Natural products targeting the PI3K-Akt-mTOR signaling pathway in cancer: A novel therapeutic strategy.

The phosphatidylinositol 3-kinase (PI3K)-Akt and the mammalian target of rapamycin (mTOR) represent two vital intracellular signaling pathways, which are associated with various aspects of cellular functions. These functions play vital roles in quiescence, survival, and growth in normal physiological circumstances as well as in various pathological disorders, including cancer. These two pathways are so intimately connected to each other that in some instances these are considered as one unique pathway crucial for cell cycle regulation. The purpose of this review is to emphasize the role of PI3K-Akt-mTOR signaling pathway in different cancer conditions and the importance of natural products targeting the PI3K-Akt-mTOR signaling pathway. This review also aims to draw the attention of scientists and researchers to the assorted beneficial effects of the numerous classes of natural products for the development of new and safe drugs for possible cancer therapy. We also summarize and critically analyze various preclinical and clinical studies on bioactive compounds and constituents, which are derived from natural products, to target the PI3K-Akt-mTOR signaling pathway for cancer prevention and intervention.

Advancing Digital Health Innovation in Oncology: Priorities for High-Value Digital Transformation in Cancer Care.

Although health care delivery is becoming increasingly digitized, driven by the pursuit of improved access, equity, efficiency, and effectiveness, progress does not appear to be equally distributed across therapeutic areas. Oncology is renowned for leading innovation in research and in care; digital pathology, digital radiology, real-world data, next-generation sequencing, patient-reported outcomes, and precision approaches driven by complex data and biomarkers are hallmarks of the field. However, remote patient monitoring, decentralized approaches to care and research, "hospital at home," and machine learning techniques have yet to be broadly deployed to improve cancer care. In response, the Digital Medicine Society and Moffitt Cancer Center convened a multistakeholder roundtable discussion to bring together leading experts in cancer care and digital innovation. This viewpoint highlights the findings from these discussions, in which experts agreed that digital innovation is lagging in oncology relative to other therapeutic areas. It reports that this lag is most likely attributed to poor articulation of the challenges in cancer care and research best suited to digital solutions, lack of incentives and support, and missing standardized infrastructure to implement digital innovations. It concludes with suggestions for actions needed to bring the promise of digitization to cancer care to improve lives.

Targeting AMPK signaling pathway by natural products for treatment of diabetes mellitus and its complications.

Diabetes affects a large population of the world. Lifestyle, obesity, dietary habits, and genetic factors contribute to this metabolic disease. A target pathway to control diabetes is the 5'-adenosine monophosphate-activated protein kinase (AMPK) signaling pathway. AMPK is a heterotrimeric protein with α, ß, and γ subunits. In several studies, AMPK activation enhanced glucose uptake into cells and inhibited intracellular glucose production. Impairment of AMPK activity is present in diabetes, according to some studies. Drugs used in the treatment of diabetes, such as metformin, are also known to act through regulation of AMPK. Thus, drugs that activate and regulate AMPK are potential candidates for the treatment of diabetes. In addition, many patients encounter important adverse effects, like hypoglycemia, while using allopathic drugs. As a result, the investigation of plant-derived natural drugs that lack adverse side effects and treat diabetes is necessary. Natural products like berberine, quercetin, resveratrol, and so forth have shown significant potential in regulating and activating the AMPK pathway which can lead to manage diabetes mellitus and its complications.

Targeting BDNF signaling by natural products: Novel synaptic repair therapeutics for neurodegeneration and behavior disorders.

Neurodegenerative disorders like Alzheimer's disease, Huntington's disease, Parkinson's disease, spinocerebellar ataxias, amyotrophic lateral sclerosis, frontotemporal dementia to prion diseases, Friedreich's ataxia, hereditary spastic paraplegia and optic atrophy type 1, and behavior disorders like neuropsychiatric, hyperactivity and autism spectrum disorders are closely associated with neurobiological deficits. Brain derived neurotrophic factor (BDNF) is an extensively studied neurotrophin. BDNF is essential for neuronal genesis, differentiation, survival, growth, plasticity, synaptic viability and transmission. BDNF has emerged as a promising target for regulating synaptic activity and plasticity. An overview of effects and mechanisms of the natural products targeting BDNF is described. This review is an attempt to enumerate the effects of various natural products on BDNF as a novel therapeutic approach for neurodegenerative and neuropsychiatric disorders.

