The urgent need for new classes of orally available, safe, and effective antivirals─covering a breadth of emerging viruses─is evidenced by the loss of life and economic challenges created by the HIV-1 and SARS-CoV-2 pandemics. As frontline interventions, small-molecule antivirals can be deployed prophylactically or postinfection to control the initial spread of outbreaks by reducing transmissibility and symptom severity. Natural products have an impressive track record of success as prototypic antivirals and continue to provide new drugs through synthesis, medicinal chemistry, and optimization decades after discovery. Here, we demonstrate an approach using computational analysis typically used for rational drug design to identify and develop natural product-inspired antivirals. This was done with the goal of identifying natural product prototypes to aid the effort of progressing toward safe, effective, and affordable broad-spectrum inhibitors of Betacoronavirus replication by targeting the highly conserved RNA 2'-O-methyltransferase (2'-O-MTase). Machaeriols RS-1 (7) and RS-2 (8) were identified using a previously outlined informatics approach to first screen for natural product prototypes, followed by in silico-guided synthesis. Both molecules are based on a rare natural product group. The machaeriols (3-6), isolated from the genus Machaerium, endemic to Amazonia, inhibited the SARS-CoV-2 2'-O-MTase more potently than the positive control, Sinefungin (2), and in silico modeling suggests distinct molecular interactions. This report highlights the potential of computationally driven screening to leverage natural product libraries and improve the efficiency of isolation or synthetic analog development.
The bacterium Burkholderia pseudomallei is typically resistant to gentamicin but rare susceptible strains have been isolated in certain regions, such as Thailand and Sarawak, Malaysia. Recently, several amino acid substitutions have been reported in the amrB gene (a subunit of the amrAB-oprA efflux pump gene) that confer gentamicin susceptibility. However, information regarding the mechanism of the substitutions conferring the susceptibility is lacking. To understand the mechanism of amino acid substitution that confers susceptibility, this study identifies the corresponding mutations in clinical gentamicin-susceptible B. pseudomallei isolates from the Malaysian Borneo (n = 46; Sarawak: 5; Sabah: 41). Three phenotypically confirmed gentamicin-susceptible (GENs) strains from Sarawak, Malaysia, were screened for mutations in the amrB gene using gene sequences of gentamicin-resistant (GENr) strains (QEH 56, QEH 57, QEH20, and QEH26) and publicly available sequences (AF072887.1 and BX571965.1) as the comparator. The effect of missense mutations on the stability of the AmrB protein was determined by calculating the average energy change value (ΔΔG). Mutagenesis analysis identified a polymorphism-associated mutation, g.1056 T > G, a possible susceptible-associated in-frame deletion, Delta V412, and a previously confirmed susceptible-associated amino acid substitution, T368R, in each of the three GENs isolates. The contribution of Delta V412 needs further confirmation by experimental mutagenesis analysis. The mechanism by which T368R confers susceptibility, as elucidated by in silico mutagenesis analysis using AmrB-modeled protein structures, is proposed to be due to the location of T368R in a highly conserved region, rather than destabilization of the AmrB protein structure.
The chemical compositions, in vitro and in silico anti-dengue activity of the essential oils of the rhizomes of Curcuma longa Linn., C. aeruginosa Roxb., and C. xanthorrhiza Roxb. had been investigated. The C. longa oil was mainly composed of ar-turmerone (54.0%) and curlone (17.7%), while the C. aeruginosa oil was rich in curzerenone (23.4%), 1,8-cineole (21.2%), and camphor (7.1%). Xanthorrhizol (21.6%), β-curcumene (19.5%), ar-curcumene (14.2%), and camphor (9.2%) were the major compounds in the C. xanthorrhiza oil. Among the oils, the C. longa oil was found to be the most active NSB-NS3 protease inhibitor (IC50 1.98 μg/mL). PLS biplot disclosed that the essential oils were classified into three separated clusters based on their characteristic chemical compositions, with C. longa positioned closest to the in vitro anti-dengue activity. Four compounds from the C. longa oil have both hydrogen and hydrophobic bonds that could be responsible for the DENV-2 NS2B-NS3 inhibitory effect.
