The potential roles of gossypol as anticancer agent: advances and future directions.

Gossypol, a polyphenolic aldehyde derived from cottonseed plants, has seen a transformation in its pharmaceutical application from a male contraceptive to a candidate for cancer therapy. This shift is supported by its recognized antitumor properties, which have prompted its investigation in the treatment of various cancers and related inflammatory conditions. This review synthesizes the current understanding of gossypol as an anticancer agent, focusing on its pharmacological mechanisms, strategies to enhance its clinical efficacy, and the status of ongoing clinical evaluations.The methodological approach to this review involved a systematic search across several scientific databases including the National Center for Biotechnology Information (NCBI), PubMed/MedLine, Google Scholar, Scopus, and TRIP. Studies were meticulously chosen to cover various aspects of gossypol, from its chemical structure and natural sources to its pharmacokinetics and confirmed anticancer efficacy. Specific MeSH terms and keywords related to gossypol's antineoplastic applications guided the search strategy.Results from selected pharmacological studies indicate that gossypol inhibits the Bcl-2 family of anti-apoptotic proteins, promoting apoptosis in tumor cells. Clinical trials, particularly phase I and II, reveal gossypol's promise as an anticancer agent, demonstrating efficacy and manageable toxicity profiles. The review identifies the development of gossypol derivatives and novel carriers as avenues to enhance therapeutic outcomes and mitigate adverse effects.Conclusively, gossypol represents a promising anticancer agent with considerable therapeutic potential. However, further research is needed to refine gossypol-based therapies, explore combination treatments, and verify their effectiveness across cancer types. The ongoing clinical trials continue to support its potential, suggesting a future where gossypol could play a significant role in cancer treatment protocols.

Natural Substances vs. Approved Drugs in the Treatment of Main Cardiovascular Disorders-Is There a Breakthrough?

Cardiovascular diseases (CVDs) are a group of diseases with a very high rate of morbidity and mortality. The clinical presentation of CVDs can vary from asymptomatic to classic symptoms such as chest pain in patients with myocardial infarction. Current therapeutics for CVDs mainly target disease symptoms. The most common CVDs are coronary artery disease, acute myocardial infarction, atrial fibrillation, chronic heart failure, arterial hypertension, and valvular heart disease. In their treatment, conventional therapies and pharmacological therapies are used. However, the use of herbal medicines in the therapy of these diseases has also been reported in the literature, resulting in a need for critical evaluation of advances related to their use. Therefore, we carried out a narrative review of pharmacological and herbal therapeutic effects reported for these diseases. Data for this comprehensive review were obtained from electronic databases such as MedLine, PubMed, Web of Science, Scopus, and Google Scholar. Conventional therapy requires an individual approach to the patients, as when patients do not respond well, this often causes allergic effects or various other unwanted effects. Nowadays, medicinal plants as therapeutics are frequently used in different parts of the world. Preclinical/clinical pharmacology studies have confirmed that some bioactive compounds may have beneficial therapeutic effects in some common CVDs. The natural products analyzed in this review are promising phytochemicals for adjuvant and complementary drug candidates in CVDs pharmacotherapy, and some of them have already been approved by the FDA. There are insufficient clinical studies to compare the effectiveness of natural products compared to approved therapeutics for the treatment of CVDs. Further long-term studies are needed to accelerate the potential of using natural products for these diseases. Despite this undoubted beneficence on CVDs, there are no strong breakthroughs supporting the implementation of natural products in clinical practice. Nevertheless, they are promising agents in the supplementation and co-therapy of CVDs.

Resveratrol and Gut Microbiota Synergy: Preventive and Therapeutic Effects.

The role of an imbalanced high-fat diet in the pathophysiology of common chronic noncommunicable diseases has been known for years. More recently, the concept of 'gut microbiota' and the interaction between their composition and gut metabolites produced from the intake of dietary products have gained the focus of researchers, mostly from the perspective of the prevention of cardiovascular and metabolic disorders, which are still the leading cause of death globally. The aim of this work is to highlight the health benefits of the interaction between resveratrol (RSV), red grape polyphenol, and gut microbiota, through aspects of their therapeutic and preventive potentials. Since changed microbiota (mostly as a consequence of antibiotic overuse) contribute to the persistence of post ('long')-COVID-19 symptoms, these aspects will be covered too. Data were obtained from the electronic databases (MedLine/PubMed), according to specific keywords regarding the protective role of resveratrol, the gut microbiota, and their synergy. RSV exerts beneficial properties in the modulation of cardiovascular, metabolic, and post-COVID-19-related disorders. In healthy individuals, it maintains an ergogenic capacity, prevents oxidative stress, and modulates the inflammatory response. Overall, it improves quality of life. The RSV-gut-microbiota interaction is beneficial in terms of maintaining human health. Along with physical activity, it is key for the prevention of chronic noncommunicable diseases.

