Phytoestrogens: Chemistry, potential health benefits, and their medicinal importance.

Phytoestrogens, also known as xenoestrogens, are secondary metabolites derived from plants that have similar structures and biological effects as human estrogens. These compounds do not directly affect biological functions but can act as agonists or antagonists depending on the level of endogenous estrogen in the body. Phytoestrogens may have an epigenetic mechanism of action independent of estrogen receptors. These compounds are found in more than 300 plant species and are synthesized through the phenylpropanoid pathway, with specific enzymes leading to various chemical structures. Phytoestrogens, primarily phenolic compounds, include isoflavonoids, flavonoids, stilbenes, and lignans. Extensive research in animals and humans has demonstrated the protective effects of phytoestrogens on estrogen-dependent diseases. Clinical trials have also shown their potential benefits in conditions such as osteoporosis, Parkinson's disease, and certain types of cancer. This review provides a concise overview of phytoestrogen classification, chemical diversity, and biosynthesis and discusses the potential therapeutic effects of phytoestrogens, as well as their preclinical and clinical development.

A Quinquennial Review on Recent Advancements and Developments in Search of Anti-malarial Agents.

Malaria has been a major parasitic disease in tropical and subtropical regions and is estimated to kill between one and two million people (mainly children) every year. Novel anti-malarial agents are urgently needed to combat the malarial parasites enduring resistance to the current medications, leading to increased morbidity and mortality. The heterocycles, holding a prominent position in chemistry and found in both natural and synthetic sources, have shown several biological activities including anti-malarial activity. Towards this goal, several research groups have reported the design and development of novel and potential anti-malarial agents like artemisinin, benzimidazole, benzothiazole, chalcone, cyclopeptide, fosmidomycin, furan, indole oxadiazole, 2-oxindoles, peroxides, pyrazole, pyrazolines, pyridines, pyrimidine, pyrrolidine, quinazoline, quinazolinone, quinolone, quinoline, thiazole, triazole and other scaffolds acting against newly emerging anti-malarial targets. The present work reports the complete quinquennial coverage of anti-malarial agents reported during 2016-2020 with a view of providing the merits and demerits of reported anti-malarial scaffolds, structure-activity relationship, along with their in vitro/ in vivo/ in silico profiles to the medicinal chemists working in the field of design and discovery of novel anti-malarial agents.

Propolis and Their Active Constituents for Chronic Diseases.

Propolis is a mass of chemically diverse phytoconstituents with gummy textures that are naturally produced by honeybees upon collection of plant resins for utilization in various life processes in beehives. Since ancient times, propolis has been a unique traditional remedy globally utilized for several purposes, and it has secured value in pharmaceutical and nutraceutical areas in recent years. The chemical composition of propolis comprises diverse constituents and deviations in the precise composition of the honeybee species, plant source used for propolis production by bees, climate conditions and harvesting season. Over 300 molecular structures have been discovered from propolis, and important classes include phenolic acids, flavonoids, terpenoids, benzofurans, benzopyrene and chalcones. Propolis has also been reported to have diverse pharmacological activities, such as antidiabetic, anti-inflammatory, antioxidant, anticancer, immunomodulatory, antibacterial, antiviral, antifungal, and anticaries. As chronic diseases have risen as a global health threat, abundant research has been conducted to track propolis and its constituents as alternative therapies for chronic diseases. Several clinical trials have also revealed the potency of propolis and its constituents for preventing and curing some chronic diseases. This review explores the beneficial effect of propolis and its active constituents with credible mechanisms and computational studies on chronic diseases.

Improving blood glucose level predictability using machine learning.