Honey clasps several medicinal and health effects as a natural food supplement. It has been established as a potential therapeutic antioxidant agent for various biodiverse ailments. Data report that it exhibits strong wound healing, antibacterial, anti-inflammatory, antifungal, antiviral, and antidiabetic effects. It also retains immunomodulatory, estrogenic regulatory, antimutagenic, anticancer, and numerous other vigor effects. Data also show that honey, as a conventional therapy, might be a novel antioxidant to abate many of the diseases directly or indirectly associated with oxidative stress. In this review, these wholesome effects have been thoroughly reviewed to underscore the mode of action of honey exploring various possible mechanisms. Evidence-based research intends that honey acts through a modulatory road of multiple signaling pathways and molecular targets. This road contemplates through various pathways such as induction of caspases in apoptosis; stimulation of TNF-α, IL-1β, IFN-γ, IFNGR1, and p53; inhibition of cell proliferation and cell cycle arrest; inhibition of lipoprotein oxidation, IL-1, IL-10, COX-2, and LOXs; and modulation of other diverse targets. The review highlights the research done as well as the apertures to be investigated. The literature suggests that honey administered alone or as adjuvant therapy might be a potential natural antioxidant medicinal agent warranting further experimental and clinical research.
Skin tissue engineering has gained significant attention as a promising alternative to traditional treatments for skin injuries. In this study, we developed 3D hydrogel-based scaffolds, Alginate, incorporating different concentrations of Curcumin and evaluated their properties, including morphology, swelling behavior, weight loss, as well as hemo- and cytocompatibility. Furthermore, we investigated the therapeutic potential of Alginate hydrogel containing different amounts of Curcumin using an in vitro wound healing model. The prepared hydrogels exhibited remarkable characteristics, SEM showed that the pore size of hydrogels was 134.64 μm with interconnected pores, making it conducive for cellular infiltration and nutrient exchange. Moreover, hydrogels demonstrated excellent biodegradability, losing 63.5% of its weight over 14 days. In addition, the prepared hydrogels had a stable release of curcumin for 3 days. The results also show the hemocompatibility of prepared hydrogels and a low amount of blood clotting. To assess the efficacy of the developed hydrogels, 3T3 fibroblast growth was examined during various incubation times. The results indicated that the inclusion of Curcumin at a concentration of 0.1 mg/mL positively influenced cellular behavior. The animal study showed that Alginate hydrogel containing 0.1 mg/mL curcumin had high wound closure(more than 80%) after 14 days. In addition, it showed up-regulation of essential wound healing genes, including TGFβ1 and VEGF, promoting tissue repair and angiogenesis. Furthermore, the treated group exhibited down-regulation of MMP9 gene expression, indicating a reduction in matrix degradation and inflammation. The observed cellular responses and gene expression changes substantiate the therapeutic efficacy of prepared hydrogels. Consequently, our study showed the healing effect of alginate-based hydrogel containing Curcumin on skin injuries.
Cancer is a complex disease characterized by dysregulated cell growth and division, posing significant challenges for effective treatment. Hispidulin, a flavonoid compound, has shown promising biological effects, particularly in the field of anticancer research. The main objective of this study is to investigate the anticancer properties of hispidulin and gain insight into its mechanistic targets in cancer cells. A comprehensive literature review was conducted to collect data on the anticancer effects of hispidulin. In vitro and in vivo studies were analyzed to identify the molecular targets and underlying mechanisms through which hispidulin exerts its anticancer activities. Hispidulin has shown significant effects on various aspects of cancer, including cell growth, proliferation, cell cycle regulation, angiogenesis, metastasis, and apoptosis. It has been observed to target both extrinsic and intrinsic apoptotic pathways, regulate cell cycle arrest, and modulate cancer progression pathways. The existing literature highlights the potential of hispidulin as a potent anticancer agent. Hispidulin exhibits promising potential as a therapeutic agent for cancer treatment. Its ability to induce apoptosis and modulate key molecular targets involved in cancer progression makes it a valuable candidate for further investigation. Additional pharmacological studies are needed to fully understand the specific targets and signaling pathways influenced by hispidulin in different types of cancer. Further research will contribute to the successful translation of hispidulin into clinical settings, allowing its utilization in conventional and advanced cancer therapies with improved therapeutic outcomes and reduced side effects.
