Withania somnifera (L.) Dunal, a Potential Source of Phytochemicals for Treating Neurodegenerative Diseases: A Systematic Review.

Withania somnifera (L.) Dunal is a medicinal plant belonging to the traditional Indian medical system, showing various therapeutic effects such as anti-cancer, anti-inflammatory, anti-microbial, anti-diabetic, and hepatoprotective activity. Of great interest is W. somnifera's potential beneficial effect against neurodegenerative diseases, since the authorized medicinal treatments can only delay disease progression and provide symptomatic relief and are not without side effects. A systematic search of PubMed and Scopus databases was performed to identify preclinical and clinical studies focusing on the applications of W. somnifera in preventing neurodegenerative diseases. Only English articles and those containing the keywords (Withania somnifera AND "neurodegenerative diseases", "neuroprotective effects", "Huntington", "Parkinson", "Alzheimer", "Amyotrophic Lateral Sclerosis", "neurological disorders") in the title or abstract were considered. Reviews, editorials, letters, meta-analyses, conference papers, short surveys, and book chapters were not considered. Selected articles were grouped by pathologies and summarized, considering the mechanism of action. The quality assessment and the risk of bias were performed using the Cochrane Handbook for Systematic Reviews of Interventions checklist. This review uses a systematic approach to summarize the results from 60 investigations to highlight the potential role of W. somnifera and its specialized metabolites in treating or preventing neurodegenerative diseases.

Cyanidin-3-O-glucoside as a Nutrigenomic Factor in Type 2 Diabetes and Its Prominent Impact on Health.

Type 2 diabetes (T2D) accounts for a global health problem. It is a complex disease as a result of the combination of environmental as well as genetic factors. Morbidity is still increasing across the world. One of the possibilities for the prevention and mitigation of the negative consequences of type 2 diabetes is a nutritional diet rich in bioactive compounds such as polyphenols. This review is focused on cyanidin-3-O-glucosidase (C3G), which belongs to the anthocyanins subclass, and its anti-diabetic properties. There are numerous pieces of evidence that C3G exerts positive effects on diabetic parameters, including in vitro and in vivo studies. It is involved in alleviating inflammation, reducing blood glucose, controlling postprandial hyperglycemia, and gene expression related to the development of T2D. C3G is one of the beneficial polyphenolic compounds that may help to overcome the public health problems associated with T2D.

An Insight into Citrus medica Linn.: A Systematic Review on Phytochemical Profile and Biological Activities.

Plant species are a reservoir of natural compounds that can potentially be used to treat different diseases. Citrus medica Linn. belonging to the Rutaceae family, has been used for centuries in medicine for its antioxidant, anti-inflammatory, antimicrobial, antiviral, and antihyperglycemic properties. These activities are ascribable not only to the presence of health-promoting macronutrients and micronutrients, such as carbohydrates, minerals, amino acids, and vitamins, but also to specialized metabolites, such as flavonoids (apigenin, hesperetin, hesperidin, naringin, naringenin, rutin, quercetin, and diosmin), coumarins (citropten, scoparone, and bergapten), terpenes (limonene, γ-terpinene, limonin, and nomilin), and phenolic acids (p-coumaric acid, trans-ferulic acid, and chlorogenic acid). In recent years, particular attention has been focused on the antioxidant, anti-inflammatory, antimicrobial activity, antidiabetic, anticancer, and neuroprotective activity of C. medica. However, although many studies have reported this species' chemical and biological properties, the literature has never been analyzed via a systematic approach. For this reason, using PubMed and Scopus as databases, we performed a systematic review of C. medica's chemical composition and biological properties to inspire new research approaches and increase its curative application.

Neurotensin(8-13) analogs as dual NTS1 and NTS2 receptor ligands with enhanced effects on a mouse model of Parkinson's disease.

The modulatory interactions between neurotensin (NT) and the dopaminergic neurotransmitter system in the brain suggest that NT may be associated with the progression of Parkinson's disease (PD). NT exerts its neurophysiological effects by interactions with the human NT receptors type 1 (hNTS1) and 2 (hNTS2). Therefore, both receptor subtypes are promising targets for the development of novel NT-based analogs for the treatment of PD. In this study, we used a virtually guided molecular modeling approach to predict the activity of NT(8-13) analogs by investigating the docking models of ligands designed for binding to the human NTS1 and NTS2 receptors. The importance of the residues at positions 8 and/or 9 for hNTS1 and hNTS2 receptor binding affinity was experimentally confirmed by radioligand binding assays. Further in vitro ADME profiling and in vivo studies revealed that, compared to the parent peptide NT(8-13), compound 10 exhibited improved stability and BBB permeability combined with a significant enhancement of the motor function and memory in a mouse model of PD. The herein reported NTS1/NTS2 dual-specific NT(8-13) analogs represent an attractive tool for the development of therapeutic strategies against PD and potentially other CNS disorders.

