Mother's little helper turned a foe: Alprazolam use, misuse, and abuse.

Benzodiazepines are effective in managing anxiety and related disorders when used properly (short-term). Their inappropriate use, however, carries significant risks, involving amnesia, rebound insomnia, rebound anxiety, depression, dependence, abuse, addiction, and an intense and exceedingly prolonged withdrawal, among other complications. Benzodiazepines also amplify the effects of opioids and, consequently, have been implicated in approximately 30 % of opioid overdose deaths. Despite their unfavorable profile, sharp increases in medical and non-medical use of benzodiazepines have been steadily reported worldwide. Alprazolam (Xanax®), a potent, short-acting benzodiazepine, is among the most prescribed and abused anxiolytics in the United States. This medication is commonly co-abused with opioids, increasing the likelihood for oversedation, overdose, and death. Notwithstanding these risks, it is surprising that research investigating how benzodiazepines, such as alprazolam, interact with opioids is severely lacking in clinical and preclinical settings. This review therefore aims to present our current knowledge of benzodiazepine use and misuse, with an emphasis on alprazolam when data is available, and particularly in populations at higher risk for developing substance use disorders. Additionally, the potential mechanism(s) surrounding tolerance, dependence and abuse liability are discussed. Despite their popularity, our understanding of how benzodiazepines and opioids interact is less than adequate. Therefore, it is now more important than ever to understand the short- and long-term consequences of benzodiazepine/alprazolam use.

Novel Insights in the Application of Probiotic Yeast Saccharomyces boulardii in Dairy Products and Health Promotion.

Probiotic organisms are increasingly being incorporated into foods in order to develop products to prevent and reduce many diseases. Saccharomyces boulardii, a probiotic yeast with unique properties, such as viability over a wide pH range, antibiotic resistance, and the ability to reach a steady state, has an advantage over bacterial probiotics. The present review highlights the potential application of S. boulardii in functional fermented dairy products and the genetic engineering of this probiotic microorganism as a therapeutic agent for the treatment of various infectious diseases. It was found that probiotic yeast stimulates the growth of lactic acid bacteria in dairy products, creating favorable conditions and positively affecting the product's sensory characteristics. Moreover, its viability of more than 106 cfu/mL at the end of the yogurt shelf life confirms its probiotic effect. On the other hand, there is a growing interest in the design of probiotic strains to improve their characteristics and fill existing gaps in their spectrum of action such as the inhibition of some bacterial toxins, as well as anti-inflammatory and immunomodulatory effects. The strengthening of immune functions and effective therapies against various diseases by S. boulardii was confirmed. However, considering this yeast species' potential, further research is necessary to accurately determine the functional properties in terms of incorporation into food matrices and from the aspect of health and well-being claims.

Mobilizing Stockpile of Nature: Phytochemicals, Herbal Extracts, and Dietary Supplements for Managing Metabolic Diseases with Concentric Focus on Obesity

Obesity and associated health impairments are proven to exhibit multifocal health disorders along with increasing co-morbidity. Underlying obesity pathology is linked up with almost every major disease, which may increase the risk of heart disease, hypertension, diabetes, cancer, osteoarthritis, etc. The prevalence of overweight and obesity is on the rise around the world, which enormously affects the life span of individuals. Due to the foggier nature of the underlying pathology, the efficacy is questionable for conventional treatments. The traditional therapy of obesity may involve synthetic moieties and surgical procedures, which have many harmful side effects and chances of recurrent severity. Scientists are continuously focusing on prophylactic remedies alongside maintaining a proper lifestyle. In that context, nature always helped with traditional medications. As per folklore medicine reports, many plants have been used to treat obesity and its associated complications. This review compiles a vast array of datasets, including the impact of obesity and the need for the introduction of phytochemicals in place of conventional pharmacotherapies, the impact of phytochemicals along with the reported mechanisms of action, recent clinical trial reports, and recently explored dietary supplements. The primary objective of this presentation is to chart the future trajectory of phytochemical research for metabolic disorders, establishing a foundational framework for future investigations to build upon.

