Current Pharmaceutical Biotechnology - Volume 22, Issue 11, 2021

The main obstacle to biopharmaceutical delivery in therapeutic concentration into the brain for treating neurological disorders is the presence of the Blood-Brain Barrier (BBB). The physiological process of Receptor-Mediated Transcytosis (RMT) to transport cargo through the brain endothelial cells toward brain parenchyma has prompted researchers to search for non-natural ligands that can be used to transport drugs across the BBB. Conjugation of drugs to RMT ligands would be an effective strategy for its delivery to the central nervous system. An attractive approach to identify novel transcytosing ligands is the screening by phage display combinatorial libraries. The main technology strength lies in the large variety of exogenous peptides or proteins displayed on the phage's surface. Here, we provide a mini-review of phage display technology using in vitro and in vivo BBB models for the development of peptide-mediated drug delivery systems.

Background: γ-Poly-Glutamic Acid (γ-PGA) is a naturally occurring homo-polyamide produced by various strains of Bacillus. It is made from repeating units of L-glutamic acid, D-glutamic acid, or both connected through amide linkages between α-amino and γ-carboxylic acid groups. As a biopolymer substance, the attractive properties of γ-PGA are that it is water-soluble, biodegradable, biocompatible, non-toxic, non-immunogenic, and edible. Therefore, it can be used as a green and environmentally friendly biological material. Methods: The review concentrates on the reports revealing the functions and potential use of γ-PGA and its derivatives in medicine. Results & Discussion: γ-PGA is described to possess several properties that may be exploited in medicine. The biopolymer reportedly has been successfully applied not only as a metal chelator, drug carrier/ deliverer, and gene vector, but also used safely as a vaccine adjuvant, tissue engineering material, and contrast agent. Conclusion: γ-PGA could be potentially considered as a potential biomedical material in the field of medicine.

Melanogenesis is simply defined as the production of melanin in melanosomes by melanocytes through a complex process. Melanin, a pigment derived from L-tyrosine, comes into two forms, namely eumelanin (brownish to black) and pheomelanin (red to yellow). Melanin synthesis starts via the hydroxylation of L-tyrosine to L-3,4-Dihydroxyphenylalanine (DOPA) catalyzed by the enzyme known as Tyrosinase (TYR), which triggers further conversion reaction to DOPAquinone and then to DOPAchrome. Additionally, this process is also related to two more proteins, i.e., oxygenase TYR-related Protein 1 (TYRP1), and Dopachrome Tautomerase TYRP2 (or DCT). However, TYR located in the melanosomal membrane still stands as the key enzyme to initiate the whole process of melanogenesis. Due to some deficits, melanogenesis may emerge as hypo- or hyperpigmentation in the skin. High production of melanin in melanocytes leads to hyperpigmentation- related skin disorders, including freckles, melasma, melanoma, etc., that may cause displeasure in personal appearance and reduce quality of life. Consequently, several melanogenesis inhibitors of synthetic and natural origins have been developed up to date, though most of them have been reported with serious side effects. For this reason, extensive research is still going on to find novel and more effective melanogenesis inhibitors with less side effects. In this sense, particularly flavonoids, catechins, and stilbenes from plants have been a hope to discover new inhibitors which gain significant attention from scientists. In this review, promising natural products effective in melanogenesis inhibition will be scrutinized.

Background: The general purpose of this review was to briefly describe the Gastro-Retentive Drug Delivery System (GRDDS) and to primarily focus on mechanisms of flotation for gastric retention. Methods: The principle mechanism of Floating Drug Delivery Systems (FDDS) is mainly based on hydro-dynamically controlled low-density system, which gets swollen when comes in contact with the gastric environment and remains buoyant for an extended period of time with improved bioavailability and therapeutic efficacy. The main perspective of this review was to focus on microbubble drug delivery due to its wide range of applications. Results: Microbubble is a new, economically viable, and non-invasive technique that is alternative to conventional techniques. The size of microbubbles ranges from 1-100 micrometers, which contain oxygen or air and remain suspended for prolonged drug release. Due to its great potential, microbubble is used in the therapeutic delivery of drug molecules or genetic material at their specific targeted site in various diseases. The recent research also suggests that ultrasound-mediated microbubble is more frequently used in the biomedical field for imaging of site-specific molecule targeting for the detection of disease and site-specific drug delivery. Conclusion: Gastro-retentive floating drug delivery system was considered as the most favorable approach for site-specific drug delivery. But nowadays, microbubble is gaining more popularity for its potential applications in the biomedical field. In recent years, there is much progress in microbubble for site-specific delivery of a drug or genetic material. Recent research also suggests that the ultrasound- mediated microbubble has shown a positive impact on the diagnosis and clinical management of various diseases such as liver cirrhosis, brain tumor, ocular, and urinary tract infection.

