodistributed to the other organs was observed in 2nd and 3rd hr post-administration. From the toxicity studies, NLC formulation is safe and non-toxic for the nasal administration. Rhodamine loaeded NLCs were quickly adsorbed by the olfactory tract and distributed mainly to the lungs through respiratory tract and were also detected in the trachea and olfactory bulb. Biodistribution study of dye loaded NLCs reach brain compared to the Rhodamine-solution.

Advances and applications of monoolein as a novel nanomaterial in mitigating chronic lung diseases.

Chronic lung diseases such as asthma, chronic obstructive pulmonary disease, lung cancer, and the recently emerged COVID-19, are a huge threat to human health, and among the leading causes of global morbidity and mortality every year. Despite availability of various conventional therapeutics, many patients remain poorly controlled and have a poor quality of life. Furthermore, the treatment and diagnosis of these diseases are becoming increasingly challenging. In the recent years, the application of nanomedicine has become increasingly popular as a novel strategy for diagnosis, treatment, prevention, as well as follow-up of chronic lung diseases. This is attributed to the ability of nanoscale drug carriers to achieve targeted delivery of therapeutic moieties with specificity to diseased site within the lung, thereby enhancing therapeutic outcomes of conventional therapies whilst minimizing the risks of adverse reactions. For this instance, monoolein is a polar lipid nanomaterial best known for its versatility, thermodynamic stability, biocompatibility, and biodegradability. As such, it is commonly employed in liquid crystalline systems for various drug delivery applications. In this review, we present the applications of monoolein as a novel nanomaterial-based strategy for targeted drug delivery with the potential to revolutionize therapeutic approaches in chronic lung diseases.

Evolving Era of "Sponges": Nanosponges as a Versatile Nanocarrier for the Effective Skin Delivery of Drugs.

BACKGROUND: Nanosponge, as a carrier for the skin delivery system for drugs, plays a vital role. It not only serves to administer the drug to the targeted layer of skin but also increases the drug retention and deposition on the skin. OBJECTIVE: In this review, we aim to highlight the effects of several processes and formulation variables prompting the characteristics of various nanosponges for the delivery of drugs into/ across the skin. METHODS: In the present review article, the overall introduction of nanosponges, their preparation, characteristic features, advantages, disadvantages, and factors affecting their preparation, are covered. Furthermore, an elaborative description of nanosponges for skin delivery and its toxicological perspective with some referential examples of nanosponge drugs has also been deliberated here. RESULTS: Factors associated with the formation of nanosponges can directly or indirectly affect its efficacy in the skin delivery of drugs. These nanoforms are efficient in delivering the drugs which possess lower aqueous solubility, therefore, the aqueous solubility of drugs possessing a narrow therapeutic window can easily be enhanced. It also helps in achieving targeted drug delivery, controlled release of drugs, increases bioavailability, reduces drug toxicity, decreases drug degradation, and many more. CONCLUSION: Nanosponges have been identified as potential drug delivery carriers into as well as across skin. Delivery of biologics such as vaccines, enzymes, peptides, proteins, and antibodies, is also gaining attention in the recent past.

A Review on an Artificial Intelligence Based Ophthalmic Application.

Artificial intelligence is the leading branch of technology and innovation. The utility of artificial intelligence in the field of medicine is also remarkable. From drug discovery and development to introducing products to the market, artificial intelligence can play its role. As people age, they are more prone to be affected by eye diseases around the globe. Early diagnosis and detection help minimize the risk of vision loss and provide a quality life. With the help of artificial intelligence, the workload of humans and manmade errors can be reduced to an extent. The need for artificial intelligence in the area of ophthalmic is also significant. In this review, we elaborated on the use of artificial intelligence in the field of pharmaceutical product development, mainly with its application in ophthalmic care. AI in the future has a high potential to increase the success rate in the drug discovery phase has already been established. The application of artificial intelligence for drug development, diagnosis, and treatment is also reported with the scientific evidence in this paper.

Review on nutraceuticals: phase transition from preventive to protective care.

Nutraceuticals are essential for healthcare which is an alternative medicine that has gained popularity in recent years. Nutraceuticals consist of nutrients, herbals, and dietary supplements, which make them useful in preserving and promoting health, fighting illness, and improving overall quality of life. Its success or failure will be determined by its rapid expansion, research advances, lack of standards, marketing enthusiasm, quality assurance, and regulations. Nutraceuticals have been used in different regions under different names/categories. however, globally there are no stringent pharmaceutical standards for nutraceutical health products till date, but slowly regulators are paying attention on it. Nutraceuticals can be broadly classified according to it clinical significance, source and therapeutic effects. Nutraceuticals and functional foods have grown to be a multibillion-dollar business worldwide in recent years and personalization is the emerging approach to deliver the best therapeutic effect in future. This review carries extensive information about nutraceutical history, classification, regulatory aspects and industrial perspective.

