Human herpesviruses (HHVs) are large DNA viruses with highly infectious characteristics. HHVs can induce lytic and latent infections in their host, and most of these viruses are neurotropic, with the capacity to generate severe and chronic neurological diseases of the peripheral nervous system (PNS) and central nervous system (CNS). Treatment of HHV infections based on strategies that include natural products-derived drugs is one of the most rapidly developing fields of modern medicine. Therefore, in this paper, we lend insights into the recent advances that have been achieved during the past five years in utilizing flavonoids as promising natural drugs for the treatment of HHVs infections of the nervous system such as alpha-herpesviruses (herpes simplex virus type 1, type 2, and varicella-zoster virus), beta-herpesviruses (human cytomegalovirus), and gamma-herpesviruses (Epstein-Barr virus and Kaposi sarcoma-associated herpesvirus). The neurological complications associated with infections induced by the reviewed herpesviruses are emphasized. Additionally, this work covers all possible mechanisms and pathways by which flavonoids induce promising therapeutic actions against the above-mentioned herpesviruses.

• Keywords
• Epstein–Barr virus, HSV-1, HSV-2, Kaposi sarcoma-associated herpesvirus, flavonoids, herpes simplex virus, human cytomegalovirus, mechanisms of action, nervous system, neurological diseases, varicella-zoster virus,
• MeSH
• Central Nervous System MeSH
• Flavonoids pharmacology   therapeutic use   MeSH
• Herpesviridae Infections * drug therapy   MeSH
• Epstein-Barr Virus Infections * MeSH
• Humans MeSH
• Herpesvirus 1, Human * genetics   MeSH
• Herpesvirus 4, Human genetics   MeSH
• Herpesvirus 3, Human genetics   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Review MeSH
• Names of Substances
• Flavonoids MeSH

In the current study, pyroglutamic acid (pGlu), a natural amino acid derivative, has efficiently inhibited the catalytic activities of three important enzymes, namely: Human recombinant phosphodiesterase-5A1 (PDE5A1), human angiotensin-converting enzyme (ACE), and urease. These enzymes were reported to be associated with several important clinical conditions in humans. Radioactivity-based assay, spectrophotometric-based assay, and an Electrospray Ionization-Mass Spectrometry-based method were employed to ascertain the inhibitory actions of pGlu against PDE5A1, ACE, and urease, respectively. The results unveiled that pGlu potently suppressed the activity of PDE5A1 (half-maximal inhibitory concentration; IC50 = 5.23 µM) compared with that of standard drug sildenafil citrate (IC50 = 7.14 µM). Moreover, pGlu at a concentration of 20 µg/mL was found to efficiently inhibit human ACE with 98.2% inhibition compared with that of standard captopril (99.6%; 20 µg/mL). The urease-catalyzed reaction was also remarkably inactivated by pGlu and standard acetohydroxamic acid with IC50 values of 1.8 and 3.9 µM, respectively. Remarkably, the outcome of in vitro cytotoxicity assay did not reveal any significant cytotoxic properties of pGlu against human cervical carcinoma cells and normal human fetal lung fibroblast cells. In addition to in vitro assays, molecular docking analyses were performed to corroborate the outcomes of in vitro results with predicted structure-activity relationships. In conclusion, pGlu could be presented as a natural and multifunctional agent with promising applications in the treatment of some ailments connected with the above-mentioned anti-enzymatic properties.

