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Abstract: Inhibitors of Na+/H+ exchanger (NHE) 1 have been shown to exert protective effects on various myocardial injuries. In this study, we characterized the pharmacodynamic properties of new guanidine NHE1 inhibitors (cariporide, sabiporide, KR-32511, KR-32570, and KR-33028) to analyze their myocardial protective effects. Although NHE1 is the major NHE isoform in cardiomyocytes, IC50values of these chemicals tested in rat cardiomyocytes were significantly different from those in PS120/hNHE1 cells where human NHE1 is heterologously expressed. In rat cardiomyocytes, KR-32570 and KR-33028 exhibited the highest potencies and their IC50values were 7±2 nM and 9±3 nM, respectively. The IC50values of all the chemicals tested on rat submandibular gland NHE2 were in the micromolar range, and they showed no inhibitory effects on hNHE3 and epithelial Na+ channels up to 30 μM, suggesting a high selectivity toward NHE1. Sabiporide and KR-32570 exhibited slow dissociation kinetics with NHE1 inhibition persisting even after rinsing-out. When the cytoprotective effects of chemicals against hypoxic damage of rat cardiomyocytes were examined, the order of potency was KR-32570≥KR-33028>sabiporide>cariporide>KR-32511. This order was exactly the same as that for the NHE1 inhibition in rat cardiomyocytes and did not correlate with any other properties, including the slow dissociation kinetics. Taken together, these results suggest that KR-32570 and KR-33028 are potent candidates for cardioprotective agents, and that the IC50 in the target organ is the most critical factor governing the cytoprotective effects of NHE1 inhibitors. [Copyright &y& Elsevier]

Mesenchymal stem cells (MSCs) are multipotent stem cells that are able to differentiate into multiple lineages including bone, cartilage, muscle and fat. They hold immunomodulatory properties and therapeutic ability to treat multiple diseases, including autoimmune and chronic degenerative diseases. In this article, we reviewed the different biological properties, applications and clinical trials of MSCs. Also, we discussed the basics of manufacturing conditions, quality control, and challenges facing MSCs in the clinical setting. Extensive review of the literature was conducted through the databases PubMed, Google Scholar, and Cochrane. Papers published since 2015 and covering the clinical applications and research of MSC therapy were considered. Furthermore, older papers were considered when referring to pioneering studies in the field. The most widely studied stem cells in cell therapy and tissue repair are bone marrow-derived mesenchymal stem cells. Adipose tissue-derived stem cells became more common and to a lesser extent other stem cell sources e.g., foreskin derived MSCs. MSCs therapy were also studied in the setting of COVID-19 infections, ischemic strokes, autoimmune diseases, tumor development and graft rejection. Multiple obstacles, still face the standardization and optimization of MSC therapy such as the survival and the immunophenotype and the efficiency of transplanted cells. MSCs used in clinical settings displayed heterogeneity in their function despite their extraction from healthy donors and expression of similar surface markers. Mesenchymal stem cells offer a rising therapeutic promise in various diseases. However, their potential use in clinical applications requires further investigation. [ABSTRACT FROM AUTHOR]

Spinal cord injury (SCI) is a serious and disabling injury that is often accompanied by neuropathic pain (NeP), which severely affects patients' motor and sensory functions and reduces their quality of life. Currently, there is no specific treatment for treating SCI and relieving the accompanying pain, and we can only rely on medication and physical rehabilitation, both of which are ineffective. Researchers have recently identified a novel class of glial cells, olfactory ensheathing cells (OECs), which originate from the olfactory system. Transplantation of OECs into damaged spinal cords has demonstrated their capacity to repair damaged nerves, improve the microenvironment at the point of injury, and They can also restore neural connectivity and alleviate the patient's NeP to a certain extent. Although the effectiveness of OECs transplantation has been confirmed in experiments, the specific mechanisms by which it repairs the spinal cord and relieves pain have not been articulated. Through a review of the literature, it has been established that the ability of OECs to repair and relieve pain is inextricably linked to its anti-inflammatory and immunomodulatory effects. In this regard, it is imperative to gain a deeper understanding of how OECs exert their anti-inflammatory and immunomodulatory effects. The objective of this paper is to provide a comprehensive overview of the mechanisms by which OECs exert anti-inflammatory and immunomodulatory effects. We aim to manipulate the immune microenvironment at the transplantation site through the intervention of cytokines and immune cells, with the goal of enhancing OECs' function or creating a conducive microenvironment for OECs' survival. This approach is expected to improve the therapeutic efficacy of OECs in clinical settings. However, numerous fundamental and clinical challenges remain to be addressed if OEC transplantation therapy is to become a standardized treatment in clinical practice. [ABSTRACT FROM AUTHOR]

