Pharmacological mechanism of natural antidepressants: The role of mitochondrial quality control.

BACKGROUND: Depression is a mental illness characterized by persistent sadness and a reduced capacity for pleasure. In clinical practice, SSRIs and other medications are commonly used for therapy, despite their various side effects. Natural products present distinct advantages, including synergistic interactions among multiple components and targeting multiple pathways, suggesting their tremendous potential in depression treatment. Imbalance in mitochondrial quality control (MQC) plays a significant role in the pathology of depression, emphasizing the importance of regulating MQC as a potential intervention strategy in addressing the onset and progression of depression. However, the role and mechanism through which natural products regulate MQC in depression treatments still need to be comprehensively elucidated, particularly in clinical and preclinical settings. PURPOSE: This review was aimed to summarize the findings of recent studies and outline the pharmacological mechanisms by which natural products modulate MQC to exert antidepressant effects. Additionally, it evaluated current research limitations and proposed new strategies for future preclinical and clinical applications in the depression domain. METHODS: To study the main pharmacological mechanisms underlying the regulation of MQC by natural products in the treatment of depression, we conducted a thorough search across databases such as PubMed, Web of Science, and ScienceDirect databases to classify and summarize the relationship between MQC and depression, as well as the regulatory mechanisms of natural products. RESULTS: Numerous studies have shown that irregularities in the MQC system play an important role in the pathology of depression, and the regulation of the MQC system is involved in antidepressant treatments. Natural products mainly regulate the MQC system to induce antidepressant effects by alleviating oxidative stress, balancing ATP levels, promoting mitophagy, maintaining calcium homeostasis, optimizing mitochondrial dynamics, regulating mitochondrial membrane potential, and enhancing mitochondrial biogenesis. CONCLUSIONS: We comprehensively summarized the regulation of natural products on the MQC system in antidepressants, providing a unique perspective for the application of natural products within antidepressant therapy. However, extensive efforts are imperative in clinical and preclinical investigations to delve deeper into the mechanisms underlying how antidepressant medications impact MQC, which is crucial for the development of effective antidepressant treatments.

Exertional heat stroke-induced changes in gut microbiota cause cognitive impairment in mice.

BACKGROUND: The incidence of exertional heat stroke (EHS) escalates during periods of elevated temperatures, potentially leading to persistent cognitive impairment postrecovery. Currently, effective prophylactic or therapeutic measures against EHS are nonexistent. METHODS: The selection of days 14 and 23 postinduction for detailed examination was guided by TEM of neuronal cells and HE staining of intestinal villi and the hippocampal regions. Fecal specimens from the ileum and cecum at these designated times were analyzed for changes in gut microbiota and metabolic products. Bioinformatic analyses facilitated the identification of pivotal microbial species and metabolites. The influence of supplementing these identified microorganisms on behavioral outcomes and the expression of functional proteins within the hippocampus was subsequently assessed. RESULTS: TEM analyses of neurons, coupled with HE staining of intestinal villi and the hippocampal region, indicated substantial recovery in intestinal morphology and neuronal injury on Day 14, indicating this time point for subsequent microbial and metabolomic analyses. Notably, a reduction in the Lactobacillaceae family, particularly Lactobacillus murinus, was observed. Functional annotation of 16S rDNA sequences suggested diminished lipid metabolism and glycan biosynthesis and metabolism in EHS models. Mice receiving this intervention (EHS + probiotics group) exhibited markedly reduced cognitive impairment and increased expression of BDNF/TrKB pathway molecules in the hippocampus during behavioral assessment on Day 28. CONCLUSION: Probiotic supplementation, specifically with Lactobacillus spp., appears to mitigate EHS-induced cognitive impairment, potentially through the modulation of the BDNF/TrKB signaling pathway within the hippocampus, illustrating the therapeutic potential of targeting the gut-brain axis.

Antidepressant mechanism of traditional Chinese medicine: Involving regulation of circadian clock genes.

Numerous studies have demonstrated an intimate relationship between circadian rhythm disorders and the development and prevention of depression. The biological clock genes, which constitute the molecular basis of endogenous circadian rhythms, hold promising prospects for depression treatment. Based on an extensive review of recent domestic and international research, this article presents a comprehensive analysis of how traditional Chinese medicine (TCM) intervenes in depression by regulating circadian rhythms. The findings indicate that TCM exerts its antidepressant effects by targeting specific biological clock genes such as Bmal1, clock, Arntl, Per1, Per2, Per3, Nr1d1, Cry2, and Dbp, as well as regulating circadian rhythms of hormone secretion. However, most current research is still confined to basic experimental studies, lacking clinical double-blind control trials to further validate these viewpoints. Furthermore, there is insufficient research on the signal transduction pathway between biological clock genes and pathological changes in depression. Additionally, further clarification is needed regarding the specific targets of TCM on the biological clock genes.