How to fight acute sun damage? Current skin care strategies.

Excessive exposure to sunlight can contribute for skin photo-damage, such as sunburn, dryness, wrinkles, hyperpigmentation, immunosuppressive events and skin sensitization reactions. The use of aftersun products is an effective strategy to reduce the visible signs and symptoms of acute photodamage in the skin. Aiming to unveil the active ingredients able to offset acute sun damage, this work focuses on the characterization of the aftersun products market. A total of 84 after-sun formulations from 41 international brands currently marketed in Portugal were analyzed concerning the composition described on the product label, identifying natural and synthetic/semi-synthetic ingredients with the ability to mitigate solar-induced effects. The majority of aftersun formulations contained ingredients derived from terrestrial and marine sources (> 80%). An in-depth examination of these compounds is also offered, revealing the top of the most used natural and synthetic/semi-synthetic ingredients present in aftersun products, as well as their mechanism of action. A critical appraisal of the scientific data was made aiming to highlight the scientific evidence of ingredients able to mitigate skin photodamage. Amino acids and peptides, and A. barbadensis extract were tested for their in vivo efficacy. Nevertheless, all the ingredients were analyzed with in vitro studies as preliminary screening before in vivo, ex vivo and/or clinical studies. In summary, this study provides an overview of the use of active ingredients in commercial aftersun products to understand better the benefits associated with their use in cosmetic formulations and identify opportunities for innovation.

A critical review on pharmacological properties of sulfated polysaccharides from marine macroalgae.

The marine ecosystem contains an assorted range of organisms, among which macroalgae stands out marine resources as an invaluable reservoir of structurally diverse bioactive compounds. Marine macroalgae are considered as primary consumers have gained more attention for their bioactive components. Sulfated polysaccharides (SPs) are complex polymers found in macroalgae that play a crucial role in their cell wall composition. This review consolidates high-tech methodologies employed in the extraction of macroalgal SPs, offering a valuable resource for researchers focuses in the pharmacological relevance of marine macromolecules. The pharmacological activities of SPs, focusing on their therapeutic action by encompassing diverse study models are summarized. Furthermore, in silico docking studies facilitates a comprehensive understanding of SPs interactions with their binding sites providing a valuable insight for future endeavors. The biological properties of algal SPs, along with a brief reference to mode of action based on different targets are presented. This review utilizes up-to-date research discoveries across various study models to elucidate the biological functions of SPs, focusing on their molecular-level mechanisms and offering insights for prospective investigations. Besides, the significance of SPs from seaweeds is highlighted, showcasing their potential beneficial applications in promoting human health. With promising biomedical prospects, this review explores the extensive uses and experimental evidence supporting the important roles of SPs in various fields.

Evidence of Potential Natural Products for the Management of Hypertrophic Scars.

Hypertrophic scarring is an aberrant wound-healing response to reestablish dermal integrity after an injury and can cause significant abnormalities in physical, aesthetic, functional, and psychological symptoms, impacting the patient's quality of life. There is currently no gold standard for preventing and treating hypertrophic scars. Therefore, many researchers have attempted to search for antihypertrophic scar agents with greater efficacy and fewer side effects. Natural therapeutics are becoming attractive as potential alternative anti-scarring agents because of their high efficacy, safety, biocompatibility, low cost, and easy accessibility. This review demonstrates various kinds of natural product-based therapeutics, including onion, vitamin E, Gotu kola, green tea, resveratrol, emodin, curcumin, and others, in terms of their mechanisms of action, evidence of efficacy and safety, advantages, and disadvantages when used as anti-scarring agents. We reviewed the literature based on data from in vitro, in vivo, and clinical trials. A total of 23 clinical trials were identified in this review; most clinical trials were ranked as having uncertain results (level of evidence 2b; n = 16). Although these natural products showed beneficial effects in both in vitro and in vivo studies of potential anti-scarring agents, there was limited clinical evidence to support their efficacy due to the limited quality of the studies, with individual flaws including small sample sizes, poor randomization, and blinding, and short follow-up durations. More robust and well-designed clinical trials with large-scale and prolonged follow-up durations are required to clarify the benefits and risks of these agents.