This study was designed to improve blood glucose level predictability and future hypoglycemic and hyperglycemic event alerts through a novel patient-specific supervised-machine-learning (SML) analysis of glucose level based on a continuous-glucose-monitoring system (CGM) that needs no human intervention, and minimises false-positive alerts. The CGM data over 7 to 50 non-consecutive days from 11 type-1 diabetic patients aged 18 to 39 with a mean HbA1C of 7.5% ± 1.2% were analysed using four SML models. The algorithm was constructed to choose the best-fit model for each patient. Several statistical parameters were calculated to aggregate the magnitudes of the prediction errors. The personalised solutions provided by the algorithm were effective in predicting glucose levels 30 minutes after the last measurement. The average root-mean-square-error was 20.48 mg/dL and the average absolute-mean-error was 15.36 mg/dL when the best-fit model was selected for each patient. Using the best-fit-model, the true-positive-hypoglycemia-prediction-rate was 64%, whereas the false-positive- rate was 4.0%, and the false-negative-rate was 0.015%. Similar results were found even when only CGM samples below 70 were considered. The true-positive-hyperglycemia-prediction-rate was 61%. State-of-the-art SML tools are effective in predicting the glucose level values of patients with type-1diabetes and notifying these patients of future hypoglycemic and hyperglycemic events, thus improving glycemic control. The algorithm can be used to improve the calculation of the basal insulin rate and bolus insulin, and suitable for a closed loop "artificial pancreas" system. The algorithm provides a personalised medical solution that can successfully identify the best-fit method for each patient.

Potential to inhibit growth of atherosclerotic plaque development through modulation of macrophage neopterin/7,8-dihydroneopterin synthesis.

The rise in plasma neopterin observed with increasing severity of vascular disease is a strong indicator of the inflammatory nature of atherosclerosis. Plasma neopterin originates as the oxidation product of 7,8-dihydroneopterin secreted by gamma-interferon stimulated macrophages within atherosclerotic plaques. Neopterin is increasingly being used as a marker of inflammation during clinical management of patients with a range of disorders including atherosclerosis. Yet the role of 7,8-dihydroneopterin/neopterin synthesis during the inflammatory process and plaque formation remains poorly understood and controversial. This is partially due to the unresolved role oxidants play in atherosclerosis and the opposing roles of 7,8-dihydroneopterin/neopterin. Neopterin can act as pro-oxidant, enhancing oxidant damage and triggering apoptosis in a number of different cell types. Neopterin appears to have some cellular signalling properties as well as being able to chelate and enhance the reactivity of transition metal ions during Fenton reactions. In contrast, 7,8-dihydroneopterin is also a radical scavenger, reacting with and neutralizing a range of reactive oxygen species including hypochlorite, nitric oxide and peroxyl radicals, thus protecting lipoproteins and various cell types including macrophages. This has led to the suggestion that 7,8-dihydroneopterin is synthesized to protect macrophages from the oxidants released during inflammation. The oxidant/antioxidant activity observed in vitro appears to be determined both by the relative concentration of these compounds and the specific chemistry of the in vitro system under study. How these activities might influence or modulate the development of atherosclerotic plaque in vivo will be explored in this review.

Effects of naltrexone on the intake of ethanol and flavored solutions in rats.

It has been suggested that the endogenous opioid system may mediate the intake of preferred fluids, perhaps through an attenuation of reinforcement properties causing a subsequent shift in palatability. The purpose of the present study was to investigate the effects of the nonspecific opiate antagonist naltrexone on the intake of 10% ethanol, 0.1% saccharin, 0.0006% quinine, 0.4% saccharin + 10% ethanol, and 0.4% saccharin + 0.04% quinine solutions. Fluid intake was measured in male Long-Evans and Wistar rats under 24-h continuous and 30-min limited-fluid-access drinking paradigms. All rats received injections of naltrexone hydrochloride (10 mg/kg, i.p.) for 5 days after baseline intake measures and were monitored for a further 5 days (after-treatment phase). Results indicated that naltrexone did not affect intake of any solution when fluids were available over 24 h. However, under limited-access conditions, naltrexone caused a decrease in the intake of all fluids except quinine in both rat strains. On the basis of these findings, it is possible that the effects of this dose of naltrexone were not due to any true conditioning effect on the reinforcement properties of ethanol, but perhaps to some nonspecific effect of the drug, such as an alteration in palatability or an attenuation of locomotor activity. As well, due to the inconsistent results in fluid intake across drinking paradigms, the present findings do not provide evidence for an effective role for opiate mediation in ethanol intake as well as any ethanol-sweet fluid intake interactions.