Nanomedicine is revolutionizing the treatment of cancer and has achieved unprecedented outcomes over the past decades. The accumulation of Nanoparticles (NPs) in different tumors relies mainly on the Enhanced Permeability and Retention (EPR) effect benefiting from the wide fenestrae of the tumor vasculature and the lack of lymphatic drainage. However, the EPR effect is recognized as a heterogeneous phenomenon resulting in heterogeneous outcomes of clinical trials. Extensive efforts are exerted to enhance the outcomes of nanomedicine in a larger cohort of patients by employing active targeting strategies. However, actively targeted NPs accumulate in tumors by the EPR effect and hence fail to achieve convincing therapeutic outcomes. These obstacles are gradually being removed by improving the understanding of the Tumor Microenvironment (TME) and the mechanistic interaction of the NPs with its different components. In this review, we provide detailed insights into the past concerns of drug targeting, the current trends of TME reengineering, and the future implications for overcoming past hurdles. Strategies explored in this regard included the use of companion diagnostics and the modulation of the protein corona associated with the systemic administration of NPs and their interaction with biological macromolecules.

Stem cell therapy efficiently targets the brain for most neurological disorders like migraine, Parkinsonism, schizophrenia, Alzheimer’s disease, and brain injury. The major obstacles in potential brain targeting are the physiological barriers like blood-brain-barrier and bloodcerebrospinal fluid barrier. The conventional injectable route or direct transplantation of stem cells results in brain injury and is less feasible clinically. The alternative to these invasive routes is the intranasal route that is non-invasive, easily repeatable technique and highly effective in brain targeting without crossing the blood-brain barrier. Extensive research has been undertaken for the delivery of stem cells to the brain via the intranasal route that holds great potential in overcoming the existing barriers. Nanotechnology is emerging as a novel interdisciplinary field in the arena of stem cell research. The combination of nanotechnology coupled with stem cell therapy has led to synergistic outcomes in diagnostic and therapeutic applications of neurological diseases. This review provides insights into stem cell-based nanotherapy for brain targeting via the intranasal route.

Background: Acute Coronary Syndrome (ACS) is the leading cause of morbidity and mortality in developed countries. Numerous groups have explored single and multiple biomarker strategies to identify diagnostic prognosticators of ACS, which will improve our ability to identify high-risk individuals. Matrix Metalloproteinase (MMP-9) is one potential biomarker, which has been widely studied in ACS. Recent reports have showed the prognostic utility of MMP-9, but due to inconsistent results, it has not been possible to draw firm conclusions. Objective: This review aims to explore the ability of MMP-9 to predict the long-term prognosis of ACS. To clarify this issue, we conducted a literature review to provide a comprehensive assessment of MMP-9 levels in ACS patients. Methods: We retrieved a total of 1501 articles from PubMed and Google Scholar. After thorough scrutiny, 12 original research articles were found fulfilling the inclusion-exclusion criteria. MMP-9’s ability as a biomarker of prognostication post ACS was reviewed. PRISMA guidelines were used for reporting. Results: The results revealed that MMP-9, apart from being an efficient diagnostic biomarker for ACS, helps in predicting the future risk of ACS with disease outcome. A positive correlation was found between plasma MMP-9 and left ventricular remodeling. A positive association was also found between cardiovascular death and higher MMP-9 levels. Conclusion: MMP-9 can be a potential prognostic marker for ACS and aids in identifying high-risk patients for intensive management during follow -up.