Bibliometric analysis and evidence of clinical efficacy and safety of digital pills.

Objectives: Digital pills are new technologies that aim to improve healthcare by increasing medication adherence. The aim of the work was a bibliometric analysis of clinical studies of digital pills and an assessment of the level of evidence of their effectiveness, safety, and prospects for the future. Materials and Methods: The studies were conducted using online databases such as ClinicalTrials.gov, Dimensions, and Web of Science for the period January 2012 to July 2022. The VOSviewer tool for building and visualizing bibliometric networks was used. Results: Bibliometric analysis of the scientific literature revealed that over the past 10 years, the number of publications about digital pills has noticeably increased, which indicates the increasing importance of this field of knowledge. The leading positions in this area are occupied by scientists from the United States, the United Kingdom, and India. Sources of financial support for authors of publications in the field of digital pills are funds from leading developer companies, budget allocations, and funds from non-commercial organizations. Public-private partnerships are an important path to develop and implement digital pills. The four main clusters of digital pill studies were highlighted and visualized: efficacy and safety analysis for serious mental disorders; treatment and costs of tuberculosis therapy; features of the treatment of diabetes, cardiovascular diseases, and AIDS; and usage monitoring. Available publications demonstrate the efficacy potential and safety of digital pills. Nevertheless, the effects of digital pills have not yet been fully studied. Conclusion: Priority areas for future research are further randomized controlled clinical trials and meta-analyses, which are necessary for a high level (I level) of evidence for therapeutic applications of digital pills, as well as pharmacoeconomic studies.

The International Natural Product Sciences Taskforce (INPST) and the power of Twitter networking exemplified through #INPST hashtag analysis.

BACKGROUND: The development of digital technologies and the evolution of open innovation approaches have enabled the creation of diverse virtual organizations and enterprises coordinating their activities primarily online. The open innovation platform titled "International Natural Product Sciences Taskforce" (INPST) was established in 2018, to bring together in collaborative environment individuals and organizations interested in natural product scientific research, and to empower their interactions by using digital communication tools. METHODS: In this work, we present a general overview of INPST activities and showcase the specific use of Twitter as a powerful networking tool that was used to host a one-week "2021 INPST Twitter Networking Event" (spanning from 31st May 2021 to 6th June 2021) based on the application of the Twitter hashtag #INPST. RESULTS AND CONCLUSION: The use of this hashtag during the networking event period was analyzed with Symplur Signals (https://www.symplur.com/), revealing a total of 6,036 tweets, shared by 686 users, which generated a total of 65,004,773 impressions (views of the respective tweets). This networking event's achieved high visibility and participation rate showcases a convincing example of how this social media platform can be used as a highly effective tool to host virtual Twitter-based international biomedical research events.

In Silico Identification of Multi-Target Ligands as Promising Hit Compounds for Neurodegenerative Diseases Drug Development.

The conventional treatment of neurodegenerative diseases (NDDs) is based on the "one molecule-one target" paradigm. To combat the multifactorial nature of NDDs, the focus is now shifted toward the development of small-molecule-based compounds that can modulate more than one protein target, known as "multi-target-directed ligands" (MTDLs), while having low affinity for proteins that are irrelevant for the therapy. The in silico approaches have demonstrated a potential to be a suitable tool for the identification of MTDLs as promising drug candidates with reduction in cost and time for research and development. In this study more than 650,000 compounds were screened by a series of in silico approaches to identify drug-like compounds with predicted activity simultaneously towards three important proteins in the NDDs symptomatic treatment: acetylcholinesterase (AChE), histone deacetylase 2 (HDAC2), and monoamine oxidase B (MAO-B). The compounds with affinities below 5.0 µM for all studied targets were additionally filtered to remove known non-specifically binding or unstable compounds. The selected four hits underwent subsequent refinement through in silico blood-brain barrier penetration estimation, safety evaluation, and molecular dynamics simulations resulting in two hit compounds that constitute a rational basis for further development of multi-target active compounds against NDDs.