Antimicrobial Activity of Gallium(III) Compounds: Pathogen-Dependent Targeting of Multiple Iron/Heme-Dependent Biological Processes.

Metals play vital roles in biological systems, with iron/heme being essential for cellular and metabolic functions necessary for survival and/or virulence in many bacterial pathogens. Given the rise of bacterial resistance to current antibiotics, there is an urgent need for the development of non-toxic and novel antibiotics that do not contribute to resistance to other antibiotics. Gallium, which mimics iron, has emerged as a promising antimicrobial agent, offering a novel approach to combat bacterial infections. Gallium does not have any known functions in biological systems. Gallium exerts its effects primarily by replacing iron in redox enzymes, effectively inhibiting bacterial growth by targeting multiple iron/heme-dependent biological processes and suppressing the development of drug resistance. The aim of this review is to highlight recent findings on the mechanisms of action of gallium and provide further insights into the development of gallium-based compounds. Understanding the mechanisms underlying gallium's biological activities is crucial for designing drugs that enhance their therapeutic therapies while minimizing side effects, offering promising avenues for the treatment of infectious diseases.

Neuroprotective actions of norepinephrine in neurological diseases.

Precise control of norepinephrine (NE) levels and NE-receptor interaction is crucial for proper function of the brain. Much evidence for this view comes from experimental studies that indicate an important role for NE in the pathophysiology and treatment of various conditions, including cognitive dysfunction, Alzheimer's disease, Parkinson's disease, multiple sclerosis, and sleep disorders. NE provides neuroprotection against several types of insults in multiple ways. It abrogates oxidative stress, attenuates neuroinflammatory responses in neurons and glial cells, reduces neuronal and glial cell activity, promotes autophagy, and ameliorates apoptotic responses to a variety of insults. It is beneficial for the treatment of neurodegenerative diseases because it improves the generation of neurotrophic factors, promotes neuronal survival, and plays an important role in the regulation of adult neurogenesis. This review aims to present the evidence supporting a principal role for NE in neuroprotection, and molecular mechanisms of neuroprotection.

Physicochemical properties, biological chemistry and mechanisms of action of caries-arresting diammine-silver(I) fluoride and silver(I)-fluoride solutions for clinical use: a critical review.

This paper serves as a Part II follow-up of our research investigations performed on the molecular structures of silver(I)-fluoride (SF) and diammine-silver(I) fluoride (SDF) complexes in solution-based commercial products for clinical application, their precise chemical compositions, and their nature in aqueous solution, the latter including rapid fluoride-exchange processes at the silver(I) ion centre monitored by 19F NMR analysis (Part I). Part I of this series also explores the mechanisms of action (MoA) of these complexes, and is therefore largely focused on their chemical reactions with constituents of human saliva, which has access to their sites of application. Such reactions were found to slowly promote the generation of potentially physiologically-active Ag/AgCl nanoparticles from primarily-generated discoloured silver(I) chloride (AgCl) precipitates, a process involving salivary electron-donors such as thiocyanate and L-cysteine. Since this research has shed new light on potential MoAs for these products, in this accompanying report (Part II), we have performed a critical review of scientific literature in order to rationalize our results in relation to current views on these mechanisms for SF and SDF products employed for the successful clinical arrest of dental caries. Following an Introduction to the subject matter ( Section 1), this paper comprises a generalized overview of silver coordination chemistry ( Section 2), which is followed by a section focused on the aqueous solution status and equilibria involved in SF chemistry ( Section 3), the latter including results acquired from an original simulation of the electronic absorption spectra of coloured SF complexes in aqueous solution (Section 3.1). Section 4 then investigates detailed rationales for the biologically-relevant ligand-exchange and redox chemistries, disposition and fates of SF, SDF and silver(I)-nitrate when employed for the treatment of dental caries, with emphasis placed on their therapeutic MoAs. This Section is supported by the provision of valuable information centralized on (1) relevant biomolecular chemistry involved in solution- and solid-state matrices ( Section 4.1); (2) SF and perhaps silver(I)-nitrate as more cost-effective alternatives to SDF therapies ( Section 4.2); and (3) the potential therapeutic benefits and effects offered by silver-based nanoparticles and their associated MoAs ( Section 4.3). Recommendations for future investigations in this area are proposed.