Caffeine promotes an ethanol-induced conditioned taste aversion: a dose-dependent interaction.

The present study examined whether caffeine administered within a dose range previously shown to promote ethanol drinking would also alter an ethanol-induced conditioned taste aversion (CTA). The results revealed a dose-dependent interaction between caffeine and ethanol where caffeine (2.5 and 10 mg/kg) promoted an ethanol-induced CTA at a low ethanol dose (1.0 g/kg) but had no effect in blocking CTA at the higher ethanol dose (1.5 g/kg). These results were found to be unrelated to an alteration in ethanol metabolism, as caffeine had no effect in altering blood ethanol levels at the doses tested. In agreement with the reward comparison hypothesis, the present results suggest that rather than attenuate ethanol's "aversive" effects, caffeine may have promoted an ethanol-induced CTA by increasing the reinforcing efficacy of ethanol.

Heterogeneity of Pneumocystis sterol profiles of samples from different sites in the same pair of lungs suggests coinfection by distinct organism populations.

Sterol profiles of samples taken from different sites of a Pneumocystis-infected human lung showed large variations in pneumocysterol similar to those that occur among samples from different patients. Thus, the influence of diet or drugs on pneumocysterol accumulation was ruled out, suggesting distinct phenotypic populations as the basis for the heterogeneity.

Differences in locomotor response to an inescapable novel environment predict sensitivity to aversive effects of amphetamine.

Differences in locomotor response to an inescapable novel environment have previously been shown to predict sensitivity to amphetamine reward, where high responders (HR), compared to low responders (LR), showed greater initial sensitivity to amphetamine self-administration. The present experiments sought to extend these findings and assessed the relationship between locomotor response to an inescapable novel environment and conditioned taste aversion (CTA) with amphetamine and lithium chloride (LiCl). Male Sprague-Dawley rats were tested for their locomotor response to an inescapable novel environment and divided into high (HR) or low (LR) responders, based on whether their locomotor scores were above or below the median activity level of the subject sample. After several days, the animals were tested in a CTA procedure and conditioned with either amphetamine or lithium chloride. Compared to HR rats, LR rats showed greater sensitivity to amphetamine CTA at the doses tested. In contrast, the results with LiCl showed no relationship between locomotor response to an inescapable novel environment and CTA. Taken together, the present results suggest that LR, compared to HR, rats show less sensitivity to the rewarding effects of amphetamine because they are more sensitive to aversive effects of amphetamine, as reflected in CTA. In contrast, HR rats display less sensitivity to aversive effects of amphetamine, which may explain their greater propensity to self-administer amphetamine.

Caffeine, nicotine and mecamylamine share stimulus properties in the preexposure conditioned taste aversion procedure.

RATIONALE: The present study examined whether nicotine and caffeine, two of the most widely used psychoactive drugs, share stimulus properties in the preexposure conditioned taste aversion (CTA) procedure. OBJECTIVES: To determine whether nicotine would attenuate the formation of a caffeine-induced CTA and further assess whether pretreatment with mecamylamine, a nicotinic receptor antagonist, would reverse nicotine's attenuating effect of a caffeine-induced CTA. METHODS: Male Wistar rats were preexposed with one of three doses of nicotine (0.6, 1.2 and 2.0 mg/kg, s.c.) for three consecutive days, then 24 h following the final preexposure injection were conditioned with caffeine (20 mg/kg and 30 mg/kg, i.p.) in a standard two-bottle test. There were four conditioning trials and four drug-free test days. In a follow-up study, rats were pretreated with mecamylamine (2 mg/kg, i.p.) prior to preexposure injections with nicotine (0.6 mg/kg, i.p.), then subsequently conditioned with caffeine (20 mg/kg, i.p.) as described above. RESULTS: The lowest nicotine dose (0.6 mg/kg) attenuated the caffeine induced CTAs (20 mg/kg and 30 mg/kg) but the higher nicotine doses showed no such attenuating effect. In addition, mecamylamine reversed the nicotine-induced attenuation of the caffeine-induced CTA and also directly attenuated it. CONCLUSIONS: These results suggested that caffeine, nicotine and mecamylamine share overlapping stimulus properties and that the nature of this relationship may involve action at the nicotinic-cholinergic receptor.