Background: Rheumatoid Arthritis (RA) is a common connective tissue disease, characteristic of chronic and invasive synovitis in single or multiple joints and vasculitis. RA is a heterogeneous disease with unclear pathogenesis. Therefore, exploring the etiology and pathogenesis of the disease is essential for identifying new promising treatment strategies for RA. Accumulated data have implicated the significant role of non-coding RNA in RA, some of which are demonstrated to regulate inflammation and autoimmunity in RA through the Toll-Like Receptor (TLR) signaling pathway. To clarify the mechanism of non-coding RNA regulating the generation of proinflammatory mediators is helpful for understanding the pathogenesis of RA. Moreover, these well established non-coding RNAs can serve as novel biotargets for RA diagnosis and treatment. Conclusion: Here, we summarize currently available data on non-coding RNAs, TLRs, and the underlying molecular mechanisms in RA. This review will provide insight into the potential use of noncoding RNA as disease diagnosis and treatment markers for RA.

Background and Objective: Emerging studies on the predictive value of Small Nucleolar RNA Host Gene 7 (SNHG7) in human neoplasms give evidence of the association of SNHG7 with the human tumor. However, whether SNHG7 can be utilized as a biomarker for carcinoma is still unknown. Therefore, this meta-analysis is aimed to assess the possibility of SNHG7 serving as a tumor biomarker. Materials and Methods: 11 studies involving 814 cancer patients were retrieved from several databases, including PubMed, Embase, the Cochrane Library, and Web of Science from 1950 to Dec 27, 2019. Data on patient survival and several clinicopathological features were extracted and analyzed. Results: Evident association between SNHG7 expression and poor Overall Survival (OS) was demonstrated (HR=1.84, 95% CI: 1.42-2.37) and high SNHG7 level was markedly correlated with tumor size (OR=2.01, 95% CI: 1.27-3.19), advanced clinical grade (III/IV) (OR=3.90, 95% CI: 2.63-5.80), Lymphatic Metastasis (LM) (OR=4.53, 95% CI: 2.71-7.55), and Distant Metastasis (DM) (OR=3.52, 95% CI: 2.58-4.80), except age and gender. Subgroup analysis showed that the predictive value of SNHG7 was consistent regardless of follow-up months, tumor location and sample size. Additionally, data from the R2 database also confirmed this association (p < 0.05). Publication bias was evaluated using Begg’s and Egger’s test. Conclusion: SNHG7 could serve for a promising biomarker to predict prognosis, progression and metastasis of human solid cancer.

Background: It has been found that there is a link between hypertension and elevated risk of Alzheimer’s Disease (AD). Herein, a meta-analysis based on Randomized Clinical Trials (RCTs) was used to assess the effect of antihypertensive drugs on cognition and behavioral symptoms of AD patients. Methods: The three databases, PubMed/Medline, Scopus, and Cochrane Library, were searched up to March 2020. The quality of the studies included in the meta-analysis was evaluated by the Jadad score. Clinical Global Impression of Change (CGIC) included in two studies, Mini-Mental State Examination (MMSE) included in three studies, and Neuropsychiatric Inventory (NPI) in three studies were the main outcomes in this systematic review. Results: Out of 1506 studies retrieved in the databases, 5 RCTs were included and analyzed in the meta-analysis. The pooled mean differences of CGIC, MMSE, and NPI in patients with AD receiving antihypertensive drugs compared to placebo were -1.76 with (95% CI = -2.66 to -0.86; P=0.0001), 0.74 (95% CI = 0.20 to 1.28; P= 0.007), and -9.49 (95% CI = -19.76 to 0.79; P = 0.07), respectively. Conclusion: The findings of the present meta-analysis show that antihypertensive drugs may improve cognition and behavioral symptoms of patients with AD. However, more well-designed RCTs with similar drugs are needed to achieve more conclusive results.