An updated pharmacological insight into calotropin as a potential therapeutic agent in cancer.

Calotropin is a pharmacologically active compound isolated from milkweed plants like Calotropis procera, Calotropis gigantea, and Asclepias currasavica that belong to the Asclepiadaceae family. All of these plants are recognised as medical traditional plants used in Asian countries. Calotropin is identified as a highly potent cardenolide that has a similar chemical structure to cardiac glycosides (such as digoxin and digitoxin). During the last few years, cytotoxic and antitumor effects of cardenolides glycosides have been reported more frequently. Among cardenolides, calotropin is identified as the most promising agent. In this updated and comprehensive review, we aimed to analyze and discuss the specific mechanisms and molecular targets of calotropin in cancer treatment to open new perspectives for the adjuvant treatment of different types of cancer. The effects of calotropin on cancer have been extensively studied in preclinical pharmacological studies in vitro using cancer cell lines and in vivo in experimental animal models that have targeted antitumor mechanisms and anticancer signaling pathways. The analyzed information from the specialized literature was obtained from scientific databases until December 2022, mainly from PubMed/MedLine, Google Scholar, Scopus, Web of Science, and Science Direct databases using specific MeSH search terms. The results of our analysis demonstrate that calotropin can be a potential chemotherapeutic/chemopreventive adjunctive agent in cancer pharmacotherapeutic management.

Pharmacological effects and therapeutic potential of natural compounds in neuropsychiatric disorders: An update.

Neuropsychiatric diseases are a group of disorders that cause significant morbidity and disability. The symptoms of psychiatric disorders include anxiety, depression, eating disorders, autism spectrum disorders (ASD), attention-deficit/hyperactivity disorder, and conduct disorder. Various medicinal plants are frequently used as therapeutics in traditional medicine in different parts of the world. Nowadays, using medicinal plants as an alternative medication has been considered due to their biological safety. Despite the wide range of medications, many patients are unable to tolerate the side effects and eventually lose their response. By considering the therapeutic advantages of medicinal plants in the case of side effects, patients may prefer to use them instead of chemical drugs. Today, the use of medicinal plants in traditional medicine is diverse and increasing, and these plants are a precious heritage for humanity. Investigation about traditional medicine continues, and several studies have indicated the basic pharmacology and clinical efficacy of herbal medicine. In this article, we discuss five of the most important and common psychiatric illnesses investigated in various studies along with conventional therapies and their pharmacological therapies. For this comprehensive review, data were obtained from electronic databases such as MedLine/PubMed, Science Direct, Web of Science, EMBASE, DynaMed Plus, ScienceDirect, and TRIP database. Preclinical pharmacology studies have confirmed that some bioactive compounds may have beneficial therapeutic effects in some common psychiatric disorders. The mechanisms of action of the analyzed biocompounds are presented in detail. The bioactive compounds analyzed in this review are promising phytochemicals for adjuvant and complementary drug candidates in the pharmacotherapy of neuropsychiatric diseases. Although comparative studies have been carefully reviewed in the preclinical pharmacology field, no clinical studies have been found to confirm the efficacy of herbal medicines compared to FDA-approved medicines for the treatment of mental disorders. Therefore, future clinical studies are needed to accelerate the potential use of natural compounds in the management of these diseases.

Resveratrol and Reproductive Health.

Resveratrol (RSV), a plant-derived polyphenol, demonstrates broad-spectrum health benefits, including anti-proliferative, anti-inflammatory, antidiabetic, anti-ischemic and antioxidant effects. The aim of this review is to give an important heads-up regarding the influence of RSV as a phytoestrogen, RSV effects on most common pregnancy-related complications, as well as its impact on the embryogenesis, spermatogenesis, and women's reproductive health. Considering the important implications of RSV on human reproductive health, this overview could provide a groundwork, encouraging more detailed research at the clinical level.

