Current approaches in smart nano-inspired drug delivery: A narrative review.

Background and Aim: The traditional drug delivery approach involves systemic administration of a drug that could be nonspecific in targeting, low on efficacy, and with severe side-effects. To address such challenges, the field of smart drug delivery has emerged aiming at designing and developing delivery systems that can target specific cells, tissues, and organs and have minimal off-target side-effects. Methods: A literature search was done to collate papers and reports about the currently available various strategies for smart nano-inspired drug delivery. The databases searched were PubMed, Scopus, and Google Scholar. Based on selection criteria, the most pertinent and recent items were included. Results: Smart drug delivery is a cutting-edge revolutionary intervention in modern medicines to ensure effective and safe administration of therapeutics to target sites. These hold great promise for targeted and controlled delivery of therapeutic agents to improve the efficacy with reduced side-effects as compared to the conventional drug delivery approaches. Current smart drug delivery approaches include nanoparticles, liposomes, micelles, and hydrogels, each with its own advantages and limitations. The success of these delivery systems lies in engineering and designing them, and optimizing their pharmacokinetics and pharmacodynamics properties. Conclusion: Development of drug delivery systems that can get beyond various physiological and clinical barriers, as observed in conventionally administered chemotherapeutics, has been possible through recent advancements. Using multifunctional targeting methodologies, smart drug delivery tries to localize therapy to the target location, reduces cytotoxicity, and improves the therapeutic index. Rapid advancements in research and development in smart drug delivery provide wider and more promising avenues to guarantee a better healthcare system, improve patient outcomes, and achieve higher levels of effective medical interventions like personalized medicine.

Self-inhibition of HER2 and HER3 at fever temperatures may prevent their hetero-dimerization.

HER2 and HER3 receptors dimerize into potent pro-oncogenic complexes involved in various aggressive and recurrent tumors. The role of febrile temperatures on the formation of HER2:HER3 complexes is unknown. To this end, molecular dynamics simulations of HER2 and HER3 were performed in the 37 °C-40 °C range. HER2 and ligand-free HER32 display inactive conformers that cannot form complexes at 40 °C, while maintaining their extended conformations able to dimerize in the 37 °C-39 °C range. Thermal therapy at particular fever points may complement existing therapy options for HER2-relevant cancers.Communicated by Ramaswamy H. Sarma.

Indian Biosimilars and Vaccines at Crossroads-Replicating the Success of Pharmagenerics.

BACKGROUND: The global pharma sector is fast shifting from generics to biologics and biosimilars with the first approval in Europe in 2006 followed by US approval in 2015. In the form of Hepatitis B vaccine, India saw its first recombinant biologics approval in 2000. Around 20% of generic medications and 62% of vaccines are now supplied by the Indian pharmaceutical industry. It is this good position in biologics and biosimilars production that could potentially improve healthcare via decreased treatment cost. India has witnessed large investments in biosimilars over the years. Numerous India-bred new players, e.g., Enzene Biosciences Ltd., are keen on biosimilars and have joined the race alongside the emerging giants, e.g., Biocon and Dr. Reddy's. A very positive sign was the remarkable disposition during the COVID-19 pandemic by Bharat Biotech and the Serum Institute of India. India's biopharmaceutical industry has been instrumental in producing and supplying preventives and therapeutics to fight COVID-19. Despite a weak supply chain and workforce pressure, the production was augmented to provide reasonably priced high-quality medications to more than 133 nations. Biosimilars could cost-effectively treat chronic diseases involving expensive conventional therapies, including diabetes, respiratory ailments, cancer, and connective tissue diseases. Biologics and biosimilars have been and are being tested to treat and manage COVID-19 symptoms characterized by inflammation and respiratory distress. PURPOSE OF REVIEW: Although India boasts many universities, research centers, and a relatively skilled workforce, its global University-Industry collaboration ranking is 24, IPR ranking remains 47 and innovation ranking 39. This reveals a wide industry-academia gap to bridge. There are gaps in effective translational research in India that must be promptly and appropriately addressed. Innovation demands strong and effective collaborations among universities, techno-incubators, and industries. METHODOLOGY: Many successful research findings in academia do not get translation opportunities supposedly due to low industrial collaboration, low IP knowledge, and publication pressure with stringent timelines. In light of this, a detailed review of literature, including policy papers, government initiatives, and corporate reviews, was carried out, and the compilation and synthesis of the secondary data were meticulously summarized for the easy comprehension of the facts and roadmap ahead. For easy comprehension, charts, figures, and compiled tables are presented. RESULTS: This review assesses India's situation in the biosimilar space, the gaps and areas to improve for Indian investment strategies, development, and innovation, addressing need for a more skilled workforce, industrial collaboration, and business models. CONCLUSIONS: This review also proposes forward an approach to empowering technopreneurs to develop MSMEs for large-scale operations to support India in taking innovative thoughts to the global level to ultimately realize a self-reliant India. The limitations of the compilation are also highlighted towards the end.

