Preparation and Preliminary Structure-Activity Relationship Studies of Schwarzinicine A Analogs as Vasorelaxant Agents.

Schwarzinicines A-D, a series of alkaloids recently discovered from Ficus schwarzii, exhibit pronounced vasorelaxant activity in rat isolated aorta. Building on this finding, a concise synthesis of schwarzinicines A and B has been reported, allowing further investigations into their biological properties. Herein, a preliminary exploration of the chemical space surrounding the structure of schwarzinicine A (1) was carried out aiming to identify structural features that are essential for vasorelaxant activity. A total of 57 analogs were synthesized and tested for vasorelaxant activity in rat isolated aorta. Both efficacy (Emax) and potency (EC50) of these analogs were compared. In addition to identifying structural features that are required for activity or associated with potency enhancement effect, four analogs showed significant potency improvements of up to 40.2-fold when compared to 1. Molecular dynamics simulation of a tetrameric 44-bound transient receptor potential canonical-6 (TRPC6) protein indicated that 44 could potentially form important interactions with the residues Glu509, Asp530, Lys748, Arg758, and Tyr521. These results may serve as a foundation for guiding further structural optimization of the schwarzinicine A scaffold, aiming to discover even more potent analogs.

Microplastic concentrations in river water and bed sediments in a tropical river: implications for water quality monitoring.

Recent increase in awareness of the extent of microplastic contamination in marine and freshwater systems has heightened concerns over the ecological and human health risks of this ubiquitous material. Assessing risks posed by microplastic in freshwater systems requires sampling to establish contamination levels, but standard sampling protocols have yet to be established. An important question is whether sampling and assessment should focus on microplastic concentrations in the water or the amount deposited on the bed. On three dates, five replicated water and bed sediment samples were collected from each of the eight sites along the upper reach of the Semenyih River, Malaysia. Microplastics were found in all 160 samples, with mean concentrations of 3.12 ± 2.49 particles/L in river water and 6027.39 ± 16,585.87 particles/m2 deposited on the surface of riverbed sediments. Fibres were the dominant type of microplastic in all samples, but fragments made up a greater proportion of the material on the bed than in the water. Within-site variability in microplastic abundance was high for both water and bed sediments, and very often greater than between-site variability. Patterns suggest that microplastic accumulation on the bed is spatially variable, and single samples are therefore inadequate for assessing bed contamination levels at a site. Sites with the highest mean concentrations in samples of water were not those with the highest concentrations on the bed, indicating that monitoring based only on water samples may not provide a good picture of either relative or absolute bed contamination levels, nor the risks posed to benthic organisms.

Relative contributions of different local sources to riverborne microplastic in a mixed landuse area within a tropical catchment.

Information on the relative contributions of microplastics coming from different sources is important to help prioritise measures to reduce river contamination levels and limit human and ecological health risks. This paper reports on work which aimed to quantitatively assess the relative concentrations and types of microplastic delivered from differed sources to a second order river. The study was undertaken in a mixed landuse area within a rapidly urbanising catchment in Malaysia. Over a six-week period, water samples were collected from road culverts and drains in residential and industrial areas across the area to assess microplastic concentrations, while inputs from atmospheric deposition and wastewater treatment plants (WWTPs) were also quantified. Microplastic fibres and fragments were the dominant material in all sources, with the majority consisting of styrene-butadiene rubber and nylon. Culverts draining main roads were the main contributor to riverborne microplastic, delivering 42.20 ± 35.29 particles/L directly to the river channel. Road inputs were up to seven times greater than those from residential (8.53 ± 9.91 particles/L) and industrial (5.67 ± 4.88 particles/L) areas. The five WWTPs had removal efficiencies of between 30.95 ± 5.51% and 69.94 ± 22.17%, with their outflows delivering microplastics to the river in concentrations similar to those in uncontrolled residential and industrial drains. Atmospheric deposition across the study area was estimated to be 76.07 ± 32.85 particles/m2/day (=8.35 ± 5.11 particles/L). Mitigation strategies in the study area should focus on improving management of water draining roads, and re-routing discharges from domestic and industrial areas to WWTPs rather than allowing them to flow directly to the river. The low efficiencies of some of the WWTPs are not unusual, and indicate the need for additional water treatment to deal with microplastic present in wastewater.

