While few studies have revealed the biological properties of brassicasterol, a phytosterol, against some biological and molecular targets, it is believed that there are still many activities yet to be studied. In this work, brassicasterol exerts a therapeutic utility in an in vitro setting against herpes simplex virus type 1 (HSV-1) and Mycobacterium tuberculosis (Mtb) as well as a considerable inhibitory property against human angiotensin-converting enzyme (ACE) that plays a dynamic role in regulating blood pressure. The antireplicative effect of brassicasterol against HSV-1 is remarkably detected (50% inhibitory concentration (IC50): 1.2 µM; selectivity index (SI): 41.7), while the potency of its effect is ameliorated through the combination with standard acyclovir with proper SI (IC50: 0.7 µM; SI: 71.4). Moreover, the capacity of this compound to induce an adequate level of antituberculosis activity against all Mtb strains examined (minimum inhibitory concentration values ranging from 1.9 to 2.4 µM) is revealed. The anti-ACE effect (12.3 µg/mL; 91.2% inhibition) is also ascertained. Molecular docking analyses propose that the mechanisms by which brassicasterol induces anti-HSV-1 and anti-Mtb might be related to inhibiting vital enzymes involved in HSV-1 replication and Mtb cell wall biosynthesis. In summary, the obtained results suggest that brassicasterol might be promising for future anti-HSV-1, antituberculosis, and anti-ACE drug design.

• Keywords
• ACE, HSV, HSV-1 DNA polymerase, HSV-1 TK, Mycobacterium tuberculosis, UDP-galactopyranose mutase, brassicasterol, human CDK2, phytosterols,
• Publication type
• Journal Article MeSH

This study explored the antitubercular properties of fucoxanthin, a marine carotenoid, against clinical isolates of Mycobacterium tuberculosis (Mtb). Two vital enzymes involved in Mtb cell wall biosynthesis, UDP-galactopyranose mutase (UGM) and arylamine-N-acetyltransferase (TBNAT), were selected as drug targets to reveal the mechanism underlying the antitubercular effect of fucoxanthin. The obtained results showed that fucoxanthin showed a clear bacteriostatic action against the all Mtb strains tested, with minimum inhibitory concentrations (MIC) ranging from 2.8 to 4.1 µM, along with a good degree of selectivity index (ranging from 6.1 to 8.9) based on cellular toxicity evaluation compared with standard drug isoniazid (INH). The potent inhibitory actions of fucoxanthin and standard uridine-5'-diphosphate against UGM were recorded to be 98.2% and 99.2%, respectively. TBNAT was potently inactivated by fucoxanthin (half maximal inhibitory concentration (IC50) = 4.8 µM; 99.1% inhibition) as compared to INH (IC50 = 5.9 µM; 97.4% inhibition). Further, molecular docking approaches were achieved to endorse and rationalize the biological findings along with envisaging structure-activity relationships. Since the clinical evidence of the last decade has confirmed the correlation between bacterial infections and autoimmune diseases, in this study we have discussed the linkage between infection with Mtb and autoimmune diseases based on previous clinical observations and animal studies. In conclusion, we propose that fucoxanthin could demonstrate great therapeutic value for the treatment of tuberculosis by acting on multiple targets through a bacteriostatic effect as well as by inhibiting UGM and TBNAT. Such outcomes may lead to avoiding or decreasing the susceptibility to autoimmune diseases associated with Mtb infection in a genetically susceptible host.

• Keywords
• Mycobacterium tuberculosis, UDP-galactopyranose mutase, arylamine-N-acetyltransferase, autoimmunity, fucoxanthin, marine carotenoid, pathogenesis,
• MeSH
• Antitubercular Agents pharmacology   MeSH
• Arylamine N-Acetyltransferase metabolism   MeSH
• Autoimmune Diseases drug therapy   MeSH
• Cell Wall drug effects   enzymology   MeSH
• Cell Line MeSH
• Intramolecular Transferases metabolism   MeSH
• Isoenzymes metabolism   MeSH
• Carotenoids pharmacology   MeSH
• Humans MeSH
• Microbial Sensitivity Tests methods   MeSH
• Mycobacterium tuberculosis drug effects   enzymology   MeSH
• Molecular Docking Simulation methods   MeSH
• Tuberculosis drug therapy   MeSH
• Xanthophylls pharmacology   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Antitubercular Agents MeSH
• Arylamine N-Acetyltransferase MeSH
• fucoxanthin MeSH Browser
• Intramolecular Transferases MeSH
• Isoenzymes MeSH
• Carotenoids MeSH
• N-acetyltransferase 1 MeSH Browser
• UDP-galactopyranose mutase MeSH Browser
• Xanthophylls 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

