Vol 25, No 4 (2024)
- Year: 2024
- Articles: 11
- URL: https://vietnamjournal.ru/1389-2010/issue/view/10059
Biotechnology
Genotoxic Impurities in Critical Analysis of Product Development: Recent Advancements, Patents, and Current Challenges
Abstract
The current review intends to regulate and accurately evaluate genotoxic contaminants in drug substance and drug product method and formulation process development, validation, and degradation pathways. The Quality by Design (QbD) principles can be applied to the systematic evaluation and control of impurities enabled by the development of modern analytical techniques, including the performance of risk assessment, the screening of Critical Process Parameters (CPPs), and the identification of the most influential variables in the optimization of the evaluation and control methods. Current difficulties in removing genotoxic contaminants and the procedures for doing so have been outlined in this review, along with the steps necessary to acquire optimum techniques and the most acceptable formulations. In addition to this, division, characterization, assessment, quantification, and formation of genotoxic impurities sources and control strategy for genotoxic impurities, handling of nitrosamine assay content of drug products in different industrial methodologies and their chemometric prospects and associated recent patents are also explored.



Advances on the Role of Ferroptosis in Ionizing Radiation Response
Abstract
Ferroptosis is an iron-dependent programmed cell death mode that is distinct from other cell death modes, and radiation is able to stimulate cellular oxidative stress and induce the production of large amounts of reactive oxygen radicals, which in turn leads to the accumulation of lipid peroxide and the onset of ferroptosis. In this review, from the perspective of the role of ferroptosis in generating a radiation response following cellular irradiation, the relationship between ferroptosis induced by ionizing radiation stress and the response to ionizing radiation is reviewed, including the roles of MAPK and Nrf2 signaling pathways in ferroptosis, resulting from the oxidative stress response to ionizing radiation, the metabolic regulatory role of the p53 gene in ferroptosis, and regulatory modes of action of iron metabolism and iron metabolism-related regulatory proteins in promoting and inhibiting ferroptosis. It provides some ideas for the follow-up research to explore the specific mechanism and regulatory network of ferroptosis in response to ionizing radiation.



Mini Review on Clinical Aspects of Monkeypox
Abstract
Monkeypox is a disease caused by the monkeypox virus, which is a type of orthopox virus that comes from the virus family Poxviridae. Its first case reported in animals and humans was in 1958 and 1970, respectively. It is a viral zoonosis disease with two modes of transmission: animal to human (via direct contact or eating the meat of an infected animal) and human to human (via contact or contact with skin lesions, body fluids, and infected persons contaminated objects). The literature depicts that monkeypox is less contagious among individuals in contrast to smallpox; the infection chain of monkeypox is nearly five to six patients approximately. It has two clades, the West African and the Central African (the Congo basin). The Congo basin subgroup of monkeypox is highly transmissible and severe. The symptoms of monkeypox include fever, lethargy, headache, lymphadenopathy, myalgia, myodynia, fainting, shivers, backache, and rashes on the face and extremities. The most common symptom of monkeypox is lymphatic hyperplasia or, lymph adenopathy or swollen lymph nodes. It is proven to be very useful in the diagnosis of monkeypox. The antiviral drugs that are used for its treatment are tecovirimat, brincidofovir and cidofovir. Tecovirimat has fewer side effects and it shows better therapeutic action in comparison to brincidofovir and cidofovir. For the prevention of monkeypox, the Center for Disease Control and Prevention recommends the administration of the same vaccine used for smallpox named INVAMUNE, which is currently in its third generation. Its first and second generations have adverse side effects in patients having HIV or atopic dermatitis.



Akkermansia muciniphila - A Potential Next-generation Probiotic for Non-alcoholic Fatty Liver Disease
Abstract
Nonalcoholic fatty liver disease (NAFLD) is a spectrum of liver conditions, and its growing prevalence is a serious concern worldwide, especially in Western countries. Researchers have pointed out several genetic mutations associated with NAFLD; however, the imbalance of the gut microbial community also plays a critical role in the progression of NAFLD. Due to the lack of approved medicine, probiotics gain special attention in controlling metabolic disorders like NAFLD. Among these probiotics, Akkermansia muciniphila (a member of natural gut microflora) is considered one of the most efficient and important in maintaining gut health, energy homeostasis, and lipid metabolism. In this perspective, we discussed the probable molecular mechanism of A. muciniphila in controlling the progression of NAFLD and restoring liver health. The therapeutic potential of A. muciniphila in NAFLD has been tested primarily on animal models, and thus, more randomized human trials should be conducted to prove its efficacy.



A Synoptic Update on Smart Lipid Nanocarrier: Cubosomes, and their Design Development, and Recent Challenges
Abstract
Cubosomes are a kind of nanoparticle that is distinct from solid particles in that they are liquid crystalline particles formed by self-assembly of a certain surfactant with a current water ratio. Their unique properties as a result of their microstructure are useful in practical applications. Cubosomes, specifically lyotropic nonlamellar liquid crystalline nanoparticles (LCNs) have gained acceptance as a medication delivery strategy for cancer and other disorders. Cubosomes are produced by the fragmentation of a solid-like phase into smaller particles. Because of its particular microstructure, which is physiologically safe and capable of allowing for the controlled release of solubilized compounds, cubic phase particles are garnering considerable attention. These cubosomes are highly adaptable carriers with promising theranostic efficacy because they can be given orally, topically, or intravenously. Throughout its operation, the drug delivery system regulates the loaded anticancer bioactive's target selectivity and drug release characteristics. This compilation examines recent advances and obstacles in the development and application of cubosomes to treat various cancers, as well as the challenges of turning it into a potential nanotechnological invasion.



Recent Developments and Applications of Biocatalytic and Chemoenzymatic Synthesis for the Generation of Diverse Classes of Drugs
Abstract
Biocatalytic and chemoenzymatic biosynthesis are powerful methods of organic chemistry that use enzymes to execute selective reactions and allow the efficient production of organic compounds. The advantages of these approaches include high selectivity, mild reaction conditions, and the ability to work with complex substrates. The utilization of chemoenzymatic techniques for the synthesis of complicated compounds has lately increased dramatically in the area of organic chemistry. Biocatalytic technologies and modern synthetic methods are utilized synergistically in a multi-step approach to a target molecule under this paradigm. Chemoenzymatic techniques are promising for simplifying access to essential bioactive compounds because of the remarkable regio- and stereoselectivity of enzymatic transformations and the reaction diversity of modern organic chemistry. Enzyme kits may include ready-to-use, reproducible biocatalysts. Its use opens up new avenues for the synthesis of active therapeutic compounds and aids in drug development by synthesizing active components to construct scaffolds in a targeted and preparative manner. This study summarizes current breakthroughs as well as notable instances of biocatalytic and chemoenzymatic synthesis. To assist organic chemists in the use of enzymes for synthetic applications, it also provides some basic guidelines for selecting the most appropriate enzyme for a targeted reaction while keeping aspects like cofactor requirement, solvent tolerance, use of whole cell or isolated enzymes, and commercial availability in mind.



Antioxidative and Anti-photooxidative Potential of Interruptins from the Edible Fern Cyclosorus terminans in Human Skin Cells
Abstract
Background:Human skin is exposed daily to oxidative stress factors such as UV light, chemical pollutants, and invading organisms. Reactive oxygen species (ROS) are intermediate molecules that cause cellular oxidative stress. In order to survive in an oxygen-rich environment, all aerobic organisms, including mammals, have evolved enzymatic and non-enzymatic defence systems. The interruptins from an edible fern Cyclosorus terminans possess antioxidative properties and can scavenge intracellular ROS in adipose-derived stem cells.
Objective:This study aimed to evaluate the antioxidative efficacy of interruptins A, B, and C in cultured human dermal fibroblasts (HDFs) and epidermal keratinocytes (HEKs). Moreover, the anti-photooxidative activity of interruptins in ultraviolet (UV)-exposed skin cells was investigated.
Methods:The intracellular ROS scavenging capacity of interruptins in skin cells was measured by flow cytometry. Their induction effects on gene expression of the endogenous antioxidant enzymes was monitored using real-time polymerase chain reaction.
Results:Interruptins A and B, but not interruptin C, were highly effective in ROS scavenging, particularly in HDFs. Interruptins A and B upregulated gene expression of superoxide dismutase (SOD)1, SOD2, catalase (CAT), and glutathione peroxidase (GPx) in HEKs, but they only induced SOD1, SOD2, and GPx gene expression in HDFs. Additionally, interruptins A and B efficiently suppressed UVA- and UVB-induced ROS generation in both HEKs and HDFs.
Conclusion:The results suggest that these naturally occurring interruptins A and B are potent natural antioxidants and therefore may have the potential in the future of inclusion in antiaging cosmeceutical products.



Inhibition of Xanthine Oxidase by 4-nitrocinnamic Acid: In Vitro and In Vivo Investigations and Docking Simulations
Abstract
Background:Cinnamic acid and its derivatives have gained significant attention in recent medicinal research due to their broad spectrum of pharmacological properties. However, the effects of these compounds on xanthine oxidase (XO) have not been systematically investigated, and the inhibitory mechanism remains unclear.
Objective:The objective of this study was to screen 18 compounds and identify the XO inhibitor with the strongest inhibitory effect. Furthermore, we aimed to study the inhibitory mechanism of the identified compound.
Methods:The effects of the inhibitors on XO were evaluated using kinetic analysis, docking simulations, and in vivo study. Among the compounds tested, 4-NA was discovered as the first XO inhibitor and exhibited the most potent inhibitory effects, with an IC50 value of 23.02 ± 0.12 µmol/L. The presence of the nitro group in 4-NA was found to be essential for enhancing XO inhibition. The kinetic study revealed that 4-NA inhibited XO in a reversible and noncompetitive manner. Moreover, fluorescence spectra analysis demonstrated that 4-NA could spontaneously form complexes with XO, referred to as 4-NA‒XO complexes, with the negative values of △H and △S.
Results:This suggests that hydrogen bonds and van der Waals forces play crucial roles in the binding process. Molecular docking studies further supported the kinetic analysis and provided insight into the optimal binding conformation, indicating that 4-NA is located at the bottom outside the catalytic center through the formation of three hydrogen bonds. Furthermore, animal studies confirmed that the inhibitory effects of 4-NA on XO resulted in a significant reduction of serum uric acid level in hyperuricemia mice.
Conclusion:This work elucidates the mechanism of 4-NA inhibiting XO, paving the way for the development of new XO inhibitors.



NAD+ Protects against Hyperlipidemia-induced Kidney Injury in Apolipoprotein E-deficient Mice
Abstract
Background:Hyperlipidemia is an independent risk factor for kidney injury. Several studies have shown that nicotinamide adenine dinucleotide (NAD+) is an important coenzyme involved in normal body metabolism. Therefore, this study aimed to investigate the possible protective effects of NAD+ against hyperlipidemia-induced kidney injury in apolipoprotein E-deficient (ApoE-/-) mice.
Methods:Twenty-five eight-week-old male ApoE-/- mice were randomly assigned into four groups: normal diet (ND), ND supplemented with NAD+ (ND+NAD+), high-fat diet (HFD), and HFD supplemented with NAD+ (HFD+NAD+). The mice were subjected to their respective diets for a duration of 16 weeks. Blood samples were obtained from the inferior vena cava, collected in serum tubes, and stored at -80 °C until use. Kidney tissues were fixed in 10% formalin and then embedded in paraffin for histological evaluation. The remainder of the kidney tissues was snap-frozen in liquid nitrogen for Western blot analysis.
Results:Metabolic parameters (total cholesterol, triglycerides, low-density lipoprotein-cholesterol, creatinine, and blood urea nitrogen) were significantly higher in the HFD group compared to the other groups. Histological analysis revealed prominent pathological manifestations in the kidneys of the HFD group. The HFD+NAD+ group showed increased levels of oxidative stress markers (NRF2 and SOD2) and decreased levels of NOX4 compared to the HFD group. Furthermore, the HFD group exhibited higher levels of TGF-β, Smad3, Collagen I, Collagen III, Bax, and Bak compared to the other groups. NAD+ supplementation in the HFD+NAD+ group significantly increased the levels of SIRT3, HO-1, Bcl-2, and Bcl-xL compared to the HFD group. Additionally, NF-κB protein expression was higher in the HFD group than in the HFD+NAD+ group.
Conclusion:These findings demonstrated that NAD+ may hold potential as a clinical treatment for kidney injury caused by hyperlipidemia.



The Treatment of Tubal Inflammatory Infertility using Yinjia Tablets through EGFR/MEK/ERK Signaling Pathway based on Network Pharmacology
Abstract
Background:Salpingitis obstructive infertility (SOI) refers to infertility caused by abnormal conditions such as tubal adhesion and blockage caused by acute and chronic salpingitis. SOI has a serious impact on women's physical and mental health and family harmony, and it is a clinical problem that needs to be solved urgently.
Objective:The purpose of the present study was to explore the potential pharmacological mechanisms of the Yinjia tablets (Yin Jia Pian, YJP) on tubal inflammation.
Methods:Networks of YJP-associated targets and tubal inflammation-related genes were constructed through the STRING database. Potential targets and pathway enrichment analysis related to the therapeutic efficacy of YJP were identified using Cytoscape and Database for Annotation, Visualization, and Integrated Discovery (metascape). E. coli was used to establish a rat model of tubal inflammation and to validate the predictions of network pharmacology and the therapeutic efficacy of YJP. H&E staining was used to observe the pathological changes in fallopian tubes. TEM observation of the ultrastructure of the fallopian tubes. ELISA was used to detect the changes of IL-6 and TNF-α in fallopian tubes. Immunohistochemistry was used to detect the expression of ESR1. The changes of Bcl-2, ERK1/2, p-ERK1/2, MEK, p-MEK, EGFR, and p-EGFR were detected by western blot.
Results:Through database analysis, it was found that YJP shared 105 identical targets with the disease. Network pharmacology analysis showed that IL-6, TNF, and EGFR belong to the top 5 core proteins associated with salpingitis, and EGFR/MEK/ERK may be the main pathway involved. The E. coli-induced disease rat model of fallopian tube tissue showed damage, mitochondrial disruption, and increased levels of the inflammatory factors IL-6 and TNF-α. Tubal inflammatory infertility rats have increased expression of Bcl-2, p-ERK1/2, p-MEK, and p-EGFR, and decreased expression of ESR1. In vivo, experiments showed that YJP improved damage of tissue, inhibited shedding of tubal cilia, and suppressed the inflammatory response of the body. Furthermore, YJP inhibited EGFR/MEK/ERK signaling, inhibited the apoptotic protein Bcl-2, and upregulated ESR1.
Conclusion:This study revealed that YJP Reducing tubal inflammation and promoting tissue repair may be associated with inhibition of the EGFR/MEK/ERK signaling pathway.



Evaluation of New Folate Receptor-mediated Mitoxantrone Targeting Liposomes In Vitro
Abstract
Background::Ligand-mediated liposomes targeting folate receptors (FRs) that are overexpressed on the surface of tumor cells may improve drug delivery. However, the properties of liposomes also affect cellular uptake and drug release.
Objective::Mitoxantrone folate targeted liposomes were prepared to increase the enrichment of drugs in tumor cells and improve the therapeutic index of drugs by changing the route of drug administration.
Methods::Liposomes were prepared with optimized formulation, including mitoxantrone folatetargeted small unilamellar liposome (MIT-FSL), mitoxantrone folate-free small unilamellar liposome (MIT-SL), mitoxantrone folate-targeted large unilamellar liposome (MIT-FLL), mitoxantrone folate-free large unilamellar liposomes (MIT-LL). Cells with different levels of folate alpha receptor (FRα) expression were used to study the differences in the enrichment of liposomes, the killing effect on tumor cells, and their ability to overcome multidrug resistance.
Results::The results of the drug release experiment showed that the particle size of liposomes affected their release behavior. Large single-compartment liposomes could hardly be effectively released, while small single-compartment liposomes could be effectively released, MIT-FSL vs MIT-FLL and MIT-SL vs MIT-LL had significant differences in the drug release rate (P(<0.0005). Cell uptake experiments results indicated that the ability of liposomes to enter folic acid receptor-expressing tumor cells could be improved after modification of folic acid ligands on the surface of liposomes and it was related to the expression of folate receptors on the cell surface. There were significant differences in cell uptake rates (p(<0.0005) for cells with high FRα expression (SPC-A-1 cells), when MIT-FSL vs MIT-SL and MIT-FLL vs MIT-LL. For cells with low FRα expression (MCF-7 cells), their cell uptake rates were still different (p(<0.05), but less pronounced than in SPC-A-1 cells. The results of the cell inhibition experiment suggest that MIT-FLL and MIT-LL had no inhibitory effect on cells, MIT-FSL had a significant inhibitory effect on cells and its IC50 value was calculated to be 4502.4 ng/mL, MIT-SL also had an inhibitory effect, and its IC50 value was 25092.1 ng/mL, there was a statistical difference (p(<0.05), MIT-FSL had a higher inhibitory rate than MIT-SL at the same drug concentration. Afterward, we did an inhibitory experiment of different MIT-loaded nanoparticles on MCF-7 cells compared to the drug-resistant cells (ADR), Observing the cell growth inhibition curve, both MIT-FSL and MIT-SL can inhibit the growth of MCF-7 and MCF-7/ADR cells. For MCF- 7 cells, at the same concentration, there is little difference between the inhibition rate of MITFSL and MIT-SL, but for MCF-7/ADR, the inhibition rate of MIT-FSL was significantly higher than that of MIT-SL at the same concentration (P(<0.05).
Conclusion::By modifying folic acid on the surface of liposomes, tumor cells with high expression of folic acid receptors can be effectively targeted, thereby increasing the enrichment of intracellular drugs and improving efficacy. It can also change the delivery pathway, increase the amount of drug entering resistant tumor cells, and overcome resistance.