Schwarzinicine A inhibits transient receptor potential canonical channels and exhibits overt vasorelaxation effects.

This study investigated the vasorelaxant effects of schwarzinicine A, an alkaloid recently reported from Ficus schwarzii Koord. Regulation of calcium homeostasis in vascular smooth muscle cells (VSMC) is viewed as one of the main mechanisms for controlling blood pressure. L-type voltage-gated calcium channel (VGCC) blockers are commonly used for controlling hypertension. Recently, the transient receptor potential canonical (TRPC) channels were found in blood vessels of different animal species with evidence of their roles in the regulation of vascular contractility. In this study, we studied the mechanism of actions of schwarzinicine A focusing on its regulation of L-type VGCC and TRPC channels. Schwarzinicine A exhibited the highest vasorelaxant effect (123.1%) compared to other calcium channel blockers. It also overtly attenuated calcium-induced contractions of the rat isolated aortae in a calcium-free environment showing its mechanism to inhibit calcium influx. Fluorometric intracellular calcium recordings confirmed its inhibition of hTRPC3-, hTRPC4-, hTRPC5- and hTRPC6-mediated calcium influx into HEK cells with IC50 values of 3, 17, 19 and 7 µM, respectively. The evidence gathered in this study suggests that schwarzinicine A blocks multiple TRPC channels and L-type VGCC to exert a significant vascular relaxation response.

Intracellular and exosomal microRNAome profiling of human vascular smooth muscle cells during replicative senescence.

Vascular aging is highly associated with cardiovascular morbidity and mortality. Although the senescence of vascular smooth muscle cells (VSMCs) has been well established as a major contributor to vascular aging, intracellular and exosomal microRNA (miRNA) signaling pathways in senescent VSMCs have not been fully elucidated. This study aimed to identify the differential expression of intracellular and exosomal miRNA in human VSMCs (hVSMCs) during replicative senescence. To achieve this aim, intracellular and exosomal miRNAs were isolated from hVSMCs and subsequently subjected to whole genome small RNA next-generation sequencing, bioinformatics analyses, and qPCR validation. Three significant findings were obtained. First, senescent hVSMC-derived exosomes tended to cluster together during replicative senescence and the molecular weight of the exosomal protein tumor susceptibility gene 101 (TSG-101) increased relative to the intracellular TSG-101, suggesting potential posttranslational modifications of exosomal TSG-101. Second, there was a significant decrease in both intracellular and exosomal hsa-miR-155-5p expression [n = 3, false discovery rate (FDR) < 0.05], potentially being a cell type-specific biomarker of hVSMCs during replicative senescence. Importantly, hsa-miR-155-5p was found to associate with cell-cycle arrest and elevated oxidative stress. Lastly, miRNAs from the intracellular pool, that is, hsa-miR-664a-3p, hsa-miR-664a-5p, hsa-miR-664b-3p, hsa-miR-4485-3p, hsa-miR-10527-5p, and hsa-miR-12136, and that from the exosomal pool, that is, hsa-miR-7704, were upregulated in hVSMCs during replicative senescence (n = 3, FDR < 0.05). Interestingly, these novel upregulated miRNAs were not functionally well annotated in hVSMCs to date. In conclusion, hVSMC-specific miRNA expression profiles during replicative senescence potentially provide valuable insights into the signaling pathways leading to vascular aging.NEW & NOTEWORTHY This is the first study on intracellular and exosomal miRNA profiling on human vascular smooth muscle cells during replicative senescence. Specific dysregulated sets of miRNAs were identified from human vascular smooth muscle cells. Hsa-miR-155-5p was significantly downregulated in both intracellular and exosomal hVSMCs, suggesting its crucial role in cellular senescence. Hsa-miR-155-5p might be the mediator in linking cellular senescence to vascular aging and atherosclerosis.