Augmentation of corticosterone release by means of a caffeine-ethanol interaction in rats.

We examined whether the acute treatment with caffeine delivered before an ethanol injection would augment plasma corticosterone (CORT) levels. The effect of caffeine on blood ethanol levels was also assessed. After 10 days of acclimatization to the colony room conditions, male Wistar rats were injected with either caffeine (5 mg/kg, ip) or saline 30 min before the delivery of ethanol (0.8 g/kg, ip) or saline, respectively. Trunk blood was then collected at 15 and 30 min after the ethanol injection for determination of plasma CORT and blood ethanol levels. CORT was measured with the use of radioimmunoassay, and blood ethanol levels were determined with the use of gas chromatography. The results showed that although caffeine and ethanol delivered singly failed to augment plasma CORT levels, the combination of both drugs produced elevations in plasma CORT levels at 15 and 30 min. These findings were found to be unrelated to changes in ethanol metabolism as caffeine failed to alter blood ethanol levels within the period tested. It was argued that the present elevations in plasma CORT levels observed in animals administered caffeine and ethanol may play a role in the caffeine-induced elevations in ethanol drinking observed elsewhere.

Caffeine promotes ethanol drinking in rats. Examination using a limited-access free choice paradigm.

There is growing evidence that caffeine may alter the pattern of intake of a variety of drugs. The present study was designed to assess the effect of caffeine pretreatment on voluntary ethanol consumption. The first experiment examined the effect of caffeine on the acquisition of ethanol intake in a limited-access-choice procedure in which water and ethanol were presented concurrently. Male Wistar rats, exposed to food and water ad lib, were presented with a daily 1-h choice session between water and progressively increasing concentrations of ethanol (2-10%). Each ethanol concentration was made available for 4-6 days for a total of 20 days of access to ethanol. Intraperitoneal injections of caffeine (5 or 10 mg/kg) or saline were administered to the rats 30 min prior to each choice session. Caffeine produced a dose-related facilitation in ethanol drinking whereby the lower caffeine dose produced enhancement in ethanol drinking. The second experiment examined the effect of caffeine on the maintenance of established ethanol consumption. Male Wistar rats, initially acclimatized to increasing concentrations of ethanol (2%-10), were presented with an additional 18 ethanol (10%) presentations, comprised of a 6-day baseline period followed by 6 days of treatment where animals were given one of three doses of caffeine (2.5, 5 or 10 mg/kg) or saline prior to ethanol presentation. A final 6-day post-treatment period followed treatment. These results revealed an inverted-U effect of caffeine dose on ethanol ingestion where the low and high caffeine doses produced no effect but the moderate dose of 5 mg/kg enhanced ethanol drinking that persisted throughout the post-treatment period. A third experiment revealed that caffeine did not alter levels of blood ethanol within the time period used for the ethanol drinking session.

The effects of aminotriazole and acetaldehyde on an ethanol drug discrimination with a conditioned taste aversion procedure.