Peptidylarginine deiminase-4: Medico-formulative strategy towards management of rheumatoid arthritis.

Peptidylarginine deiminase-4 (PAD4) is a calcium-dependent enzyme that catalyzes the conversion of arginine into citrulline of macromolecules in the body. It governs several processes including apoptosis, innate immunity (Netosis), and pluripotency. Dysregulated PAD4 plays a vital role in the occurrence and development of Rheumatoid arthritis (RA). Therefore, PAD4 is considered a promising target for diagnosing and treating RA. Over the last few years research has been carried out on PAD4 inhibitors. When administered it circulates to the entire body and inhibits PAD4 causing immunosuppression which may lead to infection. A growing number of studies have demonstrated infiltration and differentiation of monocytes and macrophages into the inflamed synovium, inducing overexpression of PAD4 levels in the inflamed joints. To overcome the above-mentioned critical issues, the targeted drug delivery systems inhibit PAD4 at the inflamed site. This review provides an update on the PAD4 inhibitors and emerging advanced drug delivery systems for the treatment of RA. Finally, we concluded that active targeting of PAD4 inhibitors to inflamed joints via hybrid nanocarriers provided an improved therapeutic efficacy, minimized extra synovial toxicity, and prevent the occurrence of inflammation in RA.

Overcoming hydrolytic degradation challenges in topical delivery: non-aqueous nano-emulsions.

INTRODUCTION: Non-aqueous nano-emulsions (NANEs) are colloidal lipid-based dispersions with nano-sized droplets formed by mixing two immiscible phases, none of which happens to be an aqueous phase. Their ability to incorporate water and oxygen sensitive drugs without any susceptibility to degradation makes them the optimum dosage form for such candidates. In NANEs, polar liquids or polyols replace the aqueous phase while surfactants remain same as used in conventional emulsions. They are a part of the nano-emulsion family albeit with substantial difference in composition and application. AREAS COVERED: The present review provides a brief insight into the strategies of loading water-sensitive drugs into NANEs. Further advancement in these anhydrous systems with the use of solid particulate surfactants in the form of Pickering emulsions is also discussed. EXPERT OPINION: NANEs offer a unique platform for delivering water-sensitive drugs by loading them in anhydrous formulation. The biggest advantage of NANEs vis-à-vis the other nano-cargos is that they can also be prepared without using equipment-intensive techniques. However, the use of NANEs in drug delivery is quite limited. Looking at the small number of studies available in this direction, a need for further research in this field is required to explore this delivery system further.

Theoretical Formulation Strategies towards Neutralizing Inter-individual Variability Associated with Tacrolimus Immunosuppressant Therapy: A Case Study on Nextgeneration Personalized Medicine.

Individualizing drug therapy and attaining maximum benefits of a drug devoid of adverse reactions is the benefit of personalized medicine. One of the important factors contributing to inter-individual variability is genetic polymorphism. As of now, dose titration is the only followed golden standard for implementing personalized medicine. Converting the genotypic data into an optimized dose has become easier now due to technology development. However, for many drugs, finding an individualized dose may not be successful, which further leads to a trial and error approach. These dose titration strategies are generally followed at the clinical level, and so industrial involvement and further standardizations are not feasible. On the other side, technologically driven pharmaceutical industries have multiple smart drug delivery systems which are underutilized towards personalized medicine. Transdisciplinary research with drug delivery science can additionally support the personalization by converting the traditional concept of "dose titration towards personalization" with novel "dose-cum-dosage form modification towards next-generation personalized medicine"; the latter approach is useful to overcome gene-based inter-individual variability by either blocking, to downregulate, or bypassing the biological protein generated by the polymorphic gene. This article elaborates an advanced approach to implementing personalized medicine with the support of novel drug delivery systems. As a case study, we further reviewed the genetic polymorphisms associated with tacrolimus and customized novel drug delivery systems to overcome these challenges factored towards personalized medicine for better clinical outcomes, thereby paving a new strategy for implementing personalized medicine for all other drug candidates.

Towards next-generation personalization of tacrolimus treatment: a review on advanced diagnostic and therapeutic approaches.

The benefit of personalized medicine is that it allows the customization of drug therapy - maximizing efficacy while avoiding side effects. Genetic polymorphisms are one of the major contributors to interindividual variability. Currently, the only gold standard for applying personalized medicine is dose titration. Because of technological advancements, converting genotypic data into an optimum dose has become easier than in earlier years. However, for many medications, determining a personalized dose may be difficult, leading to a trial-and-error method. On the other hand, the technologically oriented pharmaceutical industry has a plethora of smart drug delivery methods that are underutilized in customized medicine. This article elaborates the genetic polymorphisms of tacrolimus as case study, and extensively covers the diagnostic and therapeutic technologies which aid in the delivery of personalized tacrolimus treatment for better clinical outcomes, thereby providing a new strategy for implementing personalized medicine.