Environmental remediation using metals and inorganic and organic materials: a review.

In recent times, environmental pollution has been an alarming concern. This is increasing day-in-and-day-out, especially in the Asia-Pacific region due to the increasing population, urbanization, industrialization and inappropriate waste management measures. Pollution abatement is the need of the hour to sustain the biosphere in general and the human life in particular. A range of physical, chemical and biological strategies are commonly employed to remove pollutants from the contained water, soil and air. Physical, chemical or physicochemical remediation processes are commonly employed owing to their high efficiency, stability, recyclable property and low procurement cost as compared to metals, inorganic and organic materials. Materials of the later type include biocomposites, thin films, modified (bio)polymers, nanoparticles, nanofilters, sorbent like activated charcoal, and carbon nanotubes and nanosensors. Remediation mechanism largely follows sorption, degradation, oxidation, reduction, catalytic conversion, detection and microbial toxicity principles. This review details the mechanisms of action by these various remediating entities, their successful applications in pollution abatement, drawbacks and future prospects.HighlightsEnvironmental remediation using metals, inorganic and organic materials are discussed extensively.Major remediating approaches, viz., physical, physicochemical and chemical are elaborated citing latest references.The significance of biocomposites, biopolymers, polymers, thin films, nanoparticles, nanofilters, nanosensors and sorbents in remediation are highlighted.Pollutant removal from water, air and soil has been precisely discussed.A note on drawbacks, improvement and future prospects of remediating agents is presented.

Biochemistry, Synthesis, and Applications of Bacterial Cellulose: A Review.

The potential of cellulose nanocomposites in the new-generation super-performing nanomaterials is huge, primarily in medical and environment sectors, and secondarily in food, paper, and cosmetic sectors. Despite substantial illumination on the molecular aspects of cellulose synthesis, various process features, namely, cellular export of the nascent polysaccharide chain and arrangement of cellulose fibrils into a quasi-crystalline configuration, remain obscure. To unleash its full potential, current knowledge on nanocellulose dispersion and disintegration of the fibrillar network and the organic/polymer chemistry needs expansion. Bacterial cellulose biosynthesis mechanism for scaled-up production, namely, the kinetics, pathogenicity, production cost, and product quality/consistency remain poorly understood. The bottom-up bacterial cellulose synthesis approach makes it an interesting area for still wider and promising high-end applications, primarily due to the nanosynthesis mechanism involved and the purity of the cellulose. This study attempts to identify the knowledge gap and potential wider applications of bacterial cellulose and bacterial nanocellulose. This review also highlights the manufacture of bacterial cellulose through low-cost substrates, that is, mainly waste from brewing, agriculture, food, and sugar industries as well as textile, lignocellulosic biorefineries, and pulp mills.

Sequential-Anaerobic and Sequential-Aerobic Bioleaching of Metals (Ni, Mo, Al and V) from Spent Petroleum Catalyst in Stirred Tank Batch Reactor: A Comparative Study.