Digital Pills with Ingestible Sensors: Patent Landscape Analysis.

The modern healthcare system is directly related to the development of digital health tools and solutions. Pills with digital sensors represent a highly innovative class of new pharmaceuticals. The aim of this work was to analyze the patent landscape and to systematize the main trends in patent protection of digital pills with ingestible sensors worldwide; accordingly, to identify the patenting leaders as well as the main prevailing areas of therapy for patent protection, and the future perspectives in the field. In July 2022, a search was conducted using Internet databases, such as the EPO, USPTO, FDA and the Lens database. The patent landscape analysis shows an increase in the number of patents related to digital pills with ingestible sensors for mobile clinical monitoring, smart drug delivery, and endoscopy diagnostics. The leaders in the number of patents issued are the United States, the European Patent Office, Canada, Australia, and China. The following main areas of patenting digital pills with ingestible sensors were identified: treatment in the field of mental health; HIV/AIDS; pain control; cardiovascular diseases; diabetes; gastroenterology (including hepatitis C); oncology; tuberculosis; and transplantology. The development of scientific and practical approaches towards the implementation of effective and safe digital pills will improve treatment outcomes, increase compliance, reduce hospital stays, provide mobile clinical monitoring, have a positive impact on treatment costs and will contribute to increased patient safety.

Rilzabrutinib, an Oral BTK Inhibitor, in Immune Thrombocytopenia.

BACKGROUND: Rilzabrutinib, an oral, reversible covalent inhibitor of Bruton's tyrosine kinase, may increase platelet counts in patients with immune thrombocytopenia by means of dual mechanisms of action: decreased macrophage (Fcγ receptor)-mediated platelet destruction and reduced production of pathogenic autoantibodies. METHODS: In an international, adaptive, open-label, dose-finding, phase 1-2 clinical trial, we evaluated rilzabrutinib therapy in previously treated patients with immune thrombocytopenia. We used intrapatient dose escalation of oral rilzabrutinib over a period of 24 weeks; the lowest starting dose was 200 mg once daily, with higher starting doses of 400 mg once daily, 300 mg twice daily, and 400 mg twice daily. The primary end points were safety and platelet response (defined as at least two consecutive platelet counts of ≥50×103 per cubic millimeter and an increase from baseline of ≥20×103 per cubic millimeter without the use of rescue medication). RESULTS: Sixty patients were enrolled. At baseline, the median platelet count was 15×103 per cubic millimeter, the median duration of disease was 6.3 years, and patients had received a median of four different immune thrombocytopenia therapies previously. All the treatment-related adverse events were of grade 1 or 2 and transient. There were no treatment-related bleeding or thrombotic events of grade 2 or higher. At a median of 167.5 days (range, 4 to 293) of treatment, 24 of 60 patients (40%) overall and 18 of the 45 patients (40%) who had started rilzabrutinib treatment at the highest dose met the primary end point of platelet response. The median time to the first platelet count of at least 50×103 per cubic millimeter was 11.5 days. Among patients with a primary platelet response, the mean percentage of weeks with a platelet count of at least 50×103 per cubic millimeter was 65%. CONCLUSIONS: Rilzabrutinib was active and associated with only low-level toxic effects at all dose levels. The dose of 400 mg twice daily was identified as the dose for further testing. Overall, rilzabrutinib showed a rapid and durable clinical activity that improved with length of treatment. (Funded by Sanofi; ClinicalTrials.gov number, NCT03395210; EudraCT number, 2017-004012-19.).

SR-BI as a target of natural products and its significance in cancer.

Scavenger receptor class B type I (SR-BI) protein is an integral membrane glycoprotein. SR-BI is emerging as a multifunctional protein, which regulates autophagy, efferocytosis, cell survival and inflammation. It is well known that SR-BI plays a critical role in lipoprotein metabolism by mediating cholesteryl esters selective uptake and the bi-directional flux of free cholesterol. Recently, SR-BI has also been identified as a potential marker for cancer diagnosis, prognosis, or even a treatment target. Natural products are a promising source for the discovery of new drug leads. Multiple natural products were identified to regulate SR-BI protein expression. There are still a number of challenges in modulating SR-BI expression in cancer and in using natural products for modulation of such protein expression. In this review, our purpose is to discuss the relationship between SR-BI protein and cancer, and the molecular mechanisms regulating SR-BI expression, as well as to provide an overview of natural products that regulate SR-BI expression.