Current concepts and clinical importance of glycemic variability.

BACKGROUND AND AIMS: Evolving evidence indicate that variations in blood glucose levels are likely to be an important factor in developing diabetic complications. Monitoring glucose fluctuations in patients remains as a therapeutic challenge and more evidence needs to be created in order to bring GV into limelight. This review encapsulates the most important findings conducted and discusses on them to provide readers a better understanding on this emerging subject. METHODS: Keyword-based comprehensive desktop search was conducted to gather the relevant literature. Triple-stage cascade type content analysis of the literature was conducted to draw relevant themes of discussions. RESULTS: High glycemic variability is associated with an increased risk of development of diabetic complications especially in cardiac conditions. The widely used and accepted metrics to determine the variations in blood glucose are Standard deviation (SD), MAGE (Mean amplitude of glycemic excursions) and MODD (Mean of daily differences). Occurrence of blood glucose variations affects at a molecular level thereby causing more harm than the occurrence of hyperglycemia alone. CONCLUSION: Available data suggest that Glycemic Variability should be used as an additional marker of glycemia. Additional research globally, and in India are required.

Antiviral and immunomodulatory activity of curcumin: A case for prophylactic therapy for COVID-19.

Coronavirus disease-19 (COVID-19), a devastating respiratory illness caused by SARS-associated coronavirus-2 (SARS-CoV-2), has already affected over 64 million people and caused 1.48 million deaths, just 12 months from the first diagnosis. COVID-19 patients develop serious complications, including severe pneumonia, acute respiratory distress syndrome (ARDS), and or multiorgan failure due to exaggerated host immune response following infection. Currently, drugs that were effective against SARS-CoV are being repurposed for SARS-CoV-2. During this public health emergency, food nutraceuticals could be promising prophylactic therapeutics for COVID-19. Curcumin, a bioactive compound in turmeric, exerts diverse pharmacological activities and is widely used in foods and traditional medicines. This review presents several lines of evidence, which suggest curcumin as a promising prophylactic, therapeutic candidate for COVID-19. First, curcumin exerts antiviral activity against many types of enveloped viruses, including SARS-CoV-2, by multiple mechanisms: direct interaction with viral membrane proteins; disruption of the viral envelope; inhibition of viral proteases; induce host antiviral responses. Second, curcumin protects from lethal pneumonia and ARDS via targeting NF-κB, inflammasome, IL-6 trans signal, and HMGB1 pathways. Third, curcumin is safe and well-tolerated in both healthy and diseased human subjects. In conclusion, accumulated evidence indicates that curcumin may be a potential prophylactic therapeutic for COVID-19 in the clinic and public health settings.

Pharmacogenomic phase transition from personalized medicine to patient-centric customized delivery.

Personalized medicine has been a booming area in clinical research for the past decade, in which the detailed information about the patient genotype and clinical conditions were collected and considered to optimize the therapy to prevent adverse reactions. However, the utility of commercially available personalized medicine has not yet been maximized due to the lack of a structured protocol for implementation. In this narrative review, we explain the role of pharmacogenetics in personalized medicine, next-generation personalized medicine, i.e., patient-centric personalized medicine, in which the patient's comfort is considered along with pharmacogenomics to be a primary factor. We extensively discuss the classifications, strategies, tools, and drug delivery systems that can support the implementation of patient-centric personalized medicine from an industrial perspective.

Metformin in breast cancer: preclinical and clinical evidence.

Metformin, a well-acknowledged biguanide, safety profile and multiaction drug with low cost for management of type 2 diabetes, makes a first-class candidate for repurposing. The off-patent drug draws huge attention for repositioned for anticancer drug delivery recently. Still few unanswered questions are challenging, among them one leading question; can metformin use as a generic therapy for all breast cancer subtypes? And is metformin able to get over the problem of drug resistance? The review focused on the mechanisms of metformin action specifically for breast cancer therapy and overcoming the resistance; also discusses preclinical and ongoing and completed clinical trials. The existing limitation such as therapeutic dose specifically for cancer treatment, resistance of metformin in breast cancer and organic cation transporters heterogeneity of the drug opens up a new pathway for improved understanding and successful application as repurposed effective chemotherapeutics for breast cancer. However, much more additional research is needed to confirm the accurate efficacy of metformin treatment for prevention of cancer and its recurrence.