A Review of Recent Studies on the Antioxidant and Anti-Infectious Properties of Senna Plants.

The use of phytochemicals is gaining interest for the treatment of metabolic syndromes over the synthetic formulation of drugs. Senna is evolving as one of the important plants which have been vastly studied for its beneficial effects. Various parts of Senna species including the root, stem, leaves, and flower are found rich in numerous phytochemicals. In vitro, in vivo, and clinical experiments established that extracts from Senna plants have diverse beneficial effects by acting as a strong antioxidant and antimicrobial agent. In this review, Senna genus is comprehensively discussed in terms of its botanical characteristics, traditional use, geographic presence, and phytochemical profile. The bioactive compound richness contributes to the biological activity of Senna plant extracts. The review emphasizes on the in vivo and in vitro antioxidant and anti-infectious properties of the Senna plant. Preclinical studies confirmed the beneficial effects of the Senna plant extracts and its bioactive components in regard to the health-promoting activities. The safety, side effects, and therapeutic limitations of the Senna plant are also discussed in this review. Additional research is necessary to utilize the phenolic compounds towards its use as an alternative to pharmacological treatments and even as an ingredient in functional foods.

An Insight into Phytochemical, Pharmacological, and Nutritional Properties of Arbutus unedo L. from Morocco.

Arbutus unedo L. (Ericaceae) is an evergreen shrub widely distributed in the Mediterranean region, particularly through the Moroccan forests. It is an important medicinal plant of great scientific interest due to its nutritional, pharmacological, and chemical properties. The objective of this review is to provide insights into traditional medicinal uses and phytochemical and pharmacological properties of A. unedo from Morocco. In Morocco, the plant has been used as a traditional medicine to treat several pathological conditions. Many phytochemical compounds have been reported in the plant, of which vitamins, carotenoids, flavonoids, polyphenols, tannins, and their derivatives are the most prevalent. Leaves and fruits of A. unedo contain the most significant number of phytochemicals among the species. Furthermore, researchers have demonstrated that A. unedo exhibited antioxidant, anticancer, antibacterial, antidiabetic, antiaggregant, and antihypertensive activities due to the presence of many biochemical compounds with health-promoting properties. According to different toxicity tests, the use of A. unedo is devoid of any significant side effects and/or toxicity. Despite its nutraceutical and health-promoting properties, Moroccan A. unedo remains underexploited mainly, and most of its traditional uses have not yet undergone scientific evidence-based research; therefore, improved knowledge about the potential value of the plant would allow understanding of its biological activity based on its phytochemical compounds that may contribute to the species preservation and valorization.

Lifestyle, Oxidative Stress, and Antioxidants: Back and Forth in the Pathophysiology of Chronic Diseases.

Oxidative stress plays an essential role in the pathogenesis of chronic diseases such as cardiovascular diseases, diabetes, neurodegenerative diseases, and cancer. Long term exposure to increased levels of pro-oxidant factors can cause structural defects at a mitochondrial DNA level, as well as functional alteration of several enzymes and cellular structures leading to aberrations in gene expression. The modern lifestyle associated with processed food, exposure to a wide range of chemicals and lack of exercise plays an important role in oxidative stress induction. However, the use of medicinal plants with antioxidant properties has been exploited for their ability to treat or prevent several human pathologies in which oxidative stress seems to be one of the causes. In this review we discuss the diseases in which oxidative stress is one of the triggers and the plant-derived antioxidant compounds with their mechanisms of antioxidant defenses that can help in the prevention of these diseases. Finally, both the beneficial and detrimental effects of antioxidant molecules that are used to reduce oxidative stress in several human conditions are discussed.

Potassium channels on smooth muscle as a molecular target for plant-derived Resveratrol.