Spent petroleum catalyst as a repository of several toxic metals is recommended for metal removal before safe disposal. To evaluate an effective biotechnological approach for metal removal, a comparative study between sequential-aerobic and sequential-anaerobic bioleaching processes was conducted for the removal of metals from crushed-acetone-pretreated spent petroleum catalyst. The SEM-EDX and XPS analysis confirmed the presence of Ni, Al, Mo and V in their oxidic and sulphidic forms in spent catalyst. The bioleaching experiments were performed in stirred tank batch reactors (2.5 L), temperature 30 °C, pH 1.4 and stirring speed 250 rpm for the period of 160 h. Sulfuric acid acted as lechant for both sequential-aerobic (Acidithiobacillus ferrooxidans oxidised sulfur to sulfuric acid aerobically) and sequential-anaerobic (Acidithiobacillus ferrooxidans oxidised sulphur to sulfuric acid coupled with the ferric reduction to ferrous anaerobically) bioleaching studies. The higher Ni and V extractions compared to Al and Mo for all the studies were due to increased solubility of Ni and V, and supported by XPS which showed marginal signs of Ni and V peaks in leach residues compared to feed spent catalyst. At the end (320 h), sequential-aerobic bioleaching was resulted to 99% Ni, 65% Al, 90% Mo and 99% V extraction quite more effective than sequential-anaerobic bioleaching (88% Ni, 28% Al, 33% Mo and 77% V) and sequential-control leaching (94% Ni, 20% Al, 40% Mo and 57% V). Although anaerobic bioleaching a possible approach, aerobic condition was found to be more suitable for sulfuric acid generation by A. ferrooxidans and high yield. So aerobic bioleaching is recommended to be favourable approach compared to anaerobic counterpart for future study and extrapolation. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s12088-021-00978-8.

Virus as a Nanocarrier for Drug Delivery Redefining Medical Therapeutics - A Status Report.

Over the last two decades, drug delivery systems have evolved at a tremendous pace. Synthetic nanoparticles have played an important role in vaccine design and delivery as these have shown improved safety and efficacy over conventional formulations. Nanocarriers formulated by natural, biological building blocks have become an important tool in biomedicine. A successful nanocarrier must possess specific properties like evading the host immune system, target specificity, cellular entry, escape from endosomes, and the ability to release the active material into the cytoplasm. The virus can perform some or all of these functions, making it a suitable candidate as a naturally occurring nanocarrier. Viruses could be made non-infectious and non-replicative without compromising their ability to penetrate cells, making them useful for a vast spectrum of applications. Currently, many such carrier molecules as bio-nanocapsules are at various development stages. This review covers the advances in the field of viruses as potential nanocarriers and discusses the related technologies and strategies to target specific cells by using virus-inspired nanocarriers. These virus-based nanocarriers could provide solutions to address pressing and emerging concerns in infectious diseases in the future.

Computationally repurposed drugs and natural products against RNA dependent RNA polymerase as potential COVID-19 therapies.

Repurposing of existing drugs and drug candidates is an ideal approach to identify new potential therapies for SARS-CoV-2 that can be tested without delay in human trials of infected patients. Here we applied a virtual screening approach using Autodock Vina and molecular dynamics simulation in tandem to calculate binding energies for repurposed drugs against the SARS-CoV-2 RNA-dependent RNA polymerase (RdRp). We thereby identified 80 promising compounds with potential activity against SARS-Cov2, consisting of a mixture of antiviral drugs, natural products and drugs with diverse modes of action. A substantial proportion of the top 80 compounds identified in this study had been shown by others to have SARS-CoV-2 antiviral effects in vitro or in vivo, thereby validating our approach. Amongst our top hits not previously reported to have SARS-CoV-2 activity, were eribulin, a macrocyclic ketone analogue of the marine compound halichondrin B and an anticancer drug, the AXL receptor tyrosine kinase inhibitor bemcentinib. Our top hits from our RdRp drug screen may not only have utility in treating COVID-19 but may provide a useful starting point for therapeutics against other coronaviruses. Hence, our modelling approach successfully identified multiple drugs with potential activity against SARS-CoV-2 RdRp. Supplementary Information: The online version contains supplementary material available at 10.1186/s43556-021-00050-3.

In silico comparison of SARS-CoV-2 spike protein-ACE2 binding affinities across species and implications for virus origin.