Treatment of primary restless legs syndrome with Fu's subcutaneous needling: A case report.

RATIONALE: Fu's subcutaneous needling (FSN) is a novel acupuncture technique developed based on traditional needling principles that aims to alleviate diseases by improving local muscle conditions and blood supply. FSN have been widely used for the treatment of various diseases. Restless legs syndrome (RLS) is a common central nervous system disorder characterized by intense discomfort in the legs, particularly at night, leading to an urge to move the legs for relief. In this study, we report a case in which FSN was used to treat primary RLS. PATIENT CONCERNS: A 67-year-old patient complained of nocturnal discomfort in the right leg for over 4 months, the symptoms occurred 2-3 times, with uncontrollable movement impulses in the right leg during the onset, accompanied by a burning sensation, lasting about 2 h, accompanied by anxiety and insomnia. Imaging examinations revealed no spinal stenosis or history of kidney disease, rheumatic disease, diabetes, or Parkinson's disease. DIAGNOSES: The patient was diagnosed with primary RLS, and the International Restless Legs Syndrome Study Group rating scale (IRLS) score was 26. INTERVENTIONS: FSN was successfully performed three times per week on different days. No adverse and unanticipated events while the treatment. The total treatment course lasted for six weeks. OUTCOMES: After the treatment, the patient reported that the recent onset interval was approximately 10 days, each time lasting approximately 15 min. The patient's IRLS score was 5, After a follow-up of 2 months following the end of treatment, the patient reported that the incidence of RLS was approximately one episode within two weeks,each lasting approximately 10 min. LESSONS: FSN significantly improved leg discomfort and desire for leg movement in patients with RLS. FSN may exert its therapeutic effects by influencing connective and muscular tissues, thereby improving the condition of the central nervous system and the local blood supply in the legs. However, due to the limitation of a single clinical observation case, a randomized clinical trial with a sufficient follow-up time is needed.

Adult hippocampal neurogenesis: pharmacological mechanisms of antidepressant active ingredients in traditional Chinese medicine.

Depression is characterized by prominent indicators and manifestations, such as anhedonia, which refers to the inability to experience pleasure, and persistent feelings of hopelessness. In clinical practice, the primary treatment approach involves the utilization of selective serotonin reuptake inhibitors (SSRIs) and related pharmacological interventions. Nevertheless, it is crucial to recognize that these agents are associated with significant adverse effects. Traditional Chinese medicine (TCM) adopts a multifaceted approach, targeting diverse components, multiple targets, and various channels of action. TCM has potential antidepressant effects. Anomalies in adult hippocampal neurogenesis (AHN) constitute a pivotal factor in the pathology of depression, with the regulation of AHN emerging as a potential key measure to intervene in the pathogenesis and progression of this condition. This comprehensive review presented an overview of the pharmacological mechanisms underlying the antidepressant effects of active ingredients found in TCM. Through examination of recent studies, we explored how these ingredients modulated AHN. Furthermore, we critically assessed the current limitations of research in this domain and proposed novel strategies for preclinical investigation and clinical applications in the treatment of depression in future.

Antidepressant pharmacological mechanisms: focusing on the regulation of autophagy.

The core symptoms of depression are anhedonia and persistent hopelessness. Selective serotonin reuptake inhibitors (SSRIs) and their related medications are commonly used for clinical treatment, despite their significant adverse effects. Traditional Chinese medicine with its multiple targets, channels, and compounds, exhibit immense potential in treating depression. Autophagy, a vital process in depression pathology, has emerged as a promising target for intervention. This review summarized the pharmacological mechanisms of antidepressants by regulating autophagy. We presented insights from recent studies, discussed current research limitations, and proposed new strategies for basic research and their clinical application in depression.

Structural optimization and prospect of constructing hemoglobin oxygen carriers based on hemoglobin.