• Keywords
• ESI-mass spectrometry, angiotensin-converting enzyme, anti-enzymatic properties, cytotoxicity, phosphodiesterase 5, pyroglutamic acid, urease,
• MeSH
• Peptidyl-Dipeptidase A chemistry   genetics   metabolism   MeSH
• Cell Line MeSH
• Cyclic Nucleotide Phosphodiesterases, Type 5 chemistry   genetics   metabolism   MeSH
• Spectrometry, Mass, Electrospray Ionization MeSH
• Inhibitory Concentration 50 MeSH
• Captopril chemistry   metabolism   MeSH
• Pyrrolidonecarboxylic Acid chemistry   metabolism   toxicity   MeSH
• Hydroxamic Acids antagonists & inhibitors   metabolism   MeSH
• Humans MeSH
• Recombinant Proteins biosynthesis   chemistry   isolation & purification   MeSH
• Sildenafil Citrate chemistry   metabolism   MeSH
• Molecular Docking Simulation MeSH
• Spectrophotometry MeSH
• Protein Structure, Tertiary MeSH
• Urease antagonists & inhibitors   metabolism   MeSH
• Binding Sites MeSH
• Cell Survival drug effects   MeSH
• Structure-Activity Relationship MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• ACE protein, human MeSH Browser
• acetohydroxamic acid MeSH Browser
• Peptidyl-Dipeptidase A MeSH
• Cyclic Nucleotide Phosphodiesterases, Type 5 MeSH
• Captopril MeSH
• Pyrrolidonecarboxylic Acid MeSH
• Hydroxamic Acids MeSH
• PDE5A protein, human MeSH Browser
• Recombinant Proteins MeSH
• Sildenafil Citrate MeSH
• Urease MeSH

Studies on enzyme inhibition remain a crucial area in drug discovery since these studies have led to the discoveries of new lead compounds useful in the treatment of several diseases. In this study, protocatechuic acid (PCA), an active compound from Hibiscus sabdariffa L. has been evaluated for its inhibitory properties against jack bean urease (JBU) as well as its possible toxic effect on human gastric epithelial cells (GES-1). Anti-urease activity was evaluated by an Electrospray Ionization-Mass Spectrometry (ESI-MS) based method, while cytotoxicity was assayed by the MTT method. PCA exerted notable anti-JBU activity compared with that of acetohydroxamic acid (AHA), with IC50 values of 1.7 and 3.2 µM, respectively. PCA did not show any significant cytotoxic effect on (GES-1) cells at concentrations ranging from 1.12 to 3.12 µM. Molecular docking study revealed high spontaneous binding ability of PCA to the active site of urease. Additionally, the anti-urease activity was found to be related to the presence of hydroxyl moieties of PCA. This study presents PCA as a natural urease inhibitor, which could be used safely in the treatment of diseases caused by urease-producing bacteria.

• Keywords
• ESI-Mass spectrometry, Hibiscus sabdariffa L., cytotoxicity, molecular docking, protocatechuic acid, urease inhibitors,
• MeSH
• Cell Line MeSH
• Hibiscus chemistry   MeSH
• Spectrometry, Mass, Electrospray Ionization MeSH
• Hydroxybenzoates chemistry   MeSH
• Hydroxamic Acids chemistry   MeSH
• Humans MeSH
• Molecular Docking Simulation methods   MeSH
• Urease antagonists & inhibitors   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• acetohydroxamic acid MeSH Browser
• Hydroxybenzoates MeSH
• Hydroxamic Acids MeSH
• protocatechuic acid MeSH Browser
• Urease MeSH

For decades, Hibiscus sabdariffa L. and its phytochemicals have been shown to possess a wide range of pharmacologic properties. In this study, aqueous extract of Hibiscus sabdariffa (AEHS) and its bioactive constituent protocatechuic acid (PCA), have been evaluated in vitro for their antiviral activity against HSV-2 clinical isolates and anti-enzymatic activity against urease. Antiherpetic activity was evaluated by the titer reduction assay in infected Vero cells, and cytotoxicity was evaluated by the neutral red dye-uptake method. Anti-urease activity was determined by a developed Electrospray Ionization-Mass Spectrometry (ESI-MS)-based assay. PCA showed potent anti-HSV-2 activity compared with that of acyclovir, with EC50 values of 0.92 and 1.43 µg∙mL-1, respectively, and selectivity indices > 217 and > 140, respectively. For the first time, AEHS was shown to exert anti-urease inhibition activity, with an IC50 value of 82.4 µg∙mL-1. This, combined with its safety, could facilitate its use in practical applications as a natural urease inhibitor. Our results present Hibiscus sabdariffa L. and its bioactive compound PCA as potential therapeutic agents in the treatment of HSV-2 infection and the treatment of diseases caused by urease-producing bacteria.