Monomeric, Dimeric, and Trimeric Tropane Alkaloids from Pellacalyx saccardianus.

Seven new tropane alkaloids, including five monomeric (1-5), one dimeric (6), and one trimeric (7) 3α-nortropane ester, along with two known monomeric nortropane alkaloids (8 and 9), were isolated from the leaves and bark of Pellacalyx saccardianus. Their structures, including the absolute configuration of the enantiomeric pair of (±)-6, were elucidated by comprehensive spectroscopic analyses. Alkaloids 6 and 7 showed cytotoxicity toward human pancreatic cancer cell lines (AsPC-1, BxPC3, PANC-1, and SW1990). Alkaloids 1, 4, and 9 induced a smooth muscle relaxation effect comparable to that of atropine (Emax 106.1 ± 7.5%, 97.0 ± 5.2%, 100.9 ± 1.4%, 111.7 ± 1.7%, respectively) on isolated rat tracheal rings.

Schwarzinicines A-G, 1,4-Diarylbutanoid-Phenethylamine Conjugates from the Leaves of Ficus schwarzii.

Schwarzinicines A-G (1-7), representing the first examples of 1,4-diarylbutanoid-phenethylamine conjugates, were isolated from the leaves of Ficus schwarzii. The structures of these compounds were determined by detailed analysis of their MS, 1D and 2D NMR data. Compounds 1-4 exhibited pronounced vasorelaxant effects in the rat isolated aorta (Emax 106-120%; EC50 0.96-2.10 µM). However, compounds 1 and 2 showed no cytotoxic effects against A549, MCF-7, and HCT 116 human cancer cells (IC50 > 10 µM).

Virucidal activity of Garcinia parvifolia leaf extracts in animal cell culture.

BACKGROUND: Garcinia species contain bioactive compounds such as flavonoids, xanthones, triterpernoids, and benzophenones with antibacterial, antifungal, anti-inflammatory, and antioxidant activities. In addition, many of these compounds show interesting biological properties such as anti-human immunodeficiency virus activity. Garcinia parvifolia is used in traditional medicine. Currently, the antiviral activity of G. parvifolia is not known. METHODS: This study was conducted to determine the effects of ethyl acetate (45 L Ea), ethanol (45 L Et), and hexane (45 L H) leaf extracts of G. parvifolia on the infectivity of pseudorabies virus (PrV) in Vero cells. The antiviral effects of the extracts were determined by cytopathic effect (CPE), inhibition, attachment, and virucidal assays. RESULTS: The 50% cytotoxicity concentration (CC50) values obtained were 237.5, 555.0, and < 1.25 µg/mL for 45 L Ea, 45 L Et, and 45 L H, respectively. The 45 L Ea showed the greatest viral inhibition potency of 75% at 125 µg/mL. Both 45 L Ea and 45 l Et caused 100% residual viral inhibition at 250 µg/mL. The selectivity index values for 45 L Ea, 45 L Et, and 45 L H were 2.65, 1.75, and 0.10 showing that 45 L Ea had the greatest antiviral activity among the three extracts. CONCLUSION: This study showed that ethyl acetate is the best solvent to be used to obtain extract from G. parvifolia leaves with potent antiviral activities.

Prevention of cell-surface attachment and reduction of penicillin-binding protein 2a (PBP2a) level in methicillin-resistant Staphylococcus aureus biofilms by Acalypha wilkesiana.