Aim: We seek to provide an understanding of the binding mechanism of Remdesivir, as well as structural and conformational implications on SARS-CoV-2 virus RNA-dependent RNA polymerase upon its binding and identify its crucial pharmacophoric moieties. Background: The coronavirus disease of 2019 (COVID-19) pandemic had infected over a million people, with 65,000 deaths as of the first quarter of 2020. The current limitation of effective treatment options with no approved vaccine or targeted therapeutics for the treatment of COVID-19 has posed serious global health threats. This has necessitated several drug and vaccine development efforts across the globe. To date, the farthest in the drug development pipeline is Remdesivir. Objectives: We performed the molecular dynamics simulation, quantified the energy contributions of binding site residues using per-residue energy decomposition calculations, and subsequently generated a pharmacophore model for the identification of potential SARS-CoV-2 virus RNA-dependent RNA polymerase inhibitors. Methods: Integrative molecular dynamics simulations and thermodynamic calculations coupled with advanced post-molecular dynamics analysis techniques were employed. Results: Our analysis showed that the modulatory activity of Remdesivir is characterized by an extensive array of high-affinity and consistent molecular interactions with specific active site residues that anchor Remdemsivir within the binding pocket for efficient binding. These residues are ASP452, THR456, ARG555, THR556, VAL557, ARG624, THR680, SER681, and SER682. Results also showed that Remdesivir binding induces minimal individual amino acid perturbations, subtly interferes with deviations of C-α atoms, and restricts the systematic transition of SARS-CoV-2 RNA-dependent RNA polymerase from the “buried” hydrophobic region to the “surface-exposed” hydrophilic region. We also mapped a pharmacophore model based on the observed high-affinity interactions with SARSCoV- 2 virus RNA-dependent RNA polymerase, which showcased the crucial functional moieties of Remdesivir and was subsequently employed for virtual screening. Conclusion: The structural insights and the provided optimized pharmacophoric model would augment the design of improved analogs of Remdesivir that could expand treatment options for COVID-19.

Background: Although Semaphorin 3A (Sema3A)/ Neuropilin-1(NRP1)/Plexin A1 is one of the important targets in bone metabolism, few studies are performed on this target in the glucocorticoids- induced osteoporosis. Luteolin is a chemical component of Honeysuckle and it has various bioactivities. The effect of Luteolin on the glucocorticoids-induced osteoporosis (primary osteoblasts model) remain unknown. Objective: The aim of this study was to investigate the action of Sema3A/ NRP1/Plexin A1 in Luteolin- induced osteoprotection against high-dose Dexamethasone. Methods: The effect of Luteolin on the proliferation, late differentiation, and apoptosis of primary osteoblasts model of glucocorticoids-induced osteoporosis in vitro as well as the expression of Sema3A/ NRP1/Plexin A1 are investigated by using 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-Htetrazolium bromide, Cell Counting Kit-8, reverse transcription-quantitative real-time polymerase chain reaction, western bolting and so on. Results: Suckling SD rats’ calvarial osteoblasts were isolated and identified. The glucocorticoidsinduced primary osteoporosis cell model was established by 100 μM Dexamethasone in 48 h (P<0.01). Luteolin promotes osteoblasts either in physiological condition (without Dexamethasone) or pathological condition (with Dexamethasone) at 1 μM concentration for 48h (P<0.01). Luteolin partly reverses down-regulated expression of proliferation markers such as proliferating cell nuclear and CyclinD1. (P<0.01) Similarly, Luteolin partly reverses up-regulated expression of apoptosis markers such as Bax/B-cell lymphoma-2. (P<0.01) The expression of mRNA and protein of Sema3A/ NRP1/Plexin A1 decreased in model one which significantly increased in Luteolin protecting one. (P<0.05) Interestingly, the late differentiation marker such as osteocalcin and collagenase 133; sharply decreased in Luteolin protecting group compared with model one. (P<0.01). Conclusion: The thesis concludes that Luteolin promoted the proliferation of osteoblast and inhibited its apoptosis and late differentiation in this glucocorticoids-induced primary osteoporosis cell model. This function may be related to the expression of up-regulated Sema3A/NRP1/Plexin A1. Therefore, Luteolin may be a potential medicine for the glucocorticoids-induced osteoporosis.