Vasculoprotective effects of ginger (Zingiber officinale Roscoe) and underlying molecular mechanisms.

Ginger (Zingiber officinale Roscoe) is a common and widely used spice. It is rich in various chemical constituents, including phenolic compounds, terpenes, polysaccharides, lipids, organic acids, and raw fibers. Herein, we reviewed its effects on the vascular system. Studies utilizing cell cultures or animal models showed that ginger constituents alleviate oxidative stress and inflammation, increase nitric oxide synthesis, suppress vascular smooth muscle cell proliferation, promote cholesterol efflux from macrophages, inhibit angiogenesis, block voltage-dependent Ca2+ channels, and induce autophagy. In clinical trials, ginger was shown to have a favorable effect on serum lipids, inflammatory cytokines, blood pressure, and platelet aggregation. Taken together, these studies point to the potential benefits of ginger and its constituents in the treatment of hypertension, coronary artery disease, peripheral arterial diseases, and other vascular diseases.

Natural Products, the Continuous Source of Therapeutic Molecules for Various Diseases: Literature Landscape Analysis.

BACKGROUND: Substances present in nature have been a continuous source for the development of drugs for cardiovascular and infectious diseases, cancer, and many other diseases. As the literature concerning these natural products grows, it becomes more difficult for a reader to quickly grasp the essential facts and develop a well-informed impression of this field of research. Until now, it has also been difficult to determine which natural products and research objectives were gaining the most attention as measured by a number of citations. OBJECTIVE: The current study of all published articles concerned with natural products sought to identify which natural products and which research objectives are connected with the major contributors to scientific journals based on the number of relevant publications and the number of times each publication was cited elsewhere. METHODS: Bibliometric data, including citation data, were extracted from the Web of Science database using the search string TS=("natural product*)" and analyzed by the VOSviewer software. RESULTS: The search yielded 63,194 articles, with more than half of the manuscripts published since 2012. The ratio of original articles to reviews was 5.8:1. The major contributing countries were the United States, China, Germany, Japan, and India. Articles were published mainly in journals focused on chemistry, pharmacology or biochemistry. Curcumin, resveratrol, and terpenoids were the most frequently cited natural products. CONCLUSION: The results of the current study provide researchers from different backgrounds and healthcare professionals with a brief overview of the major trends in natural-product research in the form of a citation-based summary of the relevant literature.

Reactive Oxygen Species and Their Impact in Neurodegenerative Diseases: Literature Landscape Analysis.

Significance: The excessive production of reactive oxygen species (ROS) has been linked to neurodegenerative diseases (NDs), and, therefore, many scientific works were published on the impact of ROS on the development of prevalent NDs, such as Alzheimer's disease (AD) and Parkinson's disease (PD). Since quantitative and qualitative bibliometric analyses in this research area have not yet been done, the aim of this work is to explore the scientific literature implying ROS in NDs and to identify the major contributors, mainstream research themes, and topics on the rise. Recent Advances: Overall, 22,885 publications were identified and analyzed within the Web of Science (WoS) Core Collection electronic database (Clarivate Analytics, Philadelphia, PA). Most of the manuscripts were published in the 21st century. The publications were mainly related to the WoS categories Neurosciences and Biochemistry molecular biology. The United States is the major contributor, harboring the most productive authors and institutions. China, South Korea, and India have emerged as upcoming major contributors in the 2010s. Two most productive journals were Journal of Neurochemistry and Free Radical Biology and Medicine. Critical Issues: AD, PD, and amyotrophic lateral sclerosis were much more investigated than multiple sclerosis and Huntington's disease. Vitamin E and curcumin were frequently mentioned as potential antioxidant therapeutics, but their efficacy in treating NDs requires more clinical studies, since the existing evidence was mainly from in vitro experiments and in vivo animal studies. Future Directions: Mitochondrial dysfunction, autophagy, and nuclear factor erythroid 2-related factor 2 were among the author keywords with rising prevalence. Further research in these directions should advance our understanding of the mechanism and treatment of NDs. Antioxid. Redox Signal. 34, 402-420.

Natural products in diabetes research: quantitative literature analysis.

