Current Pharmaceutical Biotechnology - Volume 23, Issue 15, 2022

Background: Widely known facts about Sars-Cov-2 infection’s impact on urogenital system may play a relevant role in under-standing, diagnosing, and preventing male urological disorders. Sars-CoV-2 attacks the vascular endothelium of the entire organism; therefore, infection complications are visible in various organs. Relatively small number of original studies are available on Sars-CoV-2 infection and the effect on the reproductive system and fertility in men. The vast majority of publications focus only on discussing the effects of COVID-19 infection on just one aspect of male urology or fertility. Objectives: The aim of this review was to present the current understanding of the effects of COVID-19 infection on the male genitourinary system in the context of nephrological and reproductive system complications in men, considering the potential pathomechanisms causing significant nephrological disorders in the course of viral infection, as well as long-term effects of Sars-CoV-2 infection. We tried to make clinicians aware of urogenital complications in the course of COVID-19 occurrence and encourage them to create preventive procedures. Methods: The article presented has been classified by us as "review". Of course, when searching for publications and making their critique, we focused primarily on the words: “Sars-CoV-2”, “male urogenital system”, “male infertility", "lower urinary tract symptoms". Therefore, there was no explicit and rigorous work selection methodology. Search strategies were based on the experience of the authors of the work. In order to select articles for the systematic review, literature searches were conducted on PubMed (https://pubmed.ncbi.nlm.nih.gov) using the following keywords: "Sars-CoV- 2" AND “male urogenital system” OR "male infertility" The search results were retrieved and manually screened for duplicate removal. Then abstracts and titles were checked for relevance. The articles were selected if they met the following inclusion criteria: human studies, focus on Sars-CoV-2 and male urogenital system or male infertility, published from 2020 to 2021, written in English, free full-text available. We included clinical trials, meta-analyses, randomized controlled studies, reviews, systematic reviews. Results: After the literature search, a total of 267 articles were retrieved, including 153 reviews, 53 systematic reviews, and 61 original articles. Eventually, after abstract and title screening, 2 original articles, 29 reviews, and 8 systematic reviews were accepted. In our review paper, we presented data from 2 systematic reviews, 17 reviews, 2 meta-analyses, 1 case study, and 18 original articles, including 3 animals studies, 2 in vitro studies, and 14 human studies. Conclusion: Serious concerns for urologists among COVID-19 patients should be mainly orchitis, male infertility, priapism, erectile dysfunction, and lower urinary tract symptoms. It seems that the conclusions drawn should be treated with caution because, as mentioned above, in a pandemic, urinary complications are underdiagnosed and there are too few clinical trials and case reports.

Plumbagin has gained a lot of attention in research due to its various therapeutic actions. It is a secondary metabolite obtained from different plant families, such as Plumbaginaceae, Droseraceae, and Ebenceae. Various studies on plumbagin have revealed that it is a natural gift for mankind in treating chronic diseases, like cancer, diabetes, malaria, bacterial infection, and controlling cardiovascular disease. However, there are several challenges in developing plumbagin as a therapeutic agent. The first and foremost is its limited solubility and oral bioavailability. The second limitation is its toxicity. Plumbagin has a narrow therapeutic window, and literature reveals that the compound has moderate toxicity in animals. However, data are insufficient to prove that plumbagin is unsafe for humans. Despite the many therapeutic benefits of plumbagin, it remains unexploited for mankind. Thus, a systematic review of its toxicity, pharmacology, and safety is required to be performed. This review work signifies the depth of therapeutic applications proven via research, its different modes of isolation and separation of chemical constituents, and its modification. A thorough review of promising therapeutic targets via docking studies is also presented. Different methods used to quantify plumbagin from the plant are reviewed. An overview of attempts to design novel formulations which could enhance its bioavailability is also presented. The review paper will help the scientist to exploit the drug to its optimum, which will help to overcome the challenges faced during its design and developmental stages.