The present study was designed to investigate whether acetaldehyde shares stimulus properties with ethanol using the conditioned taste aversion (CTA) baseline of drug discrimination learning. Animals were trained to discriminate ethanol (0.8 g/kg, i.p.) from saline using 11 consecutive cycles consisting of a pairing day and three nonpairing days. On pairing days, all animals were injected with ethanol 30 min prior to a 20-min limited access to a saccharin solution (0.1% w/v) and then immediately injected with either LiCl (0.15 M, 1.8 meq) or distilled water. On the three following nonpairing days, animals were injected with saline and 30 min later presented with the same saccharin solution for 20 min. No injections followed on these nonpairing days. Results showed that animals acquired discriminative stimulus control for ethanol after seven pairings. Pretreatment with the catalase inhibitor did not alter the discriminative control for ethanol. Generalization tests revealed that acetaldehyde substituted for ethanol at a dose of 0.3 g/kg. The results of the present study suggest that catalase inhibition did not reverse or alter the discriminative stimulus effects of ethanol. However, generalization tests showed that acetaldehyde (0.3 g/kg) will substitute for ethanol suggesting that these two drugs share some similar properties.

Preexposure effects of nicotine and acetaldehyde on conditioned taste aversion induced by both drugs.

Previous assessments have demonstrated an interaction between ethanol and nicotine in the conditioned taste-aversion (CTA) paradigm. The present study assessed whether acetaldehyde, the primary reinforcing metabolite of ethanol, would interact with nicotine as well. In six experiments, water-deprived male Wistar rats were preexposed to either acetaldehyde (0.2 or 0.3 g/kg, IP) or nicotine (0.8, 1.2, or 2 mg/kg, SC) for 3 consecutive days and then subsequently conditioned, 24 h later, with either nicotine (0.8, 1.2, or 2 mg/kg, SC) or acetaldehyde (0.2 or 0.3 g/kg, IP), respectively. There were 4 conditioning days and 4 drug-free test days, each spaced 72 h apart. On test days, animals were offered a free choice between water and saccharin. The results of the following set of experiments demonstrated a dose-related interaction between nicotine and acetaldehyde, where lower doses of each drug failed to attenuate CTA induced by one another, but a higher nicotine dose (2 mg/kg) attenuated the formation of a CTA induced by acetaldehyde (0.3 g/kg). It was argued that the primary metabolite of ethanol may play a role in the interaction between nicotine and ethanol previously observed.

Relative taste thresholds for ethanol, saccharin, and quinine solutions in three strains of rats nonselected for ethanol: a comparative study.

C. P. Richter and K. H. Campbell (1940b) originally defined taste threshold as "the point at which the rats first indicated that they recognized a difference between the distilled water and the solutions" (p. 34). The present study sought to apply this simple behavioral measure to the investigation of strain differences in taste sensitivities, particularly with respect to predictive relationships in ethanol, saccharin, and quinine preference. Fawn-Hooded, Lewis, and Wistar rats were presented with gradual increments in concentration of ethanol (0.01-15%; C. P. Richter & K. H. Campbell, 1940a), saccharin (0.002-3%) or quinine (0.0001-0.0055). Results showed that although intake for saccharin was similar in all strains, consumption of ethanol and quinine differed among the groups. Although previous research has proposed that sweet preference is a promising behavioral marker for ethanol preference, these results suggested that bitter preference may be a more reliable predictor of ethanol preference in rats.

Differences in the consumption of ethanol and flavored solutions in three strains of rats.

Several studies have shown a correlation between ethanol consumption and the intake of flavored solutions in rats, particularly sweet solutions. This observation, however, has not been shown in all strains of rats. The present study examined whether the intake of ethanol and that of flavored solutions would be related in Lewis (LEW), Wistar (WIS), and Wistar Kyoto (WKY) rats. During phase I, all rats were presented with water and a flavored solution following a continuous access paradigm as developed by Overstreet et al.: quinine (0.25% wt/vol), saccharin (0.1% wt/vol), ethanol (ETOH) (10% vol/vol), and saccharin-quinine (SQ) solutions (0.4% wt/vol-0.04% wt/vol). During phase II, fluid presentations were reduced to a 10-min limited access schedule and were presented in the same order. Results showed strain differences in intake and preference for ETOH and SQ during both phases, but not in quinine or saccharin intake. ETOH and saccharin intake were only correlated in the LEW strain during limited access drinking, while ETOH and SQ intake were correlated in the LEW strain as well as when all strains were collapsed during continuous drinking. These findings suggested that any association between ETOH and sweet intake may not be generalizable to all rat strains. The animals used in this study may have differed in taste sensitivity, as low ETOH-consuming LEW rats were sensitive to the bitter taste of quinine alone, as well as when mixed with saccharin. Sensitivity to bitter tastes may be an important predictor of low ETOH consumption and/or preference. These data provide further evidence for the role of taste factors in the mediation of voluntary ETOH consumption in rats.