BACKGROUND: Formation of biofilm is known to enhance the virulence of methicillin-resistance Staphylococcus aureus (MRSA), which is associated with persistent infections in hospital settings. The biofilm layer essentially forms a protective barrier encapsulating the bacterial colony and thus reduces the effectiveness of chemotherapeutics. We have isolated 9EA-FC-B bioactive fraction from Acalypha wilkesiana Müll. Arg. that reverses ampicillin resistant in MRSA through inhibition of the antibiotic resistant protein, penicillin-binding protein 2a (PBP2a). In this study, we aimed to investigate the effects of 9EA-FC-B on MRSA biofilm forming capacity. METHODS: Inhibition of biofilm production and microtiter attachment assays were employed to study the anti-biofilm activity of 9EA-FC-B, while latex agglutination test was performed to investigate the effect on PBP2a in the biofilm matrix. We also attempted to characterise the chemical components of the fraction using high performance liquid chromatography (HPLC) and phytochemical analysis. RESULTS: Fraction 9EA-FC-B and ampicillin exhibited similar inhibitory effect on MRSA's biofilm production at their respective minimum inhibitory concentrations (81.56% vs 84.49%, respectively). However, the test fraction was more effective in suppressing cell surface attachment (90.85%) compared to ampicillin (37.8%). Interestingly, ampicillin enhanced the level PBP2a and in the contrary 9EA-FC-B attenuated the production of the resistant protein in the bioflim matrix. HPLC and phytochemical analysis revealed that 9EA-FC-B fraction is a complex mixture containing tannins, saponins, sterol/steroids, and glycosides. CONCLUSIONS: Bioactive fraction 9EA-FC-B inhibited the production of MRSA biofilm by preventing the initial cell-surface attachment and reducing the amount PBP2a in the matrix. PBP2a found in the biofilm matrix is believed to have a role in the development of virulence in MRSA.

Inhibition of penicillin-binding protein 2a (PBP2a) in methicillin resistant Staphylococcus aureus (MRSA) by combination of ampicillin and a bioactive fraction from Duabanga grandiflora.

BACKGROUND: The inhibition of penicillin-binding protein 2a (PBP2a) is a promising solution in overcoming resistance of methicillin resistance Staphylococcus aureus (MRSA). A potential approach in achieving this is by combining natural product with currently available antibiotics to restore the activity as well as to amplify the therapeutic ability of the drugs. We studied inhibition effects of a bioactive fraction, F-10 (isolated from the leaves of Duabanga grandiflora) alone and in combination with a beta-lactam drug, ampicillin on MRSA growth and expression of PBP2a. Additionally, phytochemical analysis was conducted on F-10 to identify the classes of phytochemicals present. METHODS: Fractionation of the ethyl acetate leaf extract was achieved by successive column chromatography which eventually led to isolation of an active fraction, F-10. Both extract and F-10 were analyzed for the presence of major classes of phytochemicals in addition to obtaining a high performance liquid chromatography (HPLC) profile to reveal the complexity of the fraction F-10. Broth microdilution method was employed to determine minimum inhibitory concentration (MIC) of the extract and fractions against MRSA. Evaluation of synergistic activity of the active fraction with ampicillin was determined using checkerboard methodand kinetic growth experiments. Effect of combination treatments on expression of PBP2a, a protein that confers resistance to beta-lactam antibiotics, was elucidated with the Western blot assay. RESULTS: MIC of F-10 against MRSA was 750 mg/L which showed an improved activity by 4-fold compared to its crude extract (MIC = 3000 mg/L). Phytochemical analysis revealed occurrence of tannins, saponin, flavonoids, sterols, and glycosides in F10 fraction. In FIC index interpretation, the most synergistic activity was achieved for combinations of 1/64 × MIC ampicillin + 1/4 × MIC F-10. The combination also evidently inhibited MRSA growth in kinetic growth curve assay. As a result of this synergistic interaction, MIC of ampicillin against MRSA was reduced to 0.78 mg/L (64-fold) from initial value of 50 mg/L. Western blot analysis suggested inhibition of PBP2a in MRSA cultures grown in synergistic combination treatment in which no PBP2a band was expressed. CONCLUSIONS: The results demonstrated synergism between fraction F-10 of D. grandiflora with ampicillin in suppressing MRSA growth via PBP2a inhibition.