Mechanisms of treatment effects using allogeneic, umbilical cord-derived mesenchymal stromal stem cells (MSCs) in knee osteoarthritis: a pharmacological clinical study protocol.

BACKGROUND: Knee osteoarthritis (KOA) presents a prevalent orthopedic condition causing substantial impairment in the quality of life and imposing a significant societal and economic burden. Mesenchymal stromal/stem cells (MSCs), known for their regenerative properties and immunomodulatory effects, have emerged as a promising therapeutic avenue in regenerative medicine. Despite MSCs' therapeutic potential, their precise mechanisms of action in KOA remain underexplored. METHODS: Conducted as a randomized, open-label clinical trial, 20 patients will be enrolled, with 10 in the intervention group and 10 in the control group. The primary focus will be to explore the molecular mechanisms associated with MSC therapy. Biomarkers and gene expressions related to cartilage metabolism, inflammation, immune modulation, and pain in the synovial fluid, blood, and tissue samples will be analyzed. Patients will undergo pre- and post-treatment evaluations using patient-reported outcome measures (PROMs) and comprehensive clinical assessments. DISCUSSION: This is an exploratory study with the goal to provide comprehensive insights into the therapeutic effects of MSCs on a molecular level, potentially paving the way for optimized and more effective MSC-based therapies in the management of KOA, as well as furthering the development of novel treatment strategies. TRIAL REGISTRATION: ClinicalTrials.gov, NCT06078059. Registered on 5 October 2023.

Mass spectrometry imaging as a promising analytical technique for herbal medicines: an updated review.

Herbal medicines (HMs) have long played a pivotal role in preventing and treating various human diseases and have been studied widely. However, the complexities present in HM metabolites and their unclear mechanisms of action have posed significant challenges in the modernization of traditional Chinese medicine (TCM). Over the past two decades, mass spectrometry imaging (MSI) has garnered increasing attention as a robust analytical technique that enables the simultaneous execution of qualitative, quantitative, and localization analyses without complex sample pretreatment. With advances in technical solutions, MSI has been extensively applied in the field of HMs. MSI, a label-free ion imaging technique can comprehensively map the spatial distribution of HM metabolites in plant native tissues, thereby facilitating the effective quality control of HMs. Furthermore, the spatial dimension information of small molecule endogenous metabolites within animal tissues provided by MSI can also serve as a supplement to uncover pharmacological and toxicological mechanisms of HMs. In the review, we provide an overview of the three most common MSI techniques. In addition, representative applications in HM are highlighted. Finally, we discuss the current challenges and propose several potential solutions. We hope that the summary of recent findings will contribute to the application of MSI in exploring metabolites and mechanisms of action of HMs.

Galvanic vestibular stimulation modulates EEG markers of voluntary movement in Parkinson's disease.

We recently showed that vestibular stimulation can produce a long-lasting alleviation of motor features in Parkinson's disease. Here we investigated whether components of the motor related cortical response that are commonly compromised in Parkinson's - the Bereitschaftspotential and mu-rhythm event-related desynchronization - are modulated by concurrent, low frequency galvanic vestibular stimulation (GVS) during repetitive limb movement amongst 17 individuals with idiopathic Parkinson's disease. Relative to sham, GVS was favourably associated with higher amplitudes during the late and movement phases of the Bereitschaftspotential and with a more pronounced decrease in spectral power within the mu-rhythm range during finger-tapping. These data increase understanding of how GVS interacts with the preparation and execution of voluntary movement and give added impetus to explore its therapeutic effects on Parkinsonian motor features.