Sperm quality is preserved through the crucial involvement of antioxidants, which play a vital role in minimizing the occurrence of reactive oxygen species (ROS) during the cryopreservation process. The suitability of the type and concentration of antioxidants are species-dependent, and this study is crucial in order to improve the quality of the climbing perch sperm post-cryopreservation. Therefore, this study aimed to determine the best type and concentration of antioxidants for cryopreservation of climbing perch Anabas testudineus sperm. To achieve this, 6 types of antioxidants, namely, ascorbic acid, beta-carotene, glutathione, butylated hydroxytoluene (BHT), myo-inositol, and alpha-tocopherol, with inclusion of a control were tested in 3 replications at three concentration levels of 0 mg/L (control), 20 mg/L, 40 mg/L, and 60 mg/L. Sperm was diluted in a glucose-base extender at a ratio of 1:60 (sperm: glucose base), then 10 % DMSO and 5 % egg yolk was added before cryopreservation for two weeks. The results showed that the type and concentration of antioxidants had a significant effect on the motility and viability of cryopreserved climbing perch sperm (P
Heparins are a family of sulfated linear negatively charged polysaccharides that have been widely used for their anticoagulant, antithrombotic, antitumor, anti-inflammatory, and antiviral properties. Additionally, it has been used for acute cerebral infarction relief as well as other pharmacological actions. However, heparin's self-aggregated macrocomplex may reduce blood circulation time and induce life-threatening thrombocytopenia (HIT) complicating the use of heparins. Nonetheless, the conjugation of heparin to immuno-stealth biomolecules may overcome these obstacles. An immunostealth recombinant viral capsid protein (VP28) was expressed and conjugated with heparin to form a novel nanoparticle (VP28-heparin). VP28-heparin was characterized and tested to determine its immunogenicity, anticoagulation properties, effects on total platelet count, and risk of inducing HIT in animal models. The synthesized VP28-heparin trimeric nanoparticle was non-immunogenic, possessed an average hydrodynamic size (8.81 ± 0.58 nm) optimal for the evasion renal filtration and reticuloendothelial system uptake (hence prolonging circulating half-life). Additionally, VP28-heparin did not induce mouse death or reduce blood platelet count when administered at a high dosein vivo(hence reducing HIT risks). The VP28-heparin nanoparticle also exhibited superior anticoagulation properties (2.2× higher prothrombin time) and comparable activated partial thromboplastin time, but longer anticoagulation period when compared to unfractionated heparin. The anticoagulative effects of the VP28-heparin can also be reversed using protamine sulfate. Thus, VP28-heparin may be an effective and safe heparin derivative for therapeutic use.