Inhibitory effect of Duabanga grandiflora on MRSA biofilm formation via prevention of cell-surface attachment and PBP2a production.

Formation of biofilms is a major factor for nosocomial infections associated with methicillin-resistance Staphylococcus aureus (MRSA). This study was carried out to determine the ability of a fraction, F-10, derived from the plant Duabanga grandiflora to inhibit MRSA biofilm formation. Inhibition of biofilm production and microtiter attachment assays were employed to study the anti-biofilm activity of F-10, while latex agglutination test was performed to study the influence of F-10 on penicillin-binding protein 2a (PBP2a) level in MRSA biofilm. PBP2a is a protein that confers resistance to beta-lactam antibiotics. The results showed that, F-10 at minimum inhibitory concentration (MIC, 0.75 mg/mL) inhibited biofilm production by 66.10%; inhibited cell-surface attachment by more than 95%; and a reduced PBP2a level in the MRSA biofilm was observed. Although ampicilin was more effective in inhibiting biofilm production (MIC of 0.05 mg/mL, 84.49%) compared to F-10, the antibiotic was less effective in preventing cell-surface attachment. A higher level of PBP2a was detected in ampicillin-treated MRSA showing the development of further resistance in these colonies. This study has shown that F-10 possesses anti-biofilm activity, which can be attributed to its ability to reduce cell-surface attachment and attenuate the level of PBP2a that we postulated to play a crucial role in mediating biofilm formation.

Cytotoxicity and apoptotic activities of alpha-, gamma- and delta-tocotrienol isomers on human cancer cells.

BACKGROUND: Tocotrienols, especially the gamma isomer was discovered to possess cytotoxic effects associated with the induction of apoptosis in numerous cancers. Individual tocotrienol isomers are believed to induce dissimilar apoptotic mechanisms in different cancer types. This study was aimed to compare the cytotoxic potency of alpha-, gamma- and delta-tocotrienols, and to explore their resultant apoptotic mechanisms in human lung adenocarcinoma A549 and glioblastoma U87MG cells which are scarcely researched. METHODS: The cytotoxic effects of alpha-, gamma- and delta-tocotrienols in both A549 and U87MG cancer cells were first determined at the cell viability and morphological aspects. DNA damage types were then identified by comet assay and flow cytometric study was carried out to support the incidence of apoptosis. The involvements of caspase-8, Bid, Bax and mitochondrial membrane permeability (MMP) in the execution of apoptosis were further expounded. RESULTS: All tocotrienols inhibited the growth of A549 and U87MG cancer cells in a concentration- and time-dependent manner. These treated cancer cells demonstrated some hallmarks of apoptotic morphologies, apoptosis was further confirmed by cell accumulation at the pre-G1 stage. All tocotrienols induced only double strand DNA breaks (DSBs) and no single strand DNA breaks (SSBs) in both treated cancer cells. Activation of caspase-8 leading to increased levels of Bid and Bax as well as cytochrome c release attributed by the disruption of mitochondrial membrane permeability in both A549 and U87MG cells were evident. CONCLUSIONS: This study has shown that delta-tocotrienol, in all experimental approaches, possessed a higher efficacy (shorter induction period) and effectiveness (higher induction rate) in the execution of apoptosis in both A549 and U87MG cancer cells as compared to alpha- and gamma-tocotrienols. Tocotrienols in particular the delta isomer can be an alternative chemotherapeutic agent for treating lung and brain cancers.

Evidence to support cultivated fruiting body of Ophiocordyceps sinensis (Ascomycota)'s role in relaxing airway smooth muscle.