The current global shortage of organ resources, the imbalance in donor-recipient demand and the increasing number of high-risk donors make organ preservation a necessity to consider appropriate storage options. The current method of use often has risks such as blood group mismatch, short shelf life, and susceptibility. HBOCs have positive effects such as anti-apoptotic, anti-inflammatory, antioxidant and anti-proliferative, which have significant advantages in organ storage. Therefore, it is the common pursuit of researchers to design and synthesize HBOCs with safety, ideal oxygen-carrying capacity, easy storage, etc. that are widely applicable and optimal for different organs. There has been a recent advancement in understanding HBOCs mechanisms, which is discussed in this review.

Tracking Research on Hemoglobin-Based Oxygen Carriers: A Scientometric Analysis and In-Depth Review.

Numerous studies on the formulation and clinical applications of novel hemoglobin-based oxygen carriers (HBOCs) are reported in the scientific literature. However, there are fewer scientometric analysis related to HBOCs. Here, we illustrate recent studies on HBOCs using both a scientometric analysis approach and a scope review method. We used the former to investigate research on HBOCs from 1991 to 2022, exploring the current hotspots and research trends, and then we comprehensively analyzed the relationship between concepts based on the keyword analysis. The evolution of research fields, knowledge structures, and research topics in which HBOCs located are revealed by scientometric analysis. The elucidation of type, acting mechanism, potential clinical practice, and adverse effects of HBOCs helps to clarify the prospects of this biological agent. Scientometrics analyzed 1034 publications in this research field, and these findings provide a promising roadmap for further study.

Knockdown of SDC-1 Gene Alleviates the Metabolic Pathway for the Development of MODS.

This study aims to reveal the metabolic differences between SDC-1 knockout mice and wild-type mice and the metabolic differences caused by shock in SDC-1 knockout mice by integrating transcriptomics and metabolomics. A total of 1009 differential metabolites were differentially expressed based on untargeted metabolomics and high-resolution mass spectrometry detection techniques. According to Kyoto Encyclopedia of Genes and Genomes enrichment, SDC-1 knockout significantly altered fat digestion and absorption, GnRH signaling pathway, fructose and mannose metabolism, and some other amino-related metabolic pathways and significantly modulated positively regulated longevity regulatory pathways, longevity regulatory pathways-worm, nicotinamide and niacinamide metabolism, and vitamin digestion and absorption pathways after its shock. Our findings indicate that SDC-1 knockout may have potential therapeutic effects in hemorrhagic shock by increasing nicotinamide metabolism.

Identification of potential targets against SARS-CoV-2 of antiviral drugs based on photoaffinity probes.

Facing the sudden outbreak of coronavirus disease 2019 (COVID-19), it is extremely urgent to develop effective antiviral drugs against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Drug repurposing is a promising strategy for the treatment of COVID-19. To identify the precise target protein of marketed medicines, we initiate a chemical biological program to identify precise target of potential antivirus drugs. In this study, two types of recombinant human coronavirus SARS-CoV-2 RdRp protein capturing probes with various photoaffinity labeling units were designed and synthesized based on the structure of FDA-approved drugs stavudine, remdesivir, acyclovir, and aladenosine. Fortunately, it was found that one novel photoaffinity probe, RD-1, could diaplayed good affinity with SARS-CoV-2 RdRp around the residue ARG_553. In addition, RD-1 probe also exhibited potent inhibitory activity against 3CLpro protease. Taken together, our findings will elucidate the structural basis for the efficacy of marketed drugs, and explore a rapid and efficient strategy of drug repurposing based on the identification of new targets. Moreover, these results could also provide a scientific basis for the clinical application of marketed drugs.

The potential role of the orexin system in premenstrual syndrome.

Premenstrual syndrome (PMS) occurs recurrently during the luteal phase of a woman's menstrual cycle and disappears after menstruation ends. It is characterized by abnormal changes in both the body and mood, and in certain cases, severe disruptions in daily life and even suicidal tendencies. Current drugs for treating PMS, such as selective serotonin reuptake inhibitors, do not yield satisfactory results. Orexin, a neuropeptide produced in the lateral hypothalamus, is garnering attention in the treatment of neurological disorders and is believed to modulate the symptoms of PMS. This paper reviews the advancements in research on sleep disturbances, mood changes, and cognitive impairment caused by PMS, and suggests potential pathways for orexin to address these symptoms. Furthermore, it delves into the role of orexin in the molecular mechanisms underlying PMS. Orexin regulates steroid hormones, and the cyclic fluctuations of estrogen and progesterone play a crucial role in the pathogenesis of PMS. Additionally, orexin also modulates the gamma-aminobutyric acid (GABA) system and the inflammatory response involved in coordinating the mechanism of PMS. Unraveling the role of orexin in the pathogenesis of PMS will not only aid in understanding the etiology of PMS but also hold implications for orexin as a novel target for treating PMS.