Resveratrol (3,5,4'-trihydroxy-trans-stilbene) is a phytoalexin present in a variety of plant species. Resveratrol has a wide spectrum of pharmacologic properties, and it exhibits versatile biological effects on different human and animal models. The studies have shown that potassium (K) channels can be potential targets in the mechanism of resveratrol action. K channels play a crucial role in maintaining membrane potential. Inhibition of K channels causes membrane depolarization and then contraction of smooth muscles, while the activation leads to membrane hyperpolarization and subsequently, relaxation. Five diverse types of K channels have been identified in smooth muscle cells in different tissue: ATP-sensitive K channels (KATP), voltage-dependent K channels (Kv), Ca2+ - and voltage-dependent K channels (BKCa), inward rectifier K channels (Kir), and tandem two-pore K channels (K2P). The expression and activity of K channels altered in many types of diseases. Aberrant function or expression of K channels can be underlying in pathologies such as cardiac arrhythmia, diabetes mellitus, hypertension, preterm birth, preeclampsia, and various types of cancer. Modulation of K channel activity by molecular approaches and selective drug development may be a novel treatment modality for these dysfunctions in the future. The plant-derived non-toxic polyphenols, such as resveratrol, can alter K channel activity and lead to the desired outcome. This review presents the basic properties, physiological, pathophysiological functions of K channels, and pharmacological roles of resveratrol on the major types of K channels that have been determined in smooth muscle cells.

Pregnancy-induced hypertension decreases Kv1.3 potassium channel expression and function in human umbilical vein smooth muscle.

Voltage-gated potassium (Kv) channels are the largest superfamily of potassium (K) channels. A variety of Kv channels are expressed in the vascular smooth muscle cells (SMC). Studies have shown that gestational diabetes mellitus (GDM) and pregnancy-induced hypertension (PIH) cause various changes in the human umbilical vein (HUV). Recently, we have shown that 4-AP, a nonspecific Kv1-4 channel inhibitor, significantly decreases vasorelaxation induced by K channel opener pinacidil in vascular SMCs of the HUVs from normal pregnancies, but not in GDM and PIH. The goal of this study was to provide more detailed insight in the Kv channel subtypes involved in pinacidil-induced vasodilation of HUVs, as well as to investigate potential alterations of their function and expression during GDM and PIH. Margatoxin, a specific blocker of Kv1.2 and Kv1.3 channels, significantly antagonized pinacidil-induced vasorelaxation in normal pregnancy, while in HUVs from GDM and PIH that was not the case, indicating damage of Kv1.2 and Kv1.3 channel function. Immunohistochemistry and Western blot revealed similar expression of Kv1.2 channels in all groups. The expression of Kv1.3 subunit was significantly decreased in PIH, while it remained unchanged in GDM compared to normal pregnancy. Phrixotoxin, specific blocker of Kv4.2 and Kv4.3 channels, did not antagonize response to pinacidil in any of the groups. The major novel findings show that margatoxin antagonized pinacidil-induced relaxation in normal pregnancy, but not in GDM and PIH. Decreased expression of Kv1.3 channels in HUV during PIH may be important pathophysiological mechanism contributing to an increased risk of adverse pregnancy outcomes.

The influence of climate change on human cardiovascular function.

Climate change is considered to have great impact on human health. The heat waves have been associated with excess morbidity and mortality of cardiovascular diseases (CVD) across various populations and geographic locations. Important role in the heat-induced cardiovascular damage has endothelial dysfunction. It has been noticed that hot weather can impair tone and structure of the blood vessels via interfering with variety of biological factors such as nitric oxide synthesize, cytokine production and systemic inflammation. Also, due to dehydration and increased blood viscosity, by promoting thrombogenesis, heat has important impact on patients with atherosclerosis. During chronic exposure to the cold or hot weather cardiovascular function can be decreased, leading to a higher risk of developing heart attack, malignant cardiac arrhythmias, thromboembolic diseases and heat-induced sepsis like shock. It has been shown that changes in the ambient temperature through increasing blood pressure, blood viscosity, and heart rate, contribute to the cardiovascular mortality. The majority of deaths due to heat waves especially affect individuals with preexisting chronic CVD. This population can experience a decline in the health status, since extreme ambient temperature affects pharmacokinetic parameters of many cardiovascular drugs. Increased mortality from ischemic or hemorrhagic stroke can also be related to extreme temperature variations. On a cellular level, higher ambient temperature can limit storage of ATP and O2 increase amount of free radicals and toxic substances and induce neuronal apoptotic signal transduction, which all can lead to a stroke. Preserving cardiovascular function in context of extreme climate changing tends to be particularly challenging.

Malva species: Insights on its chemical composition towards pharmacological applications.