ETHNOPHARMACOLOGICAL RELEVANCE: Ophiocordyceps sinensis (O. sinensis) is a genus of Ascomycete fungus that is endemic to the alpine meadows of the Tibetan Plateau and adjoining Himalayas. It has been used traditionally as a tonic to improve respiratory health in ancient China as well as to promote vitality and longevity. Bioactive components found in O. sinensis such as adenosine, cordycepin, 3-deoxyadenosine, L-arginine and polysaccharides have gained increasing interest in recent years due to their antioxidative and other properties, which include anti-asthmatic, antiviral, immunomodulation and improvement of general health. AIM OF THE STUDY: This study's primary aim was to investigate the effect of a cultivated fruiting body of O. sinensis strain (OCS02®) on airways patency and the secondary focus was to investigate its effect on the lifespan of Caenorhabditis elegans. MATERIALS AND METHODS: A cultivated strain, OCS02®, was employed and the metabolic profile of its cold-water extract (CWE) was analysed through liquid chromatography-mass spectrometry (LC-MS). Organ bath approach was used to investigate the pharmacological properties of OCS02® CWE when applied on airway tissues obtained from adult male Sprague-Dawley rats. The airway relaxation mechanisms of OCS02® CWE were explored using pharmacological tools, where the key regulators in airway relaxation and constriction were investigated. For the longevity study, age synchronised, pos-1 RNAi-treated wild-type type Caenorhabditis elegans at the L4 stage were utilised for a lifespan assay. RESULTS: Various glycopeptides and amino acids, particularly a high concentration of L-arginine, were identified from the LC-MS analysis. In airway tissues, OCS02® CWE induced a significantly greater concentration-dependent relaxation when compared to salbutamol. The relaxation response was significantly attenuated in the presence of NG-Nitro-L-arginine methyl ester (L-NAME), 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ) and several K+ channel blockers. The longevity effect induced by OCS02® CWE (5 mg/mL and above) was observed in C. elegans by at least 17%. CONCLUSIONS: These findings suggest that the airway relaxation mechanisms of OCS02® CWE involved cGMP-dependent and cGMP-independent nitric oxide signalling pathways. This study provides evidence that the cultivated strain of OCS02® exhibits airway relaxation effects which supports the traditional use of its wild O. sinensis in strengthening respiratory health.

Cell wall perturbation sensitizes fungi to the antimalarial drug chloroquine.

Chloroquine (CQ) has been a mainstay of antimalarial drug treatment for several decades. Additional therapeutic actions of CQ have been described, including some reports of fungal inhibition. Here we investigated the action of CQ in fungi, including the yeast model Saccharomyces cerevisiae. A genomewide yeast deletion strain collection was screened against CQ, revealing that bck1Δ and slt2Δ mutants of the cell wall integrity pathway are CQ hypersensitive. This phenotype was rescued with sorbitol, consistent with cell wall involvement. The cell wall-targeting agent caffeine caused hypersensitivity to CQ, as did cell wall perturbation by sonication. The phenotypes were not caused by CQ-induced changes to cell wall components. Instead, CQ accumulated to higher levels in cells with perturbed cell walls: CQ uptake was 2- to 3-fold greater in bck1Δ and slt2Δ mutants than in wild-type yeast. CQ toxicity was synergistic with that of the major cell wall-targeting antifungal drug, caspofungin. The MIC of caspofungin against the yeast pathogen Candida albicans was decreased 2-fold by 250 µM CQ and up to 8-fold at higher CQ concentrations. Similar effects were seen in Candida glabrata and Aspergillus fumigatus. The results show that the cell wall is critical for CQ resistance in fungi and suggest that combination treatments with cell wall-targeting drugs could have potential for antifungal treatment.

Knowledge, attitude and practice of community pharmacists towards household pharmaceutical waste disposal.