The devastating impact of the COVID-19 pandemic caused by SARS-coronavirus 2 (SARS-CoV-2) has raised important questions about its origins and the mechanism of its transfer to humans. A further question was whether companion or commercial animals could act as SARS-CoV-2 vectors, with early data suggesting susceptibility is species specific. To better understand SARS-CoV-2 species susceptibility, we undertook an in silico structural homology modelling, protein-protein docking, and molecular dynamics simulation study of SARS-CoV-2 spike protein's ability to bind angiotensin converting enzyme 2 (ACE2) from relevant species. Spike protein exhibited the highest binding to human (h)ACE2 of all the species tested, forming the highest number of hydrogen bonds with hACE2. Interestingly, pangolin ACE2 showed the next highest binding affinity despite having a relatively low sequence homology, whereas the affinity of monkey ACE2 was much lower despite its high sequence similarity to hACE2. These differences highlight the power of a structural versus a sequence-based approach to cross-species analyses. ACE2 species in the upper half of the predicted affinity range (monkey, hamster, dog, ferret, cat) have been shown to be permissive to SARS-CoV-2 infection, supporting a correlation between binding affinity and infection susceptibility. These findings show that the earliest known SARS-CoV-2 isolates were surprisingly well adapted to bind strongly to human ACE2, helping explain its efficient human to human respiratory transmission. This study highlights how in silico structural modelling methods can be used to rapidly generate information on novel viruses to help predict their behaviour and aid in countermeasure development.

Response surface methodology based optimization and scale-up production of amylase from a novel bacterial strain, Bacillus aryabhattai KIIT BE-1.

A novel strain KIIT BE-1 isolated from a specialized environment, screened through starch iodine test from a set of eighty-five biodigestate isolates, produced amylase maximally when cultured for 48 h at 37 °C. The molecular and biochemical characterization confirmed it as a strain of Bacillus aryabhattai. It exhibited optimal amylase activity (3.20 U/ml) at 36 h post incubation with a media combination of starch and yeast extract for C-N source respectively. Statistical optimisation by response surface modeling showed R2 values of 0.9645 for biomass and 0.9831 for amylase activity, suggesting the significance of the model. The optimised medium (10.25 % starch, 5.0 % peptone, 5.18 % yeast extract, pH 7.3) enhanced the enzyme activity to 4.16 U/ml (1.39-fold) from 3.20 U/ml of un-optimised medium. Further, the biomass yield and the enzymatic activity in optimized medium and process conditions increased by 1.14 and 1.21 folds subjected to a 5 l scaled-up operation in a lab-scale bioreactor.

Selective in vivo molecular and cellular biocompatibility of black peppercorns by piperine-protein intrinsic atomic interaction with elicited oxidative stress and apoptosis in zebrafish eleuthero embryos.

Day to day consumption of black pepper raise concern about the detailed information about their medicinal, pharmaceutical values and knowledge about the biocompatibility with respect to ecosystem. This study investigates the in vivo selective molecular biocompatibility of its seed cover (SC) and seed core (SP) powder extract using embryonic zebrafish model. Gas chromatography mass spectrometry (GCMS) analysis of the extract prepared by grinding showed presence of different components with "piperine" as principle component. Biocompatibility analysis showed dose and time dependent selective effect of SC and SP with LC50 of 30.4 µg/ml and 35.6 µg/ml, respectively on survivability, hatching and heartbeat rate in embryonic zebrafish. Mechanistic investigation elucidated it as effect of accumulation and internalization of black pepper leading to their influence on structure and function of cellular proteins hatching enzyme (he1a), superoxide dismutase (sod1) and tumor protein (tp53) responsible for delayed hatching, oxidative stress induction and apoptosis. The study provided insight to selective biocompatibility of black pepper expedient to produce higher quality spices with respect to pharmaceutical, clinical and environmental aspects.

A Comparative Transcriptome Analysis of Volvariella volvacea Identified the Candidate Genes Involved in Fast Growth at the Mycelial Growth Stage.

The edible straw mushroom, Volvariella volvacea, is one of the most important cultivated mushrooms in tropical and sub-tropical regions. Strain improvement for V. volvacea is difficult because of the unknown mechanisms involved in its growth regulation and substrate utilization. A comparative physiological and transcriptomic study was conducted between two commercially available straw mushroom strains (v9 and v26) to explore their fast-growth regulation mechanism(s). The physiological study showed that V. volvacea v9 had a shorter growth cycle and higher biological efficiency (4% higher) than that in v26. At least 14,556 unigenes were obtained from the four cDNA libraries (two replicates per strain). Among them, the expression of 1597 unigenes was up-regulated while 1352 were down-regulated. Four heat-shock proteins were highly expressed in v9, showing that v9 has the better ability to handle stresses and/or environmental changes. Moreover, up to 14 putative transporter genes were expressed at a higher level in v9 than those in v26, implying that v9 has a better ability to transport nutrients or export xenobiotics efficiently. Our report allows to identify the candidate genes involved in the fast growth requirement of V. volvacea, which represents a valuable resource for strain improvement in this commercially important edible mushroom.