Polyphenols: Chemistry, bioavailability, bioactivity, nutritional aspects and human health benefits: A review.

Polyphenols, including phenolics, alkaloids, and terpenes, are secondary metabolites that are commonly found in fruits, vegetables, and beverages, such as tea, coffee, wine, chocolate, and beer. These compounds have gained considerable attention and market demand because of their potential health benefits. However, their application is limited due to their low absorption rates and reduced tissue distribution efficiency. Engineering polyphenol-protein complexes or conjugates can enhance the antioxidant properties, bioavailability, and stability of polyphenols and improve digestive enzyme hydrolysis, target-specific delivery, and overall biological functions. Complex polyphenols, such as melanin, tannins, and ellagitannins, can promote gut microbiota balance, bolster antioxidant defense, and improve overall human health. Despite these benefits, the safety of polyphenol complexes must be thoroughly evaluated before their use as functional food additives or supplements. This review provides a detailed overview of the types of macromolecular polyphenols, their chemical composition, and their role in food enrichment. The mechanisms by which complex polyphenols act as antioxidative, anti-inflammatory, and anticancer agents have also been discussed.

Design, synthesis, antimicrobial activity, and mechanism of novel 3-(2,4-dichlorophenyl)-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazole derivatives.

BACKGROUND: Plant pathogens cause substantial crop losses annually, posing a grave threat to global food security. Fungicides have usually been used for their control, but the rapid development of pesticide resistance renders many ineffective, therefore the search for novel and efficient green pesticides to prevent and control plant diseases has become the top priority in crop planting. RESULTS: The results of bioassay studies indicated that most of the target compounds showed certain antimicrobial activity in vitro. In particular, compound X7 showed high inhibitory activity against Xanthomonas oryzae pv. oryzae (Xoo), with an EC50 value of 27.47 µg mL-1, surpassing conventional control agents such as thiazole zinc (41.55 µg mL-1) and thiodiazole copper (53.39 µg mL-1). Further studies on molecular docking showed that X7 had a strong binding affinity with 2FBW. The morphological change observed by scanning electron microscopy indicated that the surface of Xoo appears wrinkled and cracked under X7 treatment and a total of 2662 proteins were identified by label-free proteomic analysis. Three experiments have elucidated the mechanism whereby X7 induced considerable changes in the physiological and biochemical properties of Xoo, which in turn affected the reproduction and growth of bacteria. CONCLUSION: This work represents a pivotal advancement, offering important reference for the research and development therapeutics in combating plant pathogens. © 2024 Society of Chemical Industry.

Herb-CMap: a multimodal fusion framework for deciphering the mechanisms of action in traditional Chinese medicine using Suhuang antitussive capsule as a case study.

Herbal medicines, particularly traditional Chinese medicines (TCMs), are a rich source of natural products with significant therapeutic potential. However, understanding their mechanisms of action is challenging due to the complexity of their multi-ingredient compositions. We introduced Herb-CMap, a multimodal fusion framework leveraging protein-protein interactions and herb-perturbed gene expression signatures. Utilizing a network-based heat diffusion algorithm, Herb-CMap creates a connectivity map linking herb perturbations to their therapeutic targets, thereby facilitating the prioritization of active ingredients. As a case study, we applied Herb-CMap to Suhuang antitussive capsule (Suhuang), a TCM formula used for treating cough variant asthma (CVA). Using in vivo rat models, our analysis established the transcriptomic signatures of Suhuang and identified its key compounds, such as quercetin and luteolin, and their target genes, including IL17A, PIK3CB, PIK3CD, AKT1, and TNF. These drug-target interactions inhibit the IL-17 signaling pathway and deactivate PI3K, AKT, and NF-κB, effectively reducing lung inflammation and alleviating CVA. The study demonstrates the efficacy of Herb-CMap in elucidating the molecular mechanisms of herbal medicines, offering valuable insights for advancing drug discovery in TCM.