OBJECTIVE: To assess the knowledge, attitude and practice of community pharmacists (CP) towards household pharmaceutical waste disposal. METHODS: All pharmacists attending the Malaysian Community Pharmacy Guild event held in-person were invited to self-administer a web-based survey. KEY FINDINGS: The response rate was 61% (168/276). Overall, community pharmacists have mixed knowledge (mean ± SD: 5.89 ± 1.38) and positive attitude (mean ± SD: 9.58 ± 0.81) towards household pharmaceutical waste disposal. However, few community pharmacists (18/168, 10.7%) have promotional materials encouraging safe medication disposal in their pharmacies. CONCLUSIONS: Community pharmacists do not proactively promote safe household pharmaceutical waste disposal to mitigate pharmaceutical pollutants entering the environment although they have satisfactory knowledge and attitude.

Geraniin Ameliorates Hypertensive Vascular Remodelling in a Diet-Induced Obese Animal Model through Antioxidant and Anti-Inflammatory Effects.

Geraniin, an ellagitannin, has shown a potent blood pressure-lowering effect in vivo. Therefore, this study aims to further characterize the ability of geraniin to attenuate hypertensive vascular dysfunction, a key feature of cardiovascular disease (CVD) development. Hypertension was induced in male Sprague-Dawley rats through feeding a high-fat diet (HFD) for eight weeks, followed by oral administration of 25 mg/kg/day geraniin for four weeks. The parameters of vascular dysfunction such as the structure and function of blood vessels as well as the vascular oxidative stress and inflammation were evaluated. The outcomes of geraniin-treated rats were compared with those of untreated rats on either a normal diet (ND) or HFD and with HFD-fed rats treated with captopril (40 mg/kg/day). We found that geraniin supplementation effectively ameliorated HFD-induced hypertension and abnormal remodelling of the thoracic aorta by suppressing excessive vascular superoxide (O2-) radical generation and overexpression of pro-inflammatory mediators in the circulating leukocytes. Furthermore, compared to the ND-fed rats, geraniin also independently promoted the significant enlargement of the thoracic aortic lumen for blood pressure reduction. Notably, the vascular benefits of geraniin were comparable to that of captopril. Collectively, these data suggest that geraniin can mitigate hypertensive vascular remodelling caused by overnutrition, which potentially abrogates the further development of CVDs.

Quinine interactions with tryptophan and tyrosine in malaria patients, and implications for quinine responses in the clinical setting.

OBJECTIVES: Recent work with the yeast model revealed that the antiprotozoal drug quinine competes with tryptophan for uptake via a common transport protein, causing cellular tryptophan starvation. In the present work, it was hypothesized that similar interactions may occur in malaria patients receiving quinine therapy. PATIENTS AND METHODS: A direct observational study was conducted in which plasma levels of drug and amino acids (tryptophan, tyrosine and phenylalanine) were monitored during quinine treatment of malaria patients with Plasmodium falciparum infections. RESULTS: Consistent with competition for uptake from plasma into cells, plasma tryptophan and tyrosine levels increased ≥2-fold during quinine therapy. Plasma quinine levels in individual plasma samples were significantly and positively correlated with tryptophan and tyrosine in the same samples. Control studies indicated no effect on phenylalanine. Chloroquine treatment of Plasmodium vivax-infected patients did not affect plasma tryptophan or tyrosine. During quinine treatment, plasma tryptophan was significantly lower (and quinine significantly higher) in patients experiencing adverse drug reactions. CONCLUSIONS: Plasma quinine levels during therapy are related to patient tryptophan and tyrosine levels, and these interactions can determine patient responses to quinine. The study also highlights the potential for extrapolating insights directly from the yeast model to human malaria patients.

Medicinal Mushrooms and Their Use to Strengthen Respiratory Health during and Post-COVID-19 Pandemic.