Himalayan Citrus jambhiri juice reduced renal crystallization in nephrolithiasis by possible inhibition of glycolate oxidase and matrix metalloproteinases.

ETHNOPHARMACOLOGICAL RELEVANCE: Citrus fruits are a very rich source of electrolytes and citric acid. They have been used traditionally for treating urinary ailments and renal stones. Citrus jambhiri is indigenously used as a diuretic. AIM OF THE STUDY: Present study aimed at establishing the antiurolithiatic potential of the juice of Citrus jambhiri fruits along with the elucidation of the mechanism involved in the urolithiasis disease defying activity. METHODS: The antiurolithiatic activity was established by means of nucleation, growth and aggregation assay in the in vitro settings and by means of ethylene glycol mediated calcium oxalate urolithiasis in the male Wistar rats. Docking studies were performed in an attempt to determine the mechanism of the antiurolithiatic action. RESULTS: Present study revealed the role of C. jambhiri fruit juice in reducing nucleation, growth and aggregation of calcium oxalate crystals by possible reduction in the urinary supersaturation relative to calcium oxalate and raising the zeta potential of the calcium oxalate crystals. C. jambhiri fruit juice treatment in experimental rats produced significant amelioration of hypercalciuria, hyperoxaluria, hyperphosphaturia, hyperproteinuria, hyperuricosuria, hypocitraturia and hypomagnesiuria and ion activity product of calcium oxalate. It exhibited nephroprotection against calcium oxalate crystals induced renal tubular dilation and renal tissue deterioration. Docking studies further revealed high binding potential of the phytoconstituents of C. jambhiri viz. narirutin, neohesperidin, hesperidin, rutin and citric acid with glycolate oxidase and matrix metalloproteinase-9. CONCLUSION: C. jambhiri fruit juice possesses excellent antiurolithiatic activity. The study reveals antiurolithiatic mechanism that involves restoration of equilibrium between the promoters and inhibitors of stone formation; and inhibition of matrix metalloproteinases and glycolate oxidase.

Lignans: a versatile source of anticancer drugs.

Background: Cancer is considered as the second deadliest disease globally. Plants have continuously offered unique secondary metabolites with remarkable biological applications. Lignans have gained great importance due to their biological activity. Previous studies revealed that the most remarkable bioactivity of lignan class of molecules is anticancer. They are derived from the oxidative dimerization of two phenylpropanoid units. This review covers the isolated anticancer lignans and their mechanistic aspects. Main body: A bibliographic investigation was performed by analyzing the information available on anticancer lignans in the internationally accepted scientific databases including Web of Science, SciFinder, PubMed, Scopus, and Google Scholar. In this review we have tried to sum up the isolated anticancerous lignan, its source, active plant part, extract and various cell lines used to establish different studies. Here we have included a total number of 113 natural lignans. Many studies that mainly performed in human cell lines have reported. Very few plants have been evaluated for their in vivo anticancer activity. Conclusion: It can be concluded that in near future the lignans may be an effective pharmacon for the treatment of cancer. Fruitful areas of future research may be in modifying natural lignans or synthesizing new lignans with structural diversity and potent pharmacological activities. Extensive studies are needed to be done highlighting the mechanism of anticancer action of explored and unexplored plants. The data will definitely attract many researchers to start further experimentation that might lead to the drugs for the cancer treatment.

Emerging Need of Today: Significant Utilization of Various Databases and Softwares in Drug Design and Development.

In drug discovery, in silico methods have become a very important part of the process. These approaches impact the entire development process by discovering and identifying new target proteins as well as designing potential ligands with a significant reduction of time and cost. Furthermore, in silico approaches are also preferred because of reduction in the experimental use of animals as; in vivo testing for safer drug design and repositioning of known drugs. Novel software-based discovery and development such as direct/indirect drug design, molecular modelling, docking, screening, drug-receptor interaction, and molecular simulation studies are very important tools for the predictions of ligand-target interaction pattern, pharmacodynamics as well as pharmacokinetic properties of ligands. On the other part, the computational approaches can be numerous, requiring interdisciplinary studies and the application of advanced computer technology to design effective and commercially feasible drugs. This review mainly focuses on the various databases and software used in drug design and development to speed up the process.

Himalayan Ficus palmata L. Fruit Extract Showed In Vivo Central and Peripheral Analgesic Activity Involving COX-2 and Mu Opioid Receptors.

Analgesic drugs like morphine and non-steroidal anti-inflammatory drugs exhibit several harmful effects. Here, we show for the first time the analgesic activity of Ficus palmata L. fruit extract (FPFE) on different analgesic rat models along with the in silico studies of some of the main phytochemicals of this plant. We performed in vivo pain models, along with in silico docking studies against the active site of COX-2 protein and mu-opioid receptors. A significant (p < 0.05) analgesic effect of FPFE was observed, and it was found that rutin has good pose and score as compared to diclofenac and morphinan antagonist (X-ligand), and psoralen has binding affinity almost equal to diclofenac, but a lower binding affinity as compared to rutin. The results proved that F. palmata fruits have the potential to ameliorate painful conditions.

Role of Nitric Oxide in Neurodegeneration: Function, Regulation, and Inhibition.

Reactive nitrogen species (RNS) and reactive oxygen species (ROS), collectively known as reactive oxygen and nitrogen species (RONS), are the products of normal cellular metabolism and interact with several vital biomolecules including nucleic acid, proteins, and membrane lipids and alter their function in an irreversible manner which can lead to cell death. There is an imperative role for oxidative stress in the pathogenesis of cognitive impairments and the development and progression of neural injury. Elevated production of higher amounts of nitric oxide (NO) takes place in numerous pathological conditions, such as neurodegenerative diseases, inflammation, and ischemia, which occur concurrently with elevated nitrosative/oxidative stress. The enzyme nitric oxide synthase (NOS) is responsible for the generation of NO in different cells by conversion of Larginine (Arg) to L-citrulline. Therefore, the NO signaling pathway represents a viable therapeutic target. Naturally occurring polyphenols targeting the NO signaling pathway can be of major importance in the field of neurodegeneration and related complications. Here, we comprehensively review the importance of NO and its production in the human body and afterwards highlight the importance of various natural products along with their mechanisms against various neurodegenerative diseases involving their effect on NO production.

Anticalcifying effect of Daucus carota in experimental urolithiasis in Wistar rats.

BACKGROUND: Urolithiasis is a burgeoning disease that results from pathological biomineralization. Daucus carota L. is a widely consumed food crop with reported nephroprotective and diuretic activity. Its potential for Ashmari bhedan (destruction of stone/calculi) or treatment of urinary calculi has been explored traditionally. However, no scientific evidence is available to prove its antiurolithiatic efficacy. Moreover, establishing the antiurolithiatic effects of D. carota, an extensively consumed commodity with numerous health benefits, would provide a beneficial dietary measure for the prevention and cure of urolithiasis. OBJECTIVE: The study aimed at investigating in vivo antiurolithiatic potential of hydroethanolic extract of D. carota roots against calcium oxalate urolithiasis. MATERIALS AND METHODS: Ethylene glycol and ammonium chloride induced hyperoxaluria model of urolithiasis in male Wistar rats was used for the study. Urine and serum parameters and, kidney histopathology was used to determine the antilithic efficacy of D. carota root extract. RESULTS: D. carota extract significantly ameliorated abnormal urinary levels of calcium, oxalate, phosphate, magnesium, citrate, protein and uric acid in lithogenic rats. Serum BUN, creatinine and uric acid levels; and calcium, phosphate and oxalate deposition in kidney tissue were also rendered normal following D. carota treatment. D. carota extract also prevented oxidative stress mediated renal tissue degeneration both prophylactically and curatively. CONCLUSION: This study suggests antiurolithiatic effect of D. carota roots, which can be attributed to its anticrystallization property, ability to ameliorate urine and serum biochemistry and renal cellularity.

Rupture of Non-communicating Rudimentary Horn Pregnancy at 15 Weeks with Previous Normal Pregnancies: A Case Report.

Rudimentary horn is a mullerian anomaly that is a variant of unicornuate uterus. Rudimentary horn pregnancies are rare and associated with increased maternal morbidity and mortality. Diagnosis of rudimentary horn pregnancy and its rupture in a woman with previous vaginal delivery is challenging. Although ultrasonography is an important diagnostic tool, it has low sensitivity in making diagnosis of ruptured rudimentary horn pregnancy. Therefore, clinicians should have high index of suspicion in such cases. We report a case of G3P2L2 at 15 weeks period of gestation referred to our centre as a case of intrauterine pregnancy with acute abdomen. She underwent emergency laparotomy and was found to have ruptured rudimentary horn intraoperatively. Excision of the ruptured rudimentary horn and ipsilateral salpingectomy was done and the patient had an uneventful postoperative recovery.

Prevalence of undernutrition among children in the Garhwal Himalayas.

BACKGROUND: Nutritional status is the best indicator of the global well-being of children. In India every third child is underweight, whereas in the Garhwal Himalayas only one-fifth of the children are nutritionally normal. Information regarding the causes of such low nutritional status in children of Garhwal is lacking. OBJECTIVE: The present study was designed to identify factors that may influence the nutritional status of the children of the Garhwal Himalayas. Stunting, signifying long-term irreversible chronic undernutrition, was studied, along with wasting, which signifies acute undernutrition among children. METHODS: Forty families from one town and one village in each of the three major agroclimatic situations (high, middle, and low hills) were selected at random (total 240 families). The nutritional status of 353 children (0 to 12 years of age) was assessed by nutritional anthropometry and compared with tables of weight-for-age and height-for-age z-scores (WAZ and HAZ) identifying wasting and stunting, respectively, and compared with the World Health Organization (WHO) Growth Reference charts 2007. Chi-square test was applied to analyze the effects of age, sex, altitude, and area on the nutritional status of children. RESULTS: Of the 353 children studied, 38.2% belonged to the school-aged group, with 7% more girls than boys. Only 11.3% of the children had normal HAZ while 10.3% had normal WAZ. The largest percentages of children (31.8% HAZ and 29.1% WAZ) were clustered in the SD1 group, that is the severely stunted or wasted group. In every age group except the 9- to 12-year group, most of the children were found in the WAZ SD1 category. Gender appeared to influence the SD1 category significantly. There were 17.0% severely stunted girls (SD1), as compared to 14.8% boys; while the percentages of WAZ girls was 16.1% and boys was 13%. The situation in the urban areas was slightly better: 6.4% of the sample had normal HAZ and 7.1% had normal WAZ, compared with 4.4% and 4.6% of the rural children. In all three agroclimatic situations, the largest percentage of children fell in the HAZ SD1 (stunted) category (15.3% in the high hills, 7.3% in the middle hills, and 9.5% in the low hills). There is a significant effect of area (rural vs. urban) on stunting and wasting among children. The child's sex affects stunting only. The other two variables, altitude and age, do not show a significant relationship with stunting or wasting. CONCLUSIONS: The rate of malnutrition among children in the Garhwal is very high. The majority are severely stunted and wasted, indicating a high prevalence of both chronic and acute malnutrition. Only the area of residence (rural or urban) had an influence on a child's nutritional status.

Down syndrome: Neurobiological alterations and therapeutic targets.

Down syndrome (DS) is a genetic disease that occurs due to an aneuploidy of human chromosome 21. Trisomy of chromosome 21 is a primary genetic cause of developmental abnormalities leading to cognitive and learning deficits. Impairments in GABAergic transmission, noradrenergic neuronal loss, anomalous glutamatergic transmission and N-methyl-d-aspartate receptor signalling, mitochondrial dysfunction, increased oxidative stress and inflammation, differentially expressed microRNAs, increased expression of crucial chromosome 21 genes, and DNA hyper-methylation and hyperactive homocysteine trans-sulfuration pathway, are common incongruities that have been reported in DS and might contribute to cognitive impairment and intellectual disability. This review provides an update on metabolic and neurobiological alterations in DS. It also provides an overview of the currently available pharmacological therapies that may influence and/or reverse these alterations in DS.

Ethnopharmacological Applications Targeting Alcohol Abuse: Overview and Outlook.

Excessive alcohol consumption is the cause of several diseases and thus is of a major concern for society. Worldwide alcohol consumption has increased by many folds over the past decades. This urgently calls for intervention and relapse counteract measures. Modern pharmacological solutions induce complete alcohol self-restraint and prevent relapse, but they have many side effects. Natural products are most promising as they cause fewer adverse effects. Here we discuss in detail the medicinal plants used in various traditional/folklore medicine systems for targeting alcohol abuse. We also comprehensively describe preclinical and clinical studies done on some of these plants along with the possible mechanisms of action.

Ethnopharmacological Approaches for Dementia Therapy and Significance of Natural Products and Herbal Drugs.

Dementia is a clinical syndrome wherein gradual decline of mental and cognitive capabilities of an afflicted person takes place. Dementia is associated with various risk factors and conditions such as insufficient cerebral blood supply, toxin exposure, mitochondrial dysfunction, oxidative damage, and often coexisting with some neurodegenerative disorders such as Alzheimer's disease (AD), Huntington's disease (HD), and Parkinson's disease (PD). Although there are well-established (semi-)synthetic drugs currently used for the management of AD and AD-associated dementia, most of them have several adverse effects. Thus, traditional medicine provides various plant-derived lead molecules that may be useful for further medical research. Herein we review the worldwide use of ethnomedicinal plants in dementia treatment. We have explored a number of recognized databases by using keywords and phrases such as "dementia", "Alzheimer's," "traditional medicine," "ethnopharmacology," "ethnobotany," "herbs," "medicinal plants" or other relevant terms, and summarized 90 medicinal plants that are traditionally used to treat dementia. Moreover, we highlight five medicinal plants or plant genera of prime importance and discuss the physiological effects, as well as the mechanism of action of their major bioactive compounds. Furthermore, the link between mitochondrial dysfunction and dementia is also discussed. We conclude that several drugs of plant origin may serve as promising therapeutics for the treatment of dementia, however, pivotal evidence for their therapeutic efficacy in advanced clinical studies is still lacking.

Ethnopharmacological Approaches for Therapy of Jaundice: Part I.

Jaundice is a very common symptom especially in the developing countries. It is associated with several hepatic diseases which are still major causes of death. There are many different approaches to jaundice treatment and the growing number of ethnomedicinal studies shows the plant pharmacology as very promising direction. Many medicinal plants are used for the treatment of jaundice, however a comprehensive review on this subject has not been published. The use of medicinal plants in drug discovery is highly emphasized (based on their traditional and safe uses in different folk medicine systems from ancient times). Many sophisticated analytical techniques are emerging in the pharmaceutical field to validate and discover new biologically active chemical entities derived from plants. Here, we aim to classify and categorize medicinal plants relevant for the treatment of jaundice according to their origin, geographical location, and usage. Our search included various databases like Pubmed, ScienceDirect, Google Scholar. Keywords and phrases used for these searches included: "jaundice," "hyperbilirubinemia," "serum glutamate," "bilirubin," "Ayurveda." The first part of the review focuses on the variety of medicinal plant used for the treatment of jaundice (a total of 207 medicinal plants). In the second part, possible mechanisms of action of biologically active secondary metabolites of plants from five families for jaundice treatment are discussed.

Ethnopharmacological Approaches for Therapy of Jaundice: Part II. Highly Used Plant Species from Acanthaceae, Euphorbiaceae, Asteraceae, Combretaceae, and Fabaceae Families.

In many developing countries, jaundice is the common symptom of hepatic diseases which are a major cause of mortality. The use of natural product-based therapies is very popular for such hepatic disorders. A great number of medicinal plants have been utilized for this purpose and some facilitated the discovery of active compounds which helped the development of new synthetic drugs against jaundice. However, more epidemiological studies and clinical trials are required for the practical implementation of the plant pharmacotherapy of jaundice. The focus of this second part of our review is on several of the most prominent plants used against jaundice identified in the analysis performed in the first part of the review viz. Andrographis paniculata (Burm.f.) Nees, Silybum marianum (L.) Gaertn., Terminalia chebula Retz., Glycyrrhiza glabra L. and some species of genus Phyllanthus. Furthermore, we discuss their physiological effects, biologically active ingredients, and the potential mechanisms of action. Some of the most important active ingredients were silybin (also recommended by German commission), phyllanthin and andrographolide, whose action leads to bilirubin reduction and normalization of the levels of relevant serum enzymes indicative for the pathophysiological status of the liver.

Corrigendum: Ethnopharmacological Approaches for Therapy of Jaundice: Part II. Highly Used Plant Species from Acanthaceae, Euphorbiaceae, Asteraceae, Combretaceae, and Fabaceae Families.

[This corrects the article on p. 519 in vol. 8, PMID: 28848436.].