Intrinsic molecular insights to enhancement of biogas production from kitchen refuse using alkaline-microwave pretreatment.

The current study analyzed and optimized the concentration of NaOH for alkaline pretreatment of kitchen refuse for biogas production. Also, the benefits of microwave assistance in enhanced biogasification of kitchen refuse were evaluated. The TS, VS and structural changes were compared using standard experimental techniques. Molecular dynamics was investigated for the molecular level changes leading to higher biogasification in NaOHmicrowave combined pretreatment. The methane and biogas yields were calculated to validate the benefits of microwave assistance in efficient biogasification. The NaOH-microwave combined pretreatment showed higher VS production. Microwave treatment degraded and removed lignin more efficiently. Molecular dynamics studies revealed the induction of configurational instability in lignin and cellulose molecules with variable temperatures. The methane and biogas production increased with 6% NaOH concentration, and decreased at higher NaOH concentration till 10%. Microwave assistance declined the required NaOH concentration further to 4%. Thus, as compared to 6% NaOH concentration required for an efficient pretreatment, the kitchen refuse was efficiently pretreated with 4% NaOH concentration when combined with a 30 min duration microwaving. The experimental and computational data provided a detailed analysis proposing an optimized, novel and promising method to pretreat kitchen refuse for efficient and enhanced biogas production.

A comparative study of biogasification of wheat straw, sugarcane bagasse and pressmud.

A study to compare biogas production potentials of wheat straw, sugarcane bagasse and pressmud was conducted at pH 8.0, temperature 40 °C and substrate concentration 20 g/L. Raw substrates were thermogravimetrically and Fourier-transform infrared spectroscopically characterised. TGA showed the weight loss of samples attributable to moisture, hemicellulose, cellulose and lignin losses. FTIR analysis indicated functional groups characteristics of hemicellulose, cellulose and lignin. Biogas production was the maximum between 10th and 25th day for all the tests. WS with 10% inoculum showed the highest cumulative biogas production of 370 mL/g followed by the SB (316 mL/g) and PM (211 mL/g) counterparts. The corresponding values with 5% inoculum were 303 mL/g (WS), 244 mL/g (SB) and 152 mL/g (PM). The inoculum volume also positively affected the cumulative biogas production (22.1, 29.5 and 38.8% respectively). The higher volatile fatty acids as observed in case of WS which further facilitated higher biogas production could be due to its maximum volatile solids content (88.9%) and water swelling capacity (7.37). A consistently increasing trend in the methane content (varying between 54 and 61%) in all the tests was observed till the 20th day. The biogas (7.7-21.7 mL/g) and the methane (35-42%) contents showed a decreasing trend thereafter, the lowest being observed during the 35-40-day period.

Microbial pretreatment of lignocellulosic biomass for enhanced biomethanation and waste management.

Biogas obtained from organic remains entails a developed technology and an appreciable methane yield, but its use may not be sustainable. The potential methane yield of various lignocellulose biomass and the operational conditions employed are inherently reviewed. Although of lower methane yields compared to conventional substrates, agricultural biomass is a cheap option. The major challenges encountered during its biogasification are its recalcitrance nature primarily due to the presence of crystalline cellulose and lignin. This necessitates an essential pretreatment step through physical, chemical or biological interventions for enhanced biomethanation potential. Various pretreatment-physical, chemical, and biological-strategies have been developed to overcome the inherent recalcitrance of lignocellulose to anaerobic degradation. Biological pretreatment approach, however, outcompete other pretreatments due to their application in milder conditions, little corrosiveness, and lower byproduct formation. Such pretreatment importantly aids in selectively reducing the lignin content and crystalline nature of the lignocellulosic biomass, which would evidently enhance the hydrolysis and production of monomers for their further anaerobic digestion (AD) for methanation. A variety of applied biological pretreatment strategies comprises microaerobic treatments, ensiling or composting, separation of digestion stages, and pretreatments using various lignocellulolytic fungi alongside. The net energy output through such approaches is substantially more and relatively inexpensive compared to other established chemical and mechanical approaches. The present review highlights the use of biological agents including bacterial, fungal and/or their enzymes which trigger biodegradation of wastes and utilization of lignocellulose for biofuel production. Additionally, the different physical, chemical, and biological pretreatment strategies for biogas yield enhancement are presented.