The dramatically increasing levels of antibiotic resistance are being seen worldwide and are a significant threat to public health. Antibiotic and drug resistance is seen in various bacterial species. Antibiotic resistance is associated with increased morbidity and mortality and increased treatment costs. Antisense-related technologies include oligonucleotides that interfere with gene transcription and expression; these oligonucleotides can help treat antibiotic-resistant bacteria. The important oligonucleotides include Peptide Nucleic Acids (PNAs), Phosphorodiamidate Morpholino Oligomers (PPMOs), and Locked Nucleic Acids (LNAs). Typically, the size of these structures (oligonucleotides) is 10 to 20 bases. PNAs, PPMOs, and LNAs are highlighted in this review as targets for genes that cause the gene to be destroyed and impede bacterial growth. These results open a new perspective for therapeutic intervention. Future studies need to examine different aspects of antisense agents, such as the safety, toxicity, and pharmacokinetic properties of antisense agents in clinical treatment.

Background: Sir Alexander Fleming accidentally discovered antibiotics in 1928. Antibiotics have played a significant role in treating infectious diseases. The extensive use of antibiotics has enabled the microorganisms to develop resistance against the antibiotics given, which has become a global concern. This review aims to examine some of the mechanisms behind resistance and advanced methods for detecting drug-resistant and antibacterial drugs in the clinical pipeline. Methods: An extensive search was carried out in different databases, viz. Scopus, Embase, Cochrane, and PubMed. The keywords used in the search were antimicrobial resistance, antibiotic resistance, antimicrobial tolerance, antibiotic tolerance, and methods to reduce antimicrobial resistance. All the studies published in the English language and studies focusing on antibiotic resistance were included in the analysis. Results: The most common mechanisms involved in antimicrobial resistance are reflux pumping, antibiotic inactivation, acquired resistance, intrinsic resistance, mutation, bio-film resistance, etc. Antibacterial medicinal products for multidrug resistance (MDR) infections are active against pathogens, which are registered in the World Health Organization (WHO) priority pathogen list (PPL). Conclusion: Furthermore, their innovativeness was assessed by their lack of cross-resistance. Finally, novel antibacterial drugs without pre-existing inter-resistance, especially those with highresistance gram-negative bacteria and tuberculosis (TB), are understated and urgently required.

It has been very recently suggested that individuals with chronic gut inflammation are highly susceptible to COVID-19. They constitute the serious cases of COVID-19, in which inflammatory cytokine storm is observed. On the contrary, the healthy gut microbiota is linked with low chronic gut and systemic inflammation. This raises the idea that maintenance of the healthy gut microbiota and prevention of gut microbial dysbiosis in COVID-19 patients might avoid the increased cytokine storm, which in turn might reduce the mortality rate. It has been shown that the modulation of the gut microbiota is an effective strategy to strengthen immunity and might be a possible treatment for individuals with viral infections. Currently, there is no clinical data considering the impact of the modulation of the gut microbiota on the treatment of COVID-19. We hypothesize that targeting the gut microbiota might be a novel therapeutic approach or at least a supportive therapy. In the present review article, we described the interaction between SARS-CoV-2 and gut microbiota dysbiosis through two possible mechanisms, including aberrant immune activation and aberrant mammalian target of rapamycin (mTOR) activation. Further, the disruption of the gastrointestinal reninangiotensin system (GI RAS), dysregulation of the coagulation and fibrinolytic systems, and the activity of human serine proteases in COVID-19 pathogenesis were addressed. We also provided possible strategies to restore all the discussed aspects via gut microbiota modulation.

Probiotics are defined as “live microorganisms that confer a health benefit on the host when administered adequately.” In recent years, the cosmetic industry has tried to develop many products classified as probiotics. They can exert their benefits at the skin level because of their favorite properties, and they could prevent and treat skin diseases and represent an emerging area for skin health. The antibacterial and immunomodulatory properties make them promising candidates to target skin disorders including acne, psoriasis, and atopic dermatitis and aid wound healing. The scientific reports show that specific probiotic strains can modulate cutaneous microflora, skin immune system, lipid barrier, and skin health preservation. This review summarizes the most relevant evidence from scientific literature concerning potential topical applications of probiotics in dermatology. Altogether, the evidence reported here affords the possibility of designing new strategies based on a topical approach to prevent and treat cutaneous disorders.

Background: In the last few years, the possible etiological role of the Hepatitis B virus (HBV) in the outbreak of extrahepatic pathologies has been studied, including lymphomas. The World Health Organization (WHO) estimates that around 257 million people live with chronic HBV infection, and to date, the vaccine is the most effective means of prevention. Objective: The aim of this review was to evaluate whether the vaccination against Hepatitis B can lead to a reduction in lymphoma cases and has a protective role. Methods: A literature search was conducted in April 2020 using the databases Scopus, PubMed, and ISI Web of Science. Search terms included: “Hepatitis B vaccination AND lymphoma.” All articles evaluating the association between Hepatitis B vaccination and the prevention of lymphoma were selected. No limits were applied. Results: Eight studies were eligible to be included in the review. Data showed that association between lymphoma and HBV infection is not the same for all types of lymphomas, but it appears to be more significant for Non-Hodgkin Lymphoma (NHL). The results from all the considered articles were not unitary. This is because studies were conducted in different countries with different endemicity of Hepatitis B, different vaccination coverage, treatment of chronic Hepatitis, and prevention of its complications, as well as the availability of data for researchers. No statistically significant association was found between HBV vaccination and the development of lymphomas. Conclusion: Although the literature is still largely lacking regarding the protective effect of anti- HBV vaccination on lymphoma subtypes, the association between HBV infection and lymphoma has been confirmed in several studies. Vaccination programs eliminate the risk of HBV infection and prevent liver disease but can also indirectly reduce the risk of lymphomas.

Background: Bacterial resistance to all currently available conventional antibiotics has caused a global public health crisis and led to an imperative search for new agents. Antimicrobial peptides (AMPs) are essential components of host innate immune defense against microbial invasions. Objectives: The objective of this study was to report a novel AMP, brevinin-2KP, from the skin of the black Kaloula pulchra frog and describe its structural and biological characterization. Materials and Methods: The physical and chemical parameters of brevinin-2KP were predicted with the ExPASy Bioinformatics Resource Portal. The assembled sequences were aligned with ClustalW, and the phylogenetic tree was constructed using Mega. Circular dichroism (CD) experiments were carried out to identify the secondary structure and the stability of peptide in different solvent environments. The cytotoxicity of brevinin-2KP was evaluated by the MTT test. To determine antibacterial activity of brevinin- 2KP, a standard two-fold broth dilution method was used. SEM was carried out to observe the morphological change in the bacterial treated by brevinin-2KP. The live/dead bacterial viability was measured with a LIVE/DEAD® BacLight kit. Histamine release and mast cell degranulation assays were performed. Results: The precursor of brevinin-2KP contains 72 amino acid residues, including a conserved signal peptide, acidic propeptide with KR residues, and mature peptide with a sequence of GVITDALKGAAKTVAAELLKKAHCKLTNSC. Phylogenetic analysis based on the amino acid sequences of 34 brevinin-2 peptides from 30 anuran species demonstrates that K. pulchra is genetically closely related to the genus Hylarana. The CD spectra analysis indicates that brevinin-2KP adopts random coil in the water and an organized α-helical conformation in SDS solution. Further, this secondary structure is stable under high salt and high-temperature conditions. Brevinin-2KP is weakly active towards the tested Gram-positive and Gram-negative bacteria as well as fungi due to its membranolytic action. Moreover, brevinin-2KP inhibits the proliferation of several mammal cells with IC50 values ranging from 3.27 to 59.75 μM. In addition, brevinin-2KP promotes degranulation and histamine release of mast cells, indicating that it is involved in the inflammatory response. Conclusion: This is the first report on AMP identified from the skin of K. pulchra. Brevinin-2KP adopts a typical amphipathic α-helix conformation in membrane mimic environment and shows antimicrobial and antitumor activities by potential membranolytic mechanism. In addition, brevinin-2KP can promote degranulation and histamine release of mast cells. Brevinin-2KP is expected to become a good drug temple molecule.