COVID-19 infection has been a key threat to the public health system globally, with an estimated 248 million cases worldwide. COVID-19 patients are subject to a higher risk of developing chronic respiratory disorders that are closely associated with long-term disability, multi-morbidity, and premature mortality. Although there have been recent advancements in respiratory treatment regimens, there has also been increased interest in the use of medicinal mushrooms in bridging the unaddressed pathways of action within the treatment algorithms. In this review, we provide a collection of medicinal mushrooms that are beneficial in promoting respiratory health and potentially reducing COVID-19 symptoms in patients who are newly diagnosed and those who have recovered. While reviewing the use of immunomodulatory pathways, which have shown promising results in tackling side effects and post-COVID syndromes, we also provide insights into how the antioxidant elements present in medicinal mushrooms help to achieve the same results, especially in the prophylactic and therapeutic management of COVID-19 infection. To date, medicinal mushrooms are regarded as a functional food, which, however, need further quality, safety, and efficacy assessments. These requirements are also highlighted in the present review to promote the future development and application of medicinal mushrooms for better respiratory health.

Pharmacists' experiences on adverse drug reaction: 10 years later.

Adverse drug reaction (ADR) is one of the leading public health concerns associated with high mortality rate. Healthcare professionals, particularly pharmacists, have a significant role in monitoring and preventing ADRs. This study was conducted on Malaysian Pharmaceutical Society (MPS) pharmacists who worked at the hospitals, health clinics, and community pharmacies to determine if pharmacists' experiences on ADRs are still the same 10 years later. In 2010, a postal survey and in 2020, an online survey were conducted among these pharmacists. A total of 472 pharmacists and 208 participated in 2010 and 2020, respectively. About 82% and 90% of hospital/health clinic pharmacists (HCPs) observed an ADR over the last 6 months in 2010 and 2020, while 60% and 100% community pharmacists in 2010 and 2020 observed an ADR, respectively. Perindopril was the top drug (HCPs: p = 0.657; CPs: p = 0.98), and rash was the top ADR reported by the pharmacists in both years (HCPs: p < 0.001; CPs: p = 0.679). The most common actions taken by HCPs in 2010 were to report the ADR (p = 0.343), while in 2020, most HCPs explained to patients regarding the reaction (p = 0.061), which was also the same in the CP group in 2020 (p = 0.958). The top factor encouraging ADR reporting in both years and both pharmacist groups was the high degree of severity of the reaction (HCPs: p < 0.001; CPs: p = 0.769). While the top factors discouraging ADR reporting were a lack of information from the affected patients (HCPs: p = 0.2; CPs: p = 0.656), reaction is widely known (HCPs: p = 0.001; CPs: p = 0.144) and uncertainty of the causal relationship (HCPs: p = 0.169; CPs: p = 0.609). Majority of the pharmacists agreed that severe reactions should be reported (HCPs: p = 0.158; CPs: p = 0.501) and the main aim for reporting is to measure the incidence of ADRs (HCPs: p = 0.148; CPs: p = 0.762). Despite being able to identify ADRs during the daily practice, many pharmacists especially community pharmacists are not reporting them. There is a misconception on the purpose of reporting ADRs. An interventional program and ADR reporting training would be a useful step in improving ADR reporting practice.

Concise synthesis of the vasorelaxant alkaloids schwarzinicines A and B.

A concise synthesis of the 1,4-diarylbutanoid-phenethylamine alkaloids, schwarzinicines A (1) and B (2), recently isolated from Ficus schwarzii, is reported. Key steps include a Claisen condensation to assemble the 1,4-diaryl-2-butanone intermediate, followed by a reductive amination to furnish the core skeleton of the target compounds. The overall synthetic yields of 1 and 2 were 9.1% and 3.5%, respectively. Synthetic (-)-1, (+)-1 and (±)-1 exhibited comparable vasorelaxation as natural schwarzinicine A on rat isolated aortic rings, suggesting that the observed vasorelaxant effects were not influenced by the chirality at C-2.