The current study aimed to identify which natural products and which research directions are related to the major contributors to academic journals for diabetes therapy. Bibliometric data were extracted from the Web of Science online database using the search string TOPIC = (''natural product*' OR ''natural compound*' OR ''natural molecule*' OR 'phytochemical*' OR ''secondary metabolite*') AND TS = ('diabet*') and analysed by a bibliometric software, VOSviewer. The search yielded 3694 publications, which were collectively cited 80,791 times, with an H-index of 117 and 21.9 citations per publication on average. The top-contributing countries were India, the USA, China, South Korea and Brazil. Curcumin, flavanone, resveratrol, carotenoid, polyphenols, flavonol, flavone and berberine were the most frequently cited natural products or compound classes. Our results provide a brief overview of the major directions of natural product research in diabetes up to now and hint on promising avenues for future research.

Neurotensins and their therapeutic potential: research field study.

The natural tridecapeptide neurotensin has been emerged as a promising therapeutic scaffold for the treatment of neurological diseases and cancer. In this work, we aimed to identify the top 100 most cited original research papers as well as recent key studies related to neurotensins. The Web of Science Core Collection database was searched and the retrieved research articles were analyzed by using the VOSviewer software. The most cited original articles were published between 1973 and 2013. The top-cited article was by Carraway and Leeman reporting the discovery of neurotensin in 1973. The highly cited terms were associated with hypotension and angiotensin-converting-enzyme. The conducted analysis reveals the therapeutic potentials of neurotensin, and further impactful research toward its clinical development is warrantied.

Lignans: Quantitative Analysis of the Research Literature.

The current study provides a comprehensive overview and analysis of the lignan literature. Data for the current study were extracted from the electronic Web of Science Core Collection database via the search string TOPIC = ("lignan*") and processed by the VOSviewer software. The search yielded 10,742 publications. The ratio of original articles to reviews was 14.6:1. Over 80% of the analyzed papers have been published since the year 2000 and nearly 50% since the year 2010. Many of the publications were focused on pharmacology, chemistry, and plant sciences. The United States and Asian countries, such as China, Japan, South Korea, and India, were the most productive producers of lignan publications. Among the 5 most productive institutions was the University of Helsinki in Finland, the country that ranked 9th. Nineteen journals collectively published 3,607 lignan publications and were considered as core journals. Their impact factor did not correlate with the proportion of uncited papers. Highly cited publications usually mentioned phytoestrogen, isoflavone, daidzein, enterodiol, enterolactone, equol, genistein, and isoflavonoid. Cancer (e.g., breast cancer), cardiovascular disease, and antioxidation were the major themes. Clinical trials were estimated to contribute to 0.2-1.1% of the analyzed body of literature, so more of them should be conducted in the future to substantiate the beneficial effects and optimal dose of lignan intake in humans. Moreover, researchers can refer to these findings for future research directions and collaborations.

Neuroprotective Mechanisms of Three Natural Antioxidants on a Rat Model of Parkinson's Disease: A Comparative Study.

We compared the neuroprotective action of three natural bio-antioxidants (AOs): ellagic acid (EA), α-lipoic acid (LA), and myrtenal (Myrt) in an experimental model of Parkinson's disease (PD) that was induced in male Wistar rats through an intrastriatal injection of 6-hydroxydopamine (6-OHDA). The animals were divided into five groups: the sham-operated (SO) control group; striatal 6-OHDA-lesioned control group; and three groups of 6-OHDA-lesioned rats pre-treated for five days with EA, LA, and Myrt (50 mg/kg; intraperitoneally- i.p.), respectively. On the 2nd and the 3rd week post lesion, the animals were subjected to several behavioral tests: apomorphine-induced rotation; rotarod; and the passive avoidance test. Biochemical evaluation included assessment of main oxidative stress parameters as well as dopamine (DA) levels in brain homogenates. The results showed that all three test compounds improved learning and memory performance as well as neuromuscular coordination. Biochemical assays showed that all three compounds substantially decreased lipid peroxidation (LPO) levels, and restored catalase (CAT) activity and DA levels that were impaired by the challenge with 6-OHDA. Based on these results, we can conclude that the studied AOs demonstrate properties that are consistent with significant antiparkinsonian effects. The most powerful neuroprotective effect was observed with Myrt, and this work represents the first demonstration of its anti-Parkinsonian impact.