Stress enhances the response to reward reduction but not food-motivated responding.

The effect of a single exposure to foot shock stress on runway responding for food reinforcement was assessed in animals trained and tested with the same or changed reinforcement magnitude. Foot shock (30 1-s shocks, 1.0 mA) exerted no impact on runway responding in animals trained and tested with the same level of reinforcement magnitude regardless of the absolute level of reinforcement magnitude (i.e., either 15 pellets or 1 pellet). Similarly, foot shock exerted no impact on runway responding in animals trained with a small magnitude of reinforcement but tested with an increased magnitude of reinforcement. In contrast, foot shock enhanced the increase in runway latencies produced by a reduction in reinforcement magnitude. Because reductions in reinforcement magnitude are known to be aversive for animals, these data indicate that foot shock stress can alter the behavioral response to an aversive stimulus without disrupting behavioral responding for an appetitive reinforcer. They also suggest that stressor-induced alterations in appetitively motivated behaviors may be secondary to alterations in sensitivity to subtle aversive stimuli rather than by directly altering appetitive motivation.

Sterols of Pneumocystis carinii hominis organisms isolated from human lungs.

The opportunistic pathogen Pneumocystis carinii causes pneumonia (P. carinii pneumonia, or PCP) in immunocompromised individuals such as AIDS patients. Rat-derived P. carinii carinii organisms have distinct sterols which are not synthesized by mammals and not found in other microbes infecting mammalian lungs. The dominant sterol present in the organism is cholesterol (which is believed to be scavenged from the host), but other sterols in P. carinii carinii have an alkyl group at C-24 of the sterol side chain (C(28) and C(29) 24-alkylsterols) and a double bond at C-7 of the nucleus. Recently, pneumocysterol (C(32)), which is essentially lanosterol with a C-24 ethylidene group, was detected in lipids extracted from a formalin-fixed human P. carinii-infected lung, and its structures were elucidated by gas-liquid chromatography, mass spectrometry, and nuclear magnetic resonance spectrometry in conjunction with analyses of chemically synthesized authentic standards. The sterol composition of isolated P. carinii hominis organisms has yet to be reported. If P. carinii from animal models is to be used for identifying potential drug targets and for developing chemotherapeutic approaches to clear human infections, it is important to determine whether the 24-alkylsterols of organisms found in rats are also present in organisms in humans. In the present study, sterol analyses of P. carinii hominis organisms isolated from cryopreserved human P. carinii-infected lungs and from bronchoalveolar lavage fluid were performed. Several of the same distinct sterols (e.g., fungisterol and methylcholest-7-ene-3beta-ol) previously identified in P. carinii carinii were also present in organisms isolated from human specimens. Pneumocysterol was detected in only some of the samples.

Cocaine and ethanol interaction in the conditioned taste aversion paradigm.

The aim of this study was to examine the relationship between cocaine and ethanol in a variant of the conditioned taste aversion (CTA) paradigm. The preexposure CTA procedure formed the basis of the following set of experiments. Experiments 1a and 1b assessed whether cocaine and ethanol were functionally related with overlapping stimulus properties as reflected in the preexposure CTA procedure. Male Wistar rats with restricted water access were preexposed to cocaine or ethanol for 3 consecutive days. Twenty-four hours after the last preexposure session, rats were conditioned to either ethanol or cocaine, respectively. The results of this set of experiments revealed a symmetrical interaction between cocaine and ethanol, where cocaine and ethanol effectively blocked CTA to one another. These findings suggested that there may be overlapping stimulus properties between cocaine and ethanol, which may be detected in this procedure.