Thermostability and Substrate Specificity of GH-11 Xylanase from Thermomyces lanuginosus VAPS24.

The three dimensional structure (3D structure) of GH-11 xylanase from Thermomyces lanuginosus was obtained through homology modeling. To study the enzyme interaction with an end product of enzyme catalysis, the xylanase two sugar molecules xylose and xylobiose has been docked into the active site of GH-11 xylanase through molecular docking. Based on the free binding energy and Inhibition constant, concluded xylose makes more stable complex than xylobiose. Further, the molecular dynamic simulation studies were carried out at different temperature, i.e. 323, 333, 343 and 353 K (i.e. 50, 60, 70 and 80 °C). It has been observed that there was minor structural modification in 3D-structure of xylanase at 323, 333, and 343 K. But the helix and sheets moved out of the initial structure when simulation carried out at during 353 K (80 °C).

Vaccine and antibody production in plants: developments and computational tools.

Plants as bioreactors have been widely used to express efficient vaccine antigens against viral, bacterial and protozoan infections. To date, many different plant-based expression systems have been analyzed, with a growing preference for transient expression systems. Antibody expression in diverse plant species for therapeutic applications is well known, and this review provides an overview of various aspects of plant-based biopharmaceutical production. Here, we highlight conventional and gene expression technologies in plants along with some illustrative examples. In addition, the portfolio of products that are being produced and how they relate to the success of this field are discussed. Stable and transient gene expression in plants, agrofiltration and virus infection vectors are also reviewed. Further, the present report draws attention to antibody epitope prediction using computational tools, one of the crucial steps of vaccine design. Finally, regulatory issues, biosafety and public perception of this technology are also discussed.

Bioprospecting of novel thermostable ß-glucosidase from Bacillus subtilis RA10 and its application in biomass hydrolysis.

BACKGROUND: Saccharification is the most crucial and cost-intensive process in second generation biofuel production. The deficiency of ß-glucosidase in commercial enzyme leads to incomplete biomass hydrolysis. The decomposition of biomass at high temperature environments leads us to isolate thermotolerant microbes with ß-glucosidase production potential. RESULTS: A total of 11 isolates were obtained from compost and cow dung samples that were able to grow at 50 °C. On the basis of qualitative and quantitative estimation of ß-glucosidase enzyme production, Bacillus subtilis RA10 was selected for further studies. The medium components and growth conditions were optimized and ß-glucosidase enzyme production was enhanced up to 19.8-fold. The ß-glucosidase from B. subtilis RA10 retained 78% of activity at 80 °C temperature and 68.32% of enzyme activity was stable even at 50 °C after 48 h of incubation. The supplementation of ß-glucosidase from B. subtilis RA10 into commercial cellulase enzyme resulted in 1.34-fold higher glucose release. Furthermore, ß-glucosidase was also functionally elucidated by cloning and overexpression of full length GH1 family ß-glucosidase gene from B. subtilis RA10. The purified protein was characterized as thermostable ß-glucosidase enzyme. CONCLUSIONS: The thermostable ß-glucosidase enzyme from B. subtilis RA10 would facilitate efficient saccharification of cellulosic biomass into fermentable sugar. Consequently, after saccharification, thermostable ß-glucosidase enzyme would be recovered and reused to reduce the cost of overall bioethanol production process.

Proteomic approaches in microalgae: perspectives and applications.

Biofuels are the promising sources which are produced by various microalgae or in the form of metabolic by-products from organic or food waste products. Microalgae have been widely reported for the production of biofuels since these have a high storage of lipids as triacylglycerides, which can mainly be converted into biofuels. Recently, products such as biodiesel, bioethanol and biogas have renewed the interest toward the microalgae. The proteomics alone will not pave the way toward finding an ideal alga which will fulfill the current energy demands, but a combined approach of proteomics, genomics and bioinformatics can be pivotal for a sustainable solution. The present review emphasizes various technologies currently involved in algal proteomics for the efficient production of biofuels.