Malvaceae family is typical from the Mediterranean region, contains 240 genera and more than 4,200 species. They are most commonly used as ornamental plants, although they can also be conceived as a food resource and remedy for various diseases, such as digestive, respiratory, genitourinary, throat infections, and skeletal and skin disorders, as also injuries where they are profoundly applied for skin care and as antiseptic and demulcent. They also possess diuretic, lenitive, spasmolytic, and laxative effects, besides to be used as antidiarrheal. Thus, the present review provides in-depth data on Malva spp. potential applications and phytochemical composition for food and pharmaceutical industries. Habitat and cultivation conditions and the clinical reports related to its biological effects are also emphasized. Malva spp. possess a wide variety of chemical constituents (such as polysaccharides, coumarins, flavonoids, polyphenols, vitamins, terpenes, and tannins) found in different plant organs, especially in leaves and flowers, connected to their biological activity. In general, Malva spp. have rather moderate antimicrobial activity, high antiinflammatory and wound healing activities, strong antioxidant activity, and anticancer properties. Results from in vitro and in vivo experiments encourage more in-depth studies, namely clinical trials, towards to improve knowledge on the use of Malva spp. for the treatment of various health conditions in humans.

Effect of gestational diabetes mellitus and pregnancy-induced hypertension on human umbilical vein smooth muscle KATP channels.

Gestational diabetes mellitus (GDM) and pregnancy-induced hypertension (PIH) can jeopardize mother and/or fetus. Vascular ATP-sensitive potassium (KATP) channels most likely participate in the processes of diabetes and hypertension. The aim of this research was to examine whether GDM and PIH cause changes in the expression and function of KATP channels in vascular smooth muscle of human umbilical vein (HUV). Western blot and immunohistochemistry detected significantly decreased expression of Kir6.1 subunit of KATP channels in GDM and PIH, while the expression of SUR2B was unchanged. In GDM, a K+ channel opener, pinacidil caused reduced relaxation of the endothelium-denuded HUVs compared to normal pregnancy. However, its effects in HUVs from PIH subjects were similar to normal pregnancy. In all groups KATP channel blocker glibenclamide antagonized the relaxation of HUV induced by pinacidil without change in the maximal relaxations indicating additional KATP channel-independent mechanisms of pinacidil action. Iberiotoxin, a selective antagonist of large-conductance calcium-activated potassium channels, inhibited the relaxant effect of pinacidil in PIH, but not in normal pregnancy and GDM. Experiments performed in K+-rich solution confirmed the existence of K+-independent effects of pinacidil, which also appear to be impaired in GDM and PIH. Thus, the expression of KATP channels is decreased in GDM and PIH. In GDM, vasorelaxant response of HUV to pinacidil is reduced, while in PIH it remains unchanged. It is very likely that KATP channels modulation and more detailed insight in KATP channel-independent actions of pinacidil may be precious in the therapy of pathological pregnancies.

Berberis Plants-Drifting from Farm to Food Applications, Phytotherapy, and Phytopharmacology.

The genus Berberis includes about 500 different species and commonly grown in Europe, the United States, South Asia, and some northern areas of Iran and Pakistan. Leaves and fruits can be prepared as food flavorings, juices, and teas. Phytochemical analysis of these species has reported alkaloids, tannins, phenolic compounds and oleanolic acid, among others. Moreover, p-cymene, limonene and ocimene as major compounds in essential oils were found by gas chromatography. Berberis is an important group of the plants having enormous potential in the food and pharmaceutical industry, since they possess several properties, including antioxidant, antimicrobial, anticancer activities. Here we would like to review the biological properties of the phytoconstituents of this genus. We emphasize the cultivation control in order to obtain the main bioactive compounds, the antioxidant and antimicrobial properties in order to apply them for food preservation and for treating several diseases, such as cancer, diabetes or Alzheimer. However, further study is needed to confirm the biological efficacy as well as, the toxicity.

Piper Species: A Comprehensive Review on Their Phytochemistry, Biological Activities and Applications.

