Unveiling the Antiviral Efficacy of Forskolin: A Multifaceted In Vitro and In Silico Approach.

Coleus forskohlii (Willd.) Briq. is a medicinal herb of the Lamiaceae family. It is native to India and widely present in the tropical and sub-tropical regions of Egypt, China, Ethiopia, and Pakistan. The roots of C. forskohlii are edible, rich with pharmaceutically bioactive compounds, and traditionally reported to treat a variety of diseases, including inflammation, respiratory disorders, obesity, and viral ailments. Notably, the emergence of viral diseases is expected to quickly spread; consequently, these data impose a need for various approaches to develop broad active therapeutics for utilization in the management of future viral infectious outbreaks. In this study, the naturally occurring labdane diterpenoid derivative, Forskolin, was obtained from Coleus forskohlii. Additionally, we evaluated the antiviral potential of Forskolin towards three viruses, namely the herpes simplex viruses 1 and 2 (HSV-1 and HSV-2), hepatitis A virus (HAV), and coxsackievirus B4 (COX-B4). We observed that Forskolin displayed antiviral activity against HAV, COX-B4, HSV-1, and HSV-2 with IC50 values of 62.9, 73.1, 99.0, and 106.0 µg/mL, respectively. Furthermore, we explored the Forskolin's potential antiviral target using PharmMapper, a pharmacophore-based virtual screening platform. Forskolin's modeled structure was analyzed to identify potential protein targets linked to its antiviral activity, with results ranked based on Fit scores. Cathepsin L (PDB ID: 3BC3) emerged as a top-scoring hit, prompting further exploration through molecular docking and MD simulations. Our analysis revealed that Forskolin's binding mode within Cathepsin L's active site, characterized by stable hydrogen bonding and hydrophobic interactions, mirrors that of a co-crystallized inhibitor. These findings, supported by consistent RMSD profiles and similar binding free energies, suggest Forskolin's potential in inhibiting Cathepsin L, highlighting its promise as an antiviral agent.

Oligomeric Proanthocyanidin Complex from Avocado Seed as A Promising α-glucosidase Inhibitor: Characteristics and Mechanisms.

Although considered an abundant source of agricultural by-products, avocado (Persea americana Mill.) seed, with several biological activities and bioactive components, might become a promising resource for phytopharmaceutical development. In this study, through bioassay-guided isolation of the main α-glucosidase inhibitors in avocado seed, we discovered the major α-glucosidase inhibitor to be avocado seed oligomeric proanthocyanidin complex (ASOPC). Thiolysis and UPLC-DAD-HRESIMS showed the presence of A- and B-type procyanidins, and B-type propelargonidin with (epi)afzelechin as extension unit. Mean degree of polymerization (mDP) of ASOPC was calculated as 7.3 ± 1. Furthermore, ASOPC appeared to be a strong, reversible, competitive inhibitor of α-glucosidase, with IC50 value of 0.1 µg/mL, which was significantly lower than Acarbose (IC50 = 75.6 µg/mL), indicated that ASOPC is a potential natural α-glucosidase inhibitor. These findings would contribute to the direction of utilizing avocado seed bioactive components with the possibility to be used as natural anti-diabetic agents.

Undescribed glucosylceramide, flavonol triglycoside, and oleanane saponin from the halophyte Agathophora alopecuroides: Promising candidates for stimulating ceramide synthesis.

The phytochemical study of Agathophora alopecuroides (Chenopodiaceae) led to the isolation of previously undescribed glucosylceramide, flavonol triglycoside, and triterpene oleanane saponin, together with eight known compounds. Their structures were elucidated using NMR analysis and HR-MS as (2'R, 12E) N-[(2S, 3S, 4R)-1-(ß-D-glucopyranosyloxy)-3,4-dihydroxy-octadec-2-yl]-2-hydroxytetracos-12-enamide, namely Agathophamide A; isorhamnetin-3-O-[ß-D-xylopyranosyl-(1→3)-α-L-rhamnopyranosyl-(1→6)]-ß-D-galactopyranoside, namely Agathophoroside A; and 3-O-[4'-(ß-D-xylopyranosyl)-ß-D-glucuronopyranosyl]-28-O-ß-D-glucopyranosyl-olean-12-en-3ß-ol-28-oic acid, namely Solysaponin A. We evaluated the effect of extract and isolates on ceramide levels via the up-regulated expression of the enzyme for ceramide synthesis in HaCaT keratinocytes. Interestingly, the study results revealed that the methanol extract of A. alopecuroides, together with some isolated compounds significantly up-regulated the mRNA expression of ceramide synthase-3 by 1.2- to 4.3-fold compared with the control in HaCaT cells. These findings indicate that the halophyte A. alopecuroides is a promising source of candidate compounds that can contribute to ceramide synthesis via the up-regulated expression levels of ceramide synthase-3 in the ceramide synthesis pathway.

A novel acylated flavonol tetraglycoside and rare oleanane saponins with a unique acetal-linked dicarboxylic acid substituent from the xero-halophyte Bassia indica.