Objective. Gold nanorods (GNRs) have emerged as versatile nanoparticles with unique properties, holding promise in various modalities of cancer treatment through drug delivery and photothermal therapy. In the rapidly evolving field of nanoparticle radiosensitization (NPRS) for cancer therapy, this study assessed the potential of gold nanorods as radiosensitizing agents by quantifying the key features of NPRS, such as secondary electron emission and dose enhancement, using Monte Carlo simulations.Approach. Employing the TOPAS track structure code, we conducted a comprehensive evaluation of the radiosensitization behavior of spherical gold nanoparticles and gold nanorods. We systematically explored the impact of nanorod geometry (in particular size and aspect ratio) and orientation on secondary electron emission and deposited energy ratio, providing validated results against previously published simulations.Main results. Our findings demonstrate that gold nanorods exhibit comparable secondary electron emission to their spherical counterparts. Notably, nanorods with smaller surface-area-to-volume ratios (SA:V) and alignment with the incident photon beam proved to be more efficient radiosensitizing agents, showing superiority in emitted electron fluence. However, in the microscale, the deposited energy ratio (DER) was not markedly influenced by the SA:V of the nanorod. Additionally, our findings revealed that the geometry of gold nanoparticles has a more significant impact on the emission of M-shell Auger electrons (with energies below 3.5 keV) than on higher-energy electrons.Significance. This research investigated the radiosensitization properties of gold nanorods, positioning them as promising alternatives to the more conventionally studied spherical gold nanoparticles in the context of cancer research. With increasing interest in multimodal cancer therapy, our findings have the potential to contribute valuable insights into the perspective of gold nanorods as effective multipurpose agents for synergistic photothermal therapy and radiotherapy. Future directions may involve exploring alternative metallic nanorods as well as further optimizing the geometry and coating materials, opening new possibilities for more effective cancer treatments.
Effects of ketamine and lidocaine on electroencephalographic (EEG) changes were evaluated in minimally anaesthetized dogs, subjected to electric stimulus. Six dogs were subjected to six treatments in a crossover design with a washout period of one week. Dogs were subjected to intravenous boluses of lidocaine 2 mg/kg, ketamine 3 mg/kg, meloxicam 0.2 mg/kg, morphine 0.2 mg/kg and loading doses of lidocaine 2 mg/kg followed by continuous rate infusion (CRI) of 50 and 100 mcg/kg/min, and ketamine 3 mg/kg followed by CRI of 10 and 50 mcg/kg/min. Electroencephalogram was recorded during electrical stimulation prior to any drug treatment (before treatment) and during electrical stimulation following treatment with the drugs (after treatment) under anaesthesia. Anaesthesia was induced with propofol and maintained with halothane at a stable concentration between 0.85 and 0.95%. Pretreatment median frequency was evidently increased (P < 0.05) for all treatment groups. Lidocaine, ketamine, and morphine depressed the median frequency resulting from the posttreatment stimulation. The depression of median frequency suggested evident antinociceptive effects of these treatments in dogs. It is therefore concluded that lidocaine and ketamine can be used in the analgesic protocol for the postoperative pain management in dogs.
The role of carbon monoxide (CO) has evolved albeit controversial disputes on its toxicity. This biological gasotransmitter participates in the endogenous regulation of neurotransmitters and neuropeptides released in the nervous system. Exogenous CO gas inhalation at a lower concentration has been the subject of investigations, which have revealed its biological homeostatic mechanisms and protective effects against many pathological conditions. This therapeutic procedure of CO is, however, limited due to its immediate release, which favours haemoglobin at a high affinity with the subsequent generation of toxic carboxyhaemoglobin in tissues. In order to address this problem, carbon monoxide releasing molecule-2 (CORM-2) or also known as tricarbonyldichlororuthenium II dimer is developed to liberate a controlled amount of CO in the biological systems. In this review, we examine several potential mechanisms exerted by this therapeutic compound to produce the anti-nociceptive effect that has been demonstrated in previous studies. This review could shed light on the role of CORM-2 to reduce pain, especially in cases of chronic and neuropathic pain.
Two new bisanthraquinones, glabraquinone A and B (1-2) were isolated from the root of Prismatomeris glabra (Korth.) Valeton. In addition to the new glabraquinones, six known anthraquinones, that is, 1-hydroxy-2-methoxy-6-methylanthraquinone (3), 1,2-dimethoxy-7-methylanthraquinone (4), lucidin (5), nordamnacanthal (6), damnacanthal (7) and 2-carboxaldehyde-3-hydroxyanthraquinone (8)) and an aromatic compound, that is, catechol diethyl ether (9) were isolated and characterized in this study. Compounds 1, 4 and 9 showed mild activity, reducing N2A cell viability to 77%, 82% and 77%, respectively, in anti-neuroblastoma assay.