Piper species are aromatic plants used as spices in the kitchen, but their secondary metabolites have also shown biological effects on human health. These plants are rich in essential oils, which can be found in their fruits, seeds, leaves, branches, roots and stems. Some Piper species have simple chemical profiles, while others, such as Piper nigrum, Piper betle, and Piper auritum, contain very diverse suites of secondary metabolites. In traditional medicine, Piper species have been used worldwide to treat several diseases such as urological problems, skin, liver and stomach ailments, for wound healing, and as antipyretic and anti-inflammatory agents. In addition, Piper species could be used as natural antioxidants and antimicrobial agents in food preservation. The phytochemicals and essential oils of Piper species have shown strong antioxidant activity, in comparison with synthetic antioxidants, and demonstrated antibacterial and antifungal activities against human pathogens. Moreover, Piper species possess therapeutic and preventive potential against several chronic disorders. Among the functional properties of Piper plants/extracts/active components the antiproliferative, anti-inflammatory, and neuropharmacological activities of the extracts and extract-derived bioactive constituents are thought to be key effects for the protection against chronic conditions, based on preclinical in vitro and in vivo studies, besides clinical studies. Habitats and cultivation of Piper species are also covered in this review. In this current work, available literature of chemical constituents of the essential oils Piper plants, their use in traditional medicine, their applications as a food preservative, their antiparasitic activities and other important biological activities are reviewed.

Phytochemicals in Helicobacter pylori Infections: What Are We Doing Now?

In this critical review, plant sources used as effective antibacterial agents against Helicobacter pylori infections are carefully described. The main intrinsic bioactive molecules, responsible for the observed effects are also underlined and their corresponding modes of action specifically highlighted. In addition to traditional uses as herbal remedies, in vitro and in vivo studies focusing on plant extracts and isolated bioactive compounds with anti-H. pylori activity are also critically discussed. Lastly, special attention was also given to plant extracts with urease inhibitory effects, with emphasis on involved modes of action.

Antiulcer Agents: From Plant Extracts to Phytochemicals in Healing Promotion.

In this narrative review, we have comprehensively reviewed the plant sources used as antiulcer agents. From traditional uses as herbal remedies, we have moved on to preclinical evidence, critically discussing the in vitro and in vivo studies focusing on plant extracts and even isolated phytochemicals with antiulcerogenic potential. A particular emphasis was also paid to Helicobacter pylori activity, with emphasis on involved mechanisms of action. Lastly, the issue of safety profile of these plant products has also been addressed.

Differences in antimicrobial consumption, prescribing and isolation rate of multidrug resistant Klebsiella pneumoniae, Pseudomonas aeruginosa and Acinetobacter baumannii on surgical and medical wards.

In order to provide guidance data for clinically rational use of an antibiotics consuption, prescribing and prevalence of multidrug resistant (MDR) Klebsiella pneumoniae, Pseudomonas aeruginosa and Acinetobacter baumannii were monitored on the surgical (S) and medical (M) wards of the University Hospital Center "Dr. Dragisa Misovic-Dedinje" (Belgrade, Serbia), in the study period from 2012 to 2015. Appropriateness of antimicrobial use was evaluated using the Global-Prevalence Survey method designed by the University of Antwerp. The percentages of MDR pathogens relative to the total number of isolates of K. pneumoniae and P. aeruginosa were higher on the S (86.2% and 49.1%) than on the M (63.2% and 36.9%) wards. The percentage of MDR A. baumannii was not different between S (93.7%) and M (79.5%) wards. An overall antibiotics consumption (defined daily doses/100 bed-days) during study was 369.7 and 261.5 on the S and M wards, respectively. A total of 225 prescriptions of antimicrobials were evaluated in138 adults admitted to wards on the day of the survey. The percentage of antimicrobials prescribed for prophylaxis on the M and S wards were 0% and 25%, respectively. Therapies were more frequently empiric (S, 86.8% and M, 80%). The percentages of medical errors on the S and M wards were 74.6% and 27.3%, respectively. The quality indicators for antibiotic prescribing on the S and M wards were as follows: the incorrect choice of antimicrobials (35.6% vs. 20.0%), inappropriate dose interval (70.6% vs. 16.9%) or duration of therapy (72.5% vs. 23.1%), a non-documented stop/review data (73.6% vs. 16.9%) and divergence from guidelines (71.9% vs. 23.1%). Treatment based on biomarkers was more common on the M wards as compared to the S wards. The increasing prevalence of MDR pathogens, a very high consumption and incorrect prescribing of antimicrobials need special attention, particularly on the S wards.