In recent years, the scientific interest and particularly the economic significance of halophytic plants has been highly demanding due to the medicinal and nutraceutical potential of its bioactive compounds. A xero-halophyte Bassia indica is deemed to be a very cheap source of natural entities without chemical or biological investigation. In this context, a new acylated flavonol tetraglycoside, kaempferol-3-O-ß-d-glucopyranosyl-(1→6)-O-[ß-D-galactopyranosyl-(1→3)-2-O-trans-feruloyl-α-L-rhamnopyranosyl-(1→2)]-ß-D-glucopyranoside (14), together with rare occurring flavonol triglycoside, isorhamnetin-3-O-ß-d-glucopyranosyl-(1→6)-O-[α-L-rhamnopyranosyl-(1→2)]-ß-D-glucopyranoside (15), were isolated from the aqueous methanol extract of the aerial parts of B. indica. The study also reported an optimal separation and characterization of a new seco-glycosidic oleanane saponin with 2'R,3'S stereocenters, identified as (2'R,3'S)-3-O-[2'-hydroxy-3'-(2"-O-glycolyl)-oxo-propionic acid-ß-D-glucuronopyranosyl]-28-O-ß-D-glucopyranosyl-olean-12-en-3ß-ol-28-oic acid (17), in addition to its derivative, 3-O-[2'-(2"-O-glycolyl)-glyoxylyl-ß-D-glucuronopyranosyl]-28-O-ß-d-glucopyranosyl-olean-12-en-3ß-ol-28-oic acid (16). The structures of all isolated compounds were elucidated based on 1D, 2D NMR, and HR-MS analysis, as well as comparing with similar derivatives published in the literature. Furthermore, thirteen known compounds were isolated and identified as ß-sitosterol (1), vanillic acid (2), o-hydroxybenzoic acid (3), р-hydroxybenzoic acid (4), 6,7-dihydroxycoumarin (5), methyl caffeate (6), caffeic acid (7), quercetin (8), uracil (9), thymidine (10), tachioside (11), isorhamnetin-3-O-ß-D-glucopyranoside (12), kaempferol-3-O-rutinoside (13). The anticholinesterase activity of all isolated compounds was evaluated.

Effect of Preperitoneal Versus Epidural Analgesia on Postoperative Inflammatory Response and Pain Following Radical Cystectomy: A Prospective, Randomized Trial.

OBJECTIVES: Continuous wound infiltration of local anesthetics has been proposed as an alternative to epidural analgesia during abdominal surgery. Cytokines have a major role in inflammatory changes caused by surgery. This study aimed to compare the effects of continuous preperitoneal versus epidural analgesia on inflammatory cytokines postoperatively. MATERIALS AND METHODS: Forty patients scheduled for radical cystectomy were included in this observer-blinded, randomized trial; patients were randomly assigned into 2 groups to receive; continuous preperitoneal wound infiltration (PPB) or epidural analgesia (EDB). Serum levels of interleukins (IL1ß, IL6, IL10, and tumor necrosis factor α) were measured at baseline (before induction of anesthesia), preinfusion (before the start of local anesthetic infusion), 6 and 24 hours postoperatively. Visual Analog Scale at rest/movement (VAS-R/M), time to the first request of analgesia, total morphine consumption, sedation score, hemodynamics, and side effects were observed 24 hours postoperatively. RESULTS: There was a significant reduction in IL6, IL1ß and increase in IL10 in PPB compared with EDB at 6 and 24 hours postoperatively and compared with preinfusion levels (P≤0.001). In EDB, a significant increase in IL1ß, IL10, and tumor necrosis factor α at 6 hours compared with preinfusion levels (P≤0.002). VAS-R/M was significantly decreased at 2, 4, 6, 8, and 12 hours in EDB compared with PPB (P≤0.014), with no significant difference in the mean time to the first request of analgesia and total morphine consumption between the 2 groups. CONCLUSION: Continuous preperitoneal analgesia better attenuated postoperative inflammatory response and provided a comparable overall analgesia to that with continuous epidural analgesia following radical cystectomy.

Azithromycin to prevent bronchopulmonary dysplasia in ureaplasma-infected preterm infants: pharmacokinetics, safety, microbial response, and clinical outcomes with a 20-milligram-per-kilogram single intravenous dose.

Ureaplasma respiratory tract colonization is associated with bronchopulmonary dysplasia (BPD) in preterm infants. Previously, we demonstrated that a single intravenous (i.v.) dose of azithromycin (10 mg/kg of body weight) is safe but inadequate to eradicate Ureaplasma spp. in preterm infants. We performed a nonrandomized, single-arm open-label study of the pharmacokinetics (PK) and safety of intravenous 20-mg/kg single-dose azithromycin in 13 mechanically ventilated neonates with a gestational age between 24 weeks 0 days and 28 weeks 6 days. Pharmacokinetic data from 25 neonates (12 dosed with 10 mg/kg i.v. and 13 dosed with 20 mg/kg i.v.) were analyzed using a population modeling approach. Using a two-compartment model with allometric scaling of parameters on body weight (WT), the population PK parameter estimates were as follows: clearance, 0.21 liter/h × WT(kg)(0.75) [WT(kg)(0.75) indicates that clearance was allometrically scaled on body weight (in kilograms) with a fixed exponent of 0.75]; intercompartmental clearance, 2.1 liters/h × WT(kg)(0.75); central volume of distribution (V), 1.97 liters × WT (kg); and peripheral V, 17.9 liters × WT (kg). There was no evidence of departure from dose proportionality in azithromycin exposure over the tested dose range. The calculated area under the concentration-time curve over 24 h in the steady state divided by the MIC90 (AUC24/MIC90) for the single dose of azithromycin (20 mg/kg) was 7.5 h. Simulations suggest that 20 mg/kg for 3 days will maintain azithromycin concentrations of >MIC50 of 1 µg/ml for this group of Ureaplasma isolates for ≥ 96 h after the first dose. Azithromycin was well tolerated with no drug-related adverse events. One of seven (14%) Ureaplasma-positive subjects and three of six (50%) Ureaplasma-negative subjects developed physiologic BPD. Ureaplasma was eradicated in all treated Ureaplasma-positive subjects. Simulations suggest that a multiple-dose regimen may be efficacious for microbial clearance, but the effect on BPD remains to be determined.