Piceatannol is a naturally occurring hydroxylated resveratrol analogue that can be found in a variety of fruits and vegetables. It has been documented to have a wide range of beneficial effects, including anti-inflammatory, antioxidant, anti-aging, anti-allergic, antidiabetic, neuroprotective, cardioprotective, and chemopreventive properties. Piceatannol has significantly higher antioxidant activity than resveratrol. Piceatannol has been shown in preclinical studies to have the ability to inhibit or reduce the growth of cancers in various organs such as the brain, breast, lung, colon, cervical, liver, prostate, and skin. However, the bioavailability of Piceatannol is comparatively lower than resveratrol and other stilbenes. Several approaches have been reported in recent years to enhance its bioavailability and biological activity, and clinical trials are required to validate these findings. This review focuses on several aspects of natural stilbene Piceatannol, its chemistry, and its mechanism of action, and its promising therapeutic potential for the prevention and treatment of a wide variety of complex human diseases.
In Singapore, dose-response bioassays of Aedes aegypti (L.) adults have been conducted, but the mechanisms underlying resistance to insecticides remain unclear. In this study, we evaluated insecticide resistance and its underlying mechanism in field populations of Ae. aegypti adults.
Curcuma longa L. (Zingiberaceae family) and its polyphenolic compound curcumin have been subjected to a variety of antimicrobial investigations due to extensive traditional uses and low side effects. Antimicrobial activities for curcumin and rhizome extract of C. longa against different bacteria, viruses, fungi, and parasites have been reported. The promising results for antimicrobial activity of curcumin made it a good candidate to enhance the inhibitory effect of existing antimicrobial agents through synergism. Indeed, different investigations have been done to increase the antimicrobial activity of curcumin, including synthesis of different chemical derivatives to increase its water solubility as well ass cell up take of curcumin. This review aims to summarize previous antimicrobial studies of curcumin towards its application in the future studies as a natural antimicrobial agent.
Five Malaysian isolates of the protozoan Plasmodium falciparum Welch were cultured in vitro following the method of Trager and Jensen (1976, 1977) and subsequently cloned using the limiting dilution method of Rosario (1981). Thirty clones were obtained and were later characterized against schizontocidal drugs, chloroquine, mefloquine and quinine, using the modified in vitro microtechnique. Results showed that these local isolates were heterogeneous and most of the clones exhibited similar pattern of susceptibility as their parent isolate except for ST 168 clone and two ST 195 clones that were sensitive but two ST 165 clones, two ST 168 clones and five ST 195 clones were resistant against quinine, respectively. Results also indicated that they were pure clones compared to their parent isolate because their drug susceptibility studies were significantly different (p < 0.05).
1. The aim of this study was to investigate the effect of repeated exposure to stress on tail blood pressure (TBP) of normal as well as GCA (glycyrrhizic acid) and steroid treated rats. Male Sprague-Dawley rats (250 g) were exposed to ether vapour to achieve light anaesthesia prior to TBP recording. Rats were injected with either normal saline or naloxone prior to exposure to stress. Tail blood pressure was recorded daily for 2 weeks. 2. We found that ether stress caused a transient drop in TBP in control as well as in dexamethasone (DEX) treated rats. The stress-induced fall in blood pressure was reduced by naloxone in control rats but not in DEX treated rats. However the transient drop in TBP following stress was not seen in either GCA or deoxycorticosterone (DOC) treated rats. 3. We conclude that first, the reduction in TBP was due to the release of endogenous opioids caused by stress. Second, DOC may block the release of such endogenous opioids, preventing the drop in TBP in response to stress, while DEX did not. Third, GCA caused a similar mineralocorticoid effect on reversing stress induced hypotension.