The Effect of Protein Nutritional Support on Inflammatory Bowel Disease and Its Potential Mechanisms.

Inflammatory bowel disease (IBD), a complex chronic inflammatory bowel disorder that includes Crohn's disease (CD) and Ulcerative Colitis (UC), has become a globally increasing health concern. Nutrition, as an important factor influencing the occurrence and development of IBD, has attracted more and more attention. As the most important nutrient, protein can not only provide energy and nutrition required by patients, but also help repair damaged intestinal tissue, enhance immunity, and thus alleviate inflammation. Numerous studies have shown that protein nutritional support plays a significant role in the treatment and remission of IBD. This article presents a comprehensive review of the pathogenesis of IBD and analyzes and summarizes the potential mechanisms of protein nutritional support in IBD. Additionally, it provides an overview of the clinical effects of protein nutritional support in IBD and its impact on clinical complications. Research findings reveal that protein nutritional support demonstrates significant benefits in improving clinical symptoms, reducing the risk of complications, and improving quality of life in IBD patients. Therefore, protein nutritional support is expected to provide a new approach for the treatment of IBD.

Microbial-derived peptides with anti-mycobacterial potential.

Tuberculosis (TB), an airborne infectious disease caused by Mycobacterium tuberculosis, has become the leading cause of death. The subsequent emergence of multidrug-resistant, extensively drug-resistant and totally drug-resistant strains, brings an urgent need to discover novel anti-TB drugs. Among them, microbial-derived anti-mycobacterial peptides, including ribosomally synthesized and post-translationally modified peptides (RiPPs) and multimodular nonribosomal peptides (NRPs), now arise as promising candidates for TB treatment. This review presents 96 natural RiPP and NRP families from bacteria and fungi that have broad spectrum in vitro activities against non-resistant and drug-resistant mycobacteria. In addition, intracellular targets of 22 molecules are the subject of much attention. Meanwhile, chemical features of 38 families could be modified in order to improve properties. In final, structure-activity relationships suggest that the modifications of various groups, especially the peptide side chains, the amino acid moieties, the cyclic peptide skeletons, various special groups, stereochemistry and entire peptide chain length are important for increasing the potency.

Therapeutic Potential of Platelet-Rich Plasma in Fracture Healing: A Comprehensive Review.

Fracture healing is a dynamic process essential for the restoration of bone integrity and function. However, factors such as patient age, comorbidities, and the severity of the fracture can impede this process, leading to delayed healing or nonunion. Platelet-rich plasma (PRP) has emerged as a promising therapeutic option for enhancing fracture healing. PRP is an autologous blood product containing a concentrated mixture of platelets, growth factors, and cytokines known to promote tissue regeneration and repair. This comprehensive review provides an overview of the fracture healing process, emphasizing the importance of timely and efficient bone repair. We discuss the mechanisms underlying the purported efficacy of PRP in fracture healing, drawing upon both preclinical and clinical evidence. Preclinical studies in animal models have demonstrated the ability of PRP to accelerate fracture healing, stimulate osteogenesis, and enhance bone regeneration. Clinical studies have yielded mixed results, with some reporting positive outcomes in terms of accelerated healing and improved functional outcomes, while others have shown no significant benefits over standard treatments. Factors influencing the efficacy of PRP, such as timing of administration, PRP concentration, and patient-specific variables, are also examined. Furthermore, safety considerations and potential adverse effects associated with PRP therapy are discussed. Despite the promising preclinical findings, challenges remain in standardizing PRP formulations, optimizing administration protocols, and addressing unanswered questions regarding its long-term efficacy and safety. This review aims to provide insights into the therapeutic potential of PRP in fracture healing, informing future research directions and guiding clinical practice.