Anxiolytic effect of YangshenDingzhi granules: Integrated network pharmacology and hippocampal metabolomics.

Anxiety disorder is one of the most common mental diseases. It is mainly characterized by a sudden, recurring but indescribable panic, fear, tension and/or anxiety. Yangshendingzhi granules (YSDZ) are widely used in the treatment of anxiety disorders, but its active ingredients and underlying mechanisms are not yet clear. This study integrates network pharmacology and metabolomics to investigate the potential mechanism of action of YSDZ in a rat model of anxiety. First, potential active ingredients and targets were screened by network pharmacology. Then, predictions were verified by molecular docking, molecular dynamics and western blotting. Metabolomics was used to identify differential metabolites and metabolic pathways. All results were integrated for a comprehensive analysis. Network pharmacology analysis found that Carotene, ß-sitosterol, quercetin, Stigmasterol, and kaempferol in YSDZ exert anxiolytic effects mainly by acting on IL1ß, GABRA1, PTGS1, ESR1, and TNF targets. Molecular docking results showed that all the affinities were lower than -5 kcal/mol, and the average affinities were -7.7764 kcal/mol. Molecular dynamics simulation results showed that RMSD was lower than 2.5 A, and the overall conformational changes of proteins were small, indicating that the small molecules formed stable complexes with proteins. The results of animal experiments showed that YSDZ exerts anxiolytic effects by regulating GABRA1 and TNF-α, ameliorating pathological damage in hippocampal CA1, and regulating metabolic pathways such as thiamine, cysteine and methionine metabolism, lysine biosynthesis and degradation. Altogether, we reveal multiple mechanisms through which YSDZ exerts its anti-anxiety effects, which may provide a reference for its clinical application and drug development.

Antidepressant Active Components of Bupleurum chinense DC-Paeonia lactiflora Pall Herb Pair: Pharmacological Mechanisms.

Depression is a serious psychological disorder with a rapidly increasing incidence in recent years. Clinically, selective serotonin reuptake inhibitors are the main therapy. These drugs, have serious adverse reactions, however. Traditional Chinese medicine has the characteristics of multiple components, targets, and pathways, which has huge potential advantages for the treatment of depression. The antidepressant potential of the herbal combination of Bupleurum chinense DC (Chaihu) and Paeonia lactiflora Pall (Baishao) has been extensively studied previously. In this review, we summarized the antidepressant active components and mechanism of Chaihu-Baishao herb pair. We found that it works mainly through relieving oxidative stress, regulating HPA axis, and protecting neurons. Nevertheless, current research of this combined preparation still faces many challenges. On one hand, most of the current studies only stay at the level of animal models, lacking of sufficient clinical double-blind controlled trials for further verification. In addition, studies on the synergistic effect between different targets and signaling pathways are scarce. On the other hand, this preparation has numerous defects such as poor stability, low solubility, and difficulty in crossing the blood-brain barrier.

Breast cancer diagnosis based on guided Water Strider Algorithm.

Breast cancer is one of the main cancers that effect of the women's health. This cancer is one of the most important health issues in the world and because of that, diagnosis in the beginning and appropriate cure is very effective in the recovery and survival of patients, so image processing as a decision-making tool can assist physicians in the early diagnosis of cancer. Image processing mechanisms are simple and non-invasive methods for identifying cancer cells that accelerate early detection and ultimately increase the chances of cancer patients surviving. In this study, a pipeline methodology is proposed for optimal diagnosis of the breast cancer area in the mammography images. Based on the proposed method, after image preprocessing and filtering for noise reduction, a simple and fast tumors mass segmentation based on Otsu threshold segmentation and mathematical morphology is proposed. Afterward, for simplifying the final diagnosis, a feature extraction based on 22 structural features is utilized. To reduce and pruning the useless features, an optimized feature selection based on a new developed design of Water Strider Algorithm (WSA), called Guided WSA (GWSA). Finally, the features injected to an optimized SVM classifier based on GWSA for optimal cancer diagnosis. Simulations of the suggested method are applied to the DDSM database. A comparison of the results with several latest approaches are performed to indicate the method higher effectiveness.