Cardiac glycosides (CGs) are a class of naturally occurring steroid-like compounds, and members of this class have been in clinical use for more than 1500 years. They have been used in folk medicine as arrow poisons, abortifacients, heart tonics, emetics, and diuretics as well as in other applications. The major use of CGs today is based on their ability to inhibit the membrane-bound Na+/K+-ATPase enzyme, and they are regarded as an effective treatment for congestive heart failure (CHF), cardiac arrhythmia and atrial fibrillation. Furthermore, increasing evidence has indicated the potential cytotoxic effects of CGs against various types of cancer. In this review, we highlight some of the structural features of this class of natural products that are crucial for their efficacy, some methods of isolating these compounds from natural resources, and the structural elucidation tools that have been used. We also describe their physicochemical properties and several modern biotechnological approaches for preparing CGs that do not require plant sources.
As synthetic antioxidants that are widely used in foods are known to cause detrimental health effects, studies on natural additives as potential antioxidants are becoming increasingly important. In this work, the total phenolic content (TPC) and antioxidant activity of Ficus carica Linn latex from 18 cultivars were investigated. The TPC of latex was calculated using the Folin-Ciocalteu assay. 1,1-Diphenyl-2-picrylhydrazyl (DPPH), 2,2'-azinobis-(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) and ferric ion reducing antioxidant power (FRAP) were used for antioxidant activity assessment. The bioactive compounds from F. carica latex were extracted via maceration and ultrasound-assisted extraction (UAE) with 75% ethanol as solvent. Under the same extraction conditions, the latex of cultivar 'White Genoa' showed the highest antioxidant activity of 65.91% ± 1.73% and 61.07% ± 1.65% in DPPH, 98.96% ± 1.06% and 83.04% ± 2.16% in ABTS, and 27.08 ± 0.34 and 24.94 ± 0.84 mg TE/g latex in FRAP assay via maceration and UAE, respectively. The TPC of 'White Genoa' was 315.26 ± 6.14 and 298.52 ± 9.20 µg GAE/mL via the two extraction methods, respectively. The overall results of this work showed that F. carica latex is a potential natural source of antioxidants. This finding is useful for further advancements in the fields of food supplements, food additives and drug synthesis in the future.
Melioidosis is a potentially fatal disease caused by the saprophytic bacterium Burkholderia pseudomallei. Resistance to gentamicin is generally a hallmark of B. pseudomallei, and gentamicin is a selective agent in media used for diagnosis of melioidosis. In this study, we determined the prevalence and mechanism of gentamicin susceptibility found in B. pseudomallei isolates from Sarawak, Malaysian Borneo. We performed multilocus sequence typing and antibiotic susceptibility testing on 44 B. pseudomallei clinical isolates from melioidosis patients in Sarawak district hospitals. Whole-genome sequencing was used to identify the mechanism of gentamicin susceptibility. A novel allelic-specific PCR was designed to differentiate gentamicin-sensitive isolates from wild-type B. pseudomallei. A reversion assay was performed to confirm the involvement of this mechanism in gentamicin susceptibility. A substantial proportion (86%) of B. pseudomallei clinical isolates in Sarawak, Malaysian Borneo, were found to be susceptible to the aminoglycoside gentamicin, a rare occurrence in other regions where B. pseudomallei is endemic. Gentamicin sensitivity was restricted to genetically related strains belonging to sequence type 881 or its single-locus variant, sequence type 997. Whole-genome sequencing identified a novel nonsynonymous mutation within amrB, encoding an essential component of the AmrAB-OprA multidrug efflux pump. We confirmed the role of this mutation in conferring aminoglycoside and macrolide sensitivity by reversion of this mutation to the wild-type sequence. Our study demonstrates that alternative B. pseudomallei selective media without gentamicin are needed for accurate melioidosis laboratory diagnosis in Sarawak. This finding may also have implications for environmental sampling of other locations to test for B. pseudomallei endemicity.