Background: Ecliptae prostrata (L.) L. has been widely used in East Asia with reported biological activities, including anti-cancer properties. Objectives: We aimed to investigate the effect of ethyl acetate extract of Ecliptae prostrata (L.) L. (EAE) and its component wedelolactone on the proliferation and migration of head and neck squamous cancer cells. Methods: The proliferation of human SCC-4 and mouse CU110-1 tongue squamous carcinoma cells was assessed using the 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) method. Scratch wound assays were performed to assess cell migration rates. The levels of Ecadherin and vimentin were used as markers of the epithelial-to-mesenchymal transition (EMT). AhR, CYP1A1, and CYP1B1 levels were examined to uncover the mechanism of inhibition of cell migration by wedelolactone. Results: We found that EAE and wedelolactone decreased the proliferation of human SCC-4 cells and mouse CU110-1 cells at doses of EAE at > 25 μg/ml and wedelolactone at > 6.25 μg/ml. Similarly, both EAE and wedelolactone produced inhibitory effects against migration, but the effective doses that significantly inhibited migration were lower than those affecting proliferation. Wedelolactone below 12.5 μg/ml inhibited the epithelial-to-mesenchymal transition (EMT) with increased expression of E-cadherin and decreased expression of vimentin in SCC-4 and CU110-1 cells. Further analysis showed wedelolactone inhibited the expression of AhR and its downstream target molecules CYP1A1 and CYP1B1 in both squamous carcinoma cells at the same doses inhibiting cell migration. The addition of benzo (a)pyrene [B(a)P], an agonist of AhR, stimulated migration, especially in the CU110-1 cells with reported cancer stem cell-like characteristics. Instructively, B(a)P reversed the inhibitory effects of wedelolactone on AhR expression and cell migration, suggesting that wedelolactone antagonizes cell migration through the AhR pathway. Moreover, the higher activity of EAE and wedelolactone against the migration of cancer stem-like CU110-1 cells relative to SCC-4 cells suggests selective activity against cancer stem cells. Conclusion: Our study identifies wedelolactone as a major active component of Ecliptae prostrata (L.) L. with promising anti-cancer properties against head and neck squamous cancer cells.

Background: In the wake of the warning by WHO that the prevalence of dementia may have a rise of 125% in the Middle East by 2050, identification of the genetic risk factors in Arab populations is urgent. Objectives: To investigate the association of Single Nucleotide Polymorphisms (SNPs) in apolipoprotein E (ApoE), clusterin (CLU), tumor necrotic factor- α (TNF-α) and interleukin-6 (IL-6) genes, with risk of Alzheimer’s disease (AD) in Saudi Arabian participants. Methods: A total of 42 Saudi AD patients and 23 age-matched control participants were genotyped for eight SNPs: rs429358, rs7412 (ApoE); rs11136000, rs1532278 (CLU); rs1800629, rs1799724 (TNF-α) and rs1800796, rs1800795(IL-6), by RT-PCR using the TaqMan assay. Serum concentrations of amyloid beta peptide 1–40(Aβ1-40), amyloid beta peptide 1–42(Aβ1- 42), CLU and some other biochemical markers were measured. Results: A significant increase (p=0.004) in the serum CLU level was detected in the AD group (340.4 ± 74.6) compared with control group (265.0 ± 80.9). For rs1532278 (CLU), genotype GA was significantly higher in AD patients (57.1%) than in the control participants (26.1%), [p=0.024, OR = 4.00, 95% CI (1.20-13.28)]. For the ApoE SNP rs7412, 40.4% of patients carried a TT genotype, whereas it was completely absent in the controls [p = 0.020, OR = 30.53, 95% CI (1.73 – 540.05)].For rs429358 (ApoE), patients showed a significantly increased frequency of the TC genotype [p = 0.006, OR = 9.33, 95% CI (1.89–46.19)] and TT [p = 0.045, OR = 19.76, 95% CI (1.07–366.0)] genotype than controls. AD patients with CC genotype for ApoE rs429358 had significantly lower levels of Aβ1-40 (p=0.04) in AD patients than controls. Carriers of genotype GG for rs1800629 (TNF-α) showed significantly higher levels of serum IL-6 (p = 0.04) in AD patients. Conclusion: Genetic variants in ApoE and CLU may influence susceptibility to AD among Saudi Arabian participants.