Effective and transient mapping of protein-protein interactions: Application of novel releasable photoaffinity linkers.

Herein, two novel multifunctional releasable photoaffinity linkers were developed for effective and transient tracking interacting proteins with the overall objective of understanding their in vivo biological functions in real-time. These linkers could be used for the chemical modification of protein under moderate experimental conditions to form protein photoaffinity probes. These probes incorporated with both photoaffinity labels and tag-transfer, enable photo-crosslinking of bait proteins along with the release of unrelated groups. These photoaffinity linkers can be utilized to construct probes for disease markers, which could enable rapid diagnosis in a clinical setting at minimal interference with normal physiology.

Insight into Fluorescence Imaging and Bioorthogonal Reactions in Biological Analysis.

Fluorescence imaging is an important method in the field of biomedicine. Fluorescence imaging is nondestructive, has high efficiency and sensitivity, high resolution and allows real-time dynamic monitoring of living cells. However, it also has some disadvantages, such as high background signals and low selectivity. Bioorthogonal reactions, with the advantages of being both nondestructive and effective, are used to trace and analyze biological interactions in vivo. This review focuses on recent progress in understanding the mechanism of action of fluorescence probes.

Exploring the potential intracellular targets of vascular normalization based on active candidates.

We previously developed two candidates with potency of inducing vascular normalization, BD7 and B14. However, the definite intracellular molecular target(s) responsible for their activity remains unknown. Herein, we report the discovery and functional assessment of several multifunctional photoaffinity probes for determining the potential biological targets of active compounds. The probes bear a photoaffinity moiety and a bioorthogonal unit attached to B7 or B14 and maintained the bioactivity of the parent active molecules. Using in vitro biological assays, we preliminarily identified VEGFR-2 as a potential intracellular target for the active candidates. Our results demonstrate the utility of these multifunctional photoaffinity probes for analyzing the biological activity and subcellular localization of the intracellular target proteins of active candidates.

Discovery of novel anti-angiogenesis agents. Part 11: Development of PROTACs based on active molecules with potency of promoting vascular normalization.

Our recent investigation is focused on the discovery of anti-angiogenesis agents. Vascular normalization induced by anti-angiogenic agent appears to be a promising strategy. We have developed novel angiogenesis inhibitors with potency of promoting vascular normalization. Herein, we reported the design, synthesis and preliminary evaluation of proteolysis-targeting chimera (PROTACs) based on the previously developed anti-angiogenesis agents. Two PROTACs exhibited potent VEGFR-2 inhibition and anti-proliferative activity against HUVECs. Moreover, they were capable of reducing protein levels of VEGFR-2 in EA.hy926 cells without significant cytotoxicity against HEK293 cells. The novel PROTACs could be used to normalize the abnormal vessels, resulting in efficient delivery of drugs.

Author Correction: Screening and identification of critical transcription factors involved in the protection of cardiomyocytes against hydrogen peroxide-induced damage by Yixin-shu.

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Screening and identification of critical transcription factors involved in the protection of cardiomyocytes against hydrogen peroxide-induced damage by Yixin-shu.

Oxidative stress initiates harmful cellular responses, such as DNA damage and protein denaturation, triggering a series of cardiovascular disorders. Systematic investigations of the transcription factors (TFs) involved in oxidative stress can help reveal the underlying molecular mechanisms and facilitate the discovery of effective therapeutic targets in related diseases. In this study, an integrated strategy which integrated RNA-seq-based transcriptomics techniques and a newly developed concatenated tandem array of consensus TF response elements (catTFREs)-based proteomics approach and then combined with a network pharmacology analysis, was developed and this integrated strategy was used to investigate critical TFs in the protection of Yixin-shu (YXS), a standardized medical product used for ischaemic heart disease, against hydrogen peroxide (H2O2)-induced damage in cardiomyocytes. Importantly, YXS initiated biological process such as anti-apoptosis and DNA repair to protect cardiomyocytes from H2O2-induced damage. By using the integrated strategy, DNA-(apurinic or apyrimidinic site) lyase (Apex1), pre B-cell leukemia transcription factor 3 (Pbx3), and five other TFs with their functions involved in anti-oxidation, anti-apoptosis and DNA repair were identified. This study offers a new understanding of the mechanism underlying YXS-mediated protection against H2O2-induced oxidative stress in cardiomyocytes and reveals novel targets for oxidative stress-related diseases.