Psoromic acid (PA), a bioactive lichen-derived compound, was investigated for its inhibitory properties against herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2), along with the inhibitory effect on HSV-1 DNA polymerase, which is a key enzyme that plays an essential role in HSV-1 replication cycle. PA was found to notably inhibit HSV-1 replication (50% inhibitory concentration (IC50): 1.9 μM; selectivity index (SI): 163.2) compared with the standard drug acyclovir (ACV) (IC50: 2.6 μM; SI: 119.2). The combination of PA with ACV has led to potent inhibitory activity against HSV-1 replication (IC50: 1.1 µM; SI: 281.8) compared with that of ACV. Moreover, PA displayed equivalent inhibitory action against HSV-2 replication (50% effective concentration (EC50): 2.7 μM; SI: 114.8) compared with that of ACV (EC50: 2.8 μM; SI: 110.7). The inhibition potency of PA in combination with ACV against HSV-2 replication was also detected (EC50: 1.8 µM; SI: 172.2). Further, PA was observed to effectively inhibit HSV-1 DNA polymerase (as a non-nucleoside inhibitor) with respect to dTTP incorporation in a competitive inhibition mode (half maximal inhibitory concentration (IC50): 0.7 μM; inhibition constant (Ki): 0.3 μM) compared with reference drugs aphidicolin (IC50: 0.8 μM; Ki: 0.4 μM) and ACV triphosphate (ACV-TP) (IC50: 0.9 μM; Ki: 0.5 μM). It is noteworthy that the mechanism by which PA-induced anti-HSV-1 activity was related to its inhibitory action against HSV-1 DNA polymerase. Furthermore, the outcomes of in vitro experiments were authenticated using molecular docking analyses, as the molecular interactions of PA with the active sites of HSV-1 DNA polymerase and HSV-2 protease (an essential enzyme required for HSV-2 replication) were revealed. Since this is a first report on the above-mentioned properties, we can conclude that PA might be a future drug for the treatment of HSV infections as well as a promising lead molecule for further anti-HSV drug design.

• Keywords
• HSV, HSV replication, anti-enzymatic properties, antiherpetic, lichen metabolites, psoromic acid,
• MeSH
• Antiviral Agents * chemistry   pharmacology   MeSH
• Benzoxepins * chemistry   pharmacology   MeSH
• Chlorocebus aethiops MeSH
• DNA-Directed DNA Polymerase * chemistry   metabolism   MeSH
• Nucleic Acid Synthesis Inhibitors chemistry   pharmacology   MeSH
• Carboxylic Acids * chemistry   pharmacology   MeSH
• Humans MeSH
• Herpesvirus 1, Human physiology   MeSH
• Herpesvirus 2, Human physiology   MeSH
• Lichens chemistry   MeSH
• Virus Replication drug effects   MeSH
• Molecular Docking Simulation * MeSH
• Vero Cells MeSH
• Viral Proteins * antagonists & inhibitors   chemistry   metabolism   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Antiviral Agents * MeSH
• Benzoxepins * MeSH
• DNA-Directed DNA Polymerase * MeSH
• Nucleic Acid Synthesis Inhibitors MeSH
• Carboxylic Acids * MeSH
• psoromic acid MeSH Browser
• Viral Proteins * MeSH

Thymus bovei Benth. (TB) is an important plant in the traditional medicine of the Mediterranean region. This study investigates the health-promoting properties of TB essential oil (TB-EO) for its possible use in clinical practice with regards to its cytotoxic, anti-herpes simplex virus type 2 (HSV-2), and antihypertensive (through inhibition of human angiotensin-converting enzyme; ACE) properties. The phytochemical profile of EO (99.9%) was analyzed by Gas Chromatography with Flame-Ionization Detection (GC-FID) and Gas Chromatography-Mass Spectrometry (GC-MS). In this study, all biological methods were performed at the level of in vitro studies. The results showed that TB-EO exerted remarked cytotoxic properties against human cervical carcinoma cells, colon cancer cells, and lung adenocarcinoma cells with the half-maximal inhibitory concentration (IC50) values of 7.22, 9.30, and 8.62 µg/mL, respectively, in comparison with that of standard anticancer drug cisplatin with IC50 values of 4.24, 5.21, and 5.43 µg/mL, respectively. Fascinatingly, TB-EO showed very weak cytotoxicity on the healthy human fetal lung fibroblast cells with an IC50 value of 118.34 µg/mL compared with that of cisplatin (IC50 = 10.08 µg/mL). TB-EO, its main component geraniol, TB-EO combined with acyclovir (ACV) along with standard ACV, have displayed pronounced inhibitory properties against the replication of HSV-2 with the half-maximal effective concentration (EC50) values of 2.13, 1.92, 0.81 and 1.94 µg/mL, respectively, with corresponding selectivity indices (SI) 98.59, 109.38, 259.26 and 108.25, respectively. TB-EO and geraniol at a concentration of 15 µg/mL showed prominent inhibitory activities against ACE with % of inhibition 95.4% and 92.2%, respectively, compared with that of standard inhibitor captopril (99.8%; 15 µg/mL). Molecular docking studies were performed to unveil the mechanism of action of geraniol as well as structural parameters necessary for anti-HSV-2 activity (through the inhibition of HSV-2 protease) and ACE inhibition. This is the first report on the chemical composition of Egyptian TB-EO along with the above-mentioned biological activities. Our results may be considered as novel findings in the course of a search for new and active anticancer, anti-HSV-2 and antihypertensive agents, and expand the medicinal value of this plant and its phytochemicals in clinical practice.

• Keywords
• HSV-2, Thymus bovei Benth., anticancer, antihypertensive, essential oil, phytochemical profile,
• Publication type
• Journal Article MeSH