• Keywords
• ESI-mass spectrometry-based assay, Hibiscus sabdariffa L., anti-HSV-2 activity, bacterial infection, protocatechuic acid, urease inhibitors,
• MeSH
• Acyclovir pharmacology   MeSH
• Antiviral Agents chemistry   isolation & purification   pharmacology   MeSH
• Chlorocebus aethiops MeSH
• Hibiscus chemistry   MeSH
• Spectrometry, Mass, Electrospray Ionization MeSH
• Inhibitory Concentration 50 MeSH
• Enzyme Inhibitors chemistry   isolation & purification   pharmacology   MeSH
• Kinetics MeSH
• Herpesvirus 2, Human drug effects   MeSH
• Polyphenols chemistry   isolation & purification   pharmacology   MeSH
• Drug Evaluation, Preclinical MeSH
• Plant Extracts chemistry   isolation & purification   pharmacology   MeSH
• Urease antagonists & inhibitors   chemistry   MeSH
• Vero Cells MeSH
• Chromatography, High Pressure Liquid MeSH
• Animals MeSH
• Check Tag
• Animals MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Acyclovir MeSH
• Antiviral Agents MeSH
• Enzyme Inhibitors MeSH
• Polyphenols MeSH
• Plant Extracts MeSH
• Urease MeSH

Stomach infection with Helicobacter pylori (H. pylori) causes severe gastroduodenal diseases in a large number of patients worldwide. The H. pylori infection breaks up in early childhood, persists lifelong if not treated, and is associated with chronic gastritis and an increased risk of peptic ulcers and gastric cancer. In recent years, the problem of drug-resistant strains has become a global concern that makes the treatment more complicated and the infection persistent at higher levels when the antibiotic treatment is stopped. Such problems have led to the development of new strategies to eradicate an H. pylori infection. Currently, one of the most important strategies for the treatment of H. pylori infection is the use of urease inhibitors. Despite the fact that large numbers of molecules have been shown to exert potent inhibitory activity against H. pylori urease, most of them were prevented from being used in vivo and in clinical trials due to their hydrolytic instability, toxicity, and appearance of undesirable side effects. Therefore, it is crucial to focus attention on the available opportunities for the development of urease inhibitors with suitable pharmacokinetics, high hydrolytic stability, and free toxicological profiles. In this commentary, we aim to afford an outline on the current status of the use of urease inhibitors in the treatment of an H. pylori infection, and to discuss the possibility of their development as effective drugs in clinical trials.

• Keywords
• Helicobacter pylori (H. pylori) infection, children, drug development, pharmacokinetics, urease inhibitors,
• Publication type
• Journal Article MeSH

For decades, treatment of infectious diseases has been a strong focus of interest, for both researchers and healthcare providers. Chronic infection with Helicobacter pylori (H. pylori) has been reported to be associated with several diseases, such as ulcer disease, gastric adenocarcinoma and mucosa-associated lymphoid tissue (MALT) lymphoma. Infection with H. pylori is generally acquired during childhood and can persist indefinitely, if not treated systematically. Unfortunately, although several strategies have shown high efficacy results, treatment of the H. pylori infection fails in about 25%-30% of infected children. One main reason for this is due to the extensive use of antibiotics, which has created antibiotic resistance, associated with other adverse effects as well. Therefore, it is crucial to find alternative strategies to combat this resistance, and increase treatment efficacy results. Probiotics, which are live microorganisms that are orally administrated, have been found to be a useful regimen in the treatment of the H. pylori infection in children. Their use as a dietary supplement alone, or in combination with antibiotics, resulted in reduced side effects and higher efficacy rates of the H. pylori infection in children. Some probiotics can be considered an adjunctive treatment, especially when eradication of the H. pylori infection fails during initial treatment, and to help reduce adverse effects. However, the evidence of the beneficial role of probiotics is limited due to the small number of clinical trials that have been conducted and heterogeneity across studies in strains and dosage. Additionally, no investigations have been carried out in asymptomatic children. Therefore, large well-conducted studies are needed to evaluate the efficacy and safety of probiotics as an adjuvant therapy of the H. pylori infection.

• Keywords
• Helicobacter pylori infection, children, dietary supplements, eradication treatment, probiotics,
• Publication type
• Editorial MeSH