Tumor immunotherapy, especially immune checkpoint inhibitors (ICIs), has been applied in clinical practice, but low response to immune therapies remains a thorny issue. Oncolytic viruses (OVs) are considered promising for cancer treatment because they can selectively target and destroy tumor cells followed by spreading to nearby tumor tissues for a new round of infection. Immunogenic cell death (ICD), which is the major mechanism of OVs' anticancer effects, is induced by endoplasmic reticulum stress and reactive oxygen species overload after virus infection. Subsequent release of specific damage-associated molecular patterns (DAMPs) from different types of tumor cells can transform the tumor microenvironment from "cold" to "hot". In this paper, we broadly define ICD as those types of cell death that is immunogenic, and describe their signaling pathways respectively. Focusing on ICD, we also elucidate the advantages and disadvantages of recent combination therapies and their future prospects. [Display omitted] [ABSTRACT FROM AUTHOR]

Prostate cancer is a prevalent malignancy that is frequently managed with radiotherapy. However, resistance to radiotherapy remains a significant challenge in controlling this disease. Early radiotherapy is employed for locally confined prostate cancer (PCa), while recurrent disease post-surgery and metastatic castration-resistant prostate cancer (mCRPC) are treated with late-stage radiotherapy, including radium-223. Combination therapies to integrate radiotherapy and chemotherapy have demonstrated enhanced treatment efficacy. Nonetheless, both modalities can induce severe local and systemic toxicities. Consequently, selectively sensitizing prostate tumors to radiotherapy could improve therapeutic outcomes while minimizing systemic side effects. The mechanisms underlying radioresistance in prostate cancer are multifaceted, including DNA damage repair (DDR) pathways, hypoxia, angiogenesis, androgen receptor (AR) signaling, and immune evasion. The advent of 177Lu-PSMA-617, which was approved in 2022, has shown promise in targeting prostate-specific membrane antigen (PSMA) in advanced prostate cancer. Experimental and clinical studies have yielded promising results in suppressing prostate tumors by targeting these pathways. This paper reviews potential targets for sensitizing prostate tumors to radiotherapy. We discuss cellular and molecular mechanisms contributing to therapy resistance and examine findings from experimental and clinical trials on promising targets and drugs that can be used in combination with radiotherapy. [ABSTRACT FROM AUTHOR]

Dementia treatment has become a global research priority, driven by the increase in the aging population. Punicalagin, the primary polyphenol found in pomegranate fruit, exhibits a variety of benefits. Today, a growing body of research is showing that punicalagin is a nutraceutical for the prevention of mild cognitive impairment (MCI). However, a comprehensive review is still lacking. The aim of this paper is to provide a comprehensive review of the physicochemical properties, origin and pharmacokinetics of punicalagin, while emphasizing the significance and mechanisms of its potential role in the prevention and treatment of MCI. Preclinical and clinical studies have demonstrated that Punicalagin possesses the potential to effectively target and enhance the treatment of MCI. Potential mechanisms by which punicalagin alleviates MCI include antioxidative damage, anti-neuroinflammation, promotion of neurogenesis, and modulation of neurotransmitter interactions. Overall, punicalagin is safer and shows potential as a therapeutic compound for the prevention and treatment of MCI, although more rigorous randomized controlled trials involving large populations are required. [Display omitted] [ABSTRACT FROM AUTHOR]

The underlying mechanisms of macamide's neuroprotective effects in Alzheimer's disease (AD) were investigated in the paper. Macamides are considered as unique ingredients in maca. Improvement effects and mechanisms of macamide on cognitive impairment have not been revealed. In this study, Vina 1.1.2 was used for docking to evaluate the binding abilities of 12 main macamides to acetylcholinesterase (AChE). N-benzyl-(9Z,12Z)-octadecadienamide (M 18:2) was selected to study the following experiments because it can stably bind to AChE with a strong binding energy. The animal experiments showed that M 18:2 prevented the scopolamine (SCP)-induced cognitive impairment and neurotransmitter disorders, increased the positive rates of Nrf2 and HO-1 in hippocampal CA1, improved the synaptic plasticity by maintaining synaptic morphology and increasing the synapse density. Moreover, the contents of IL-1β, IL-6, and TNF-α in the hippocampus, serum, and colon were reduced by M 18:2. Furthermore, M 18:2 promoted colonic epithelial integrity and partially restored the composition of the gut microbiota to normal, including decreased genera Clostridiales_unclassified and Lachnospiraceae_unclassified , as well as increased genera Muribaculaceae_unclassified , Muribaculum , Alistipes , and Bacteroides , which may be the possible biomarkers of cognitive aging. In summary, M 18:2 exerted neuroprotective effects on SCP-induced AD mice possibly via activating the Nrf2/HO-1 signaling pathway and modulating the gut microbiota. [Display omitted] • Macamides could stably bind to AChE. • M 18:2 ameliorated the cognitive deficit in scopolamine-induced mice. • M 18:2 inhibited the activities of AChE, BuChE, MAO in scopolamine-induced mice. • M 18:2 improved the synaptic plasticity in scopolamine-induced mice. • M 18:2 modulated the composition of gut microbiota. [ABSTRACT FROM AUTHOR]

Protein kinases play pivotal roles in various biological functions, influencing cell differentiation, promoting survival, and regulating the cell cycle. The disruption of protein kinase activity is intricately linked to pathways in tumor development. This manuscript explores the transformative impact of protein kinase inhibitors on cancer therapy, particularly their efficacy in cases driven by targeted mutations. Focusing on key tyrosine kinase inhibitors (TKIs) like Bcr-Abl, Epidermal Growth Factor Receptor (EGFR), and Vascular Endothelial Growth Factor Receptor (VEGFR), it targets critical kinase families in cancer progression. Clinical trial details of these TKIs offer insights into their therapeutic potentials. Learning from FDA-approved kinase inhibitors, the review dissects trends in kinase drug development since imatinib's paradigm-shifting approval in 2001. TKIs have evolved into pivotal drugs, extending beyond oncology. Ongoing clinical trials explore novel kinase targets, revealing the vast potential within the human kinome. The manuscript provides a detailed analysis of advancements until 2022, discussing the roles of specific oncogenic protein kinases in cancer development and carcinogenesis. Our exploration on PubMed for relevant and significant TKIs undergoing pre-FDA approval phase III clinical trials enriches the discussion with valuable findings. While kinase inhibitors exhibit lower toxicity than traditional chemotherapy in cancer treatment, challenges like resistance and side effects emphasize the necessity of understanding resistance mechanisms, prompting the development of novel inhibitors like osimertinib targeting specific mutant proteins. The review advocates thorough research on effective combination therapies, highlighting the future development of more selective RTKIs to optimize patient-specific cancer treatment and reduce adverse events. [Display omitted] • Tyrosine kinases (TKIs) are targeted therapies that inhibit enzymes that are essential for cancer cell growth and proliferation. • FDA-approved TKIs have demonstrated significant efficacy in treating various types of cancers. • Several FDA-approved TKIs including Imatinib (Gleevec), Erlotinib (Tarceva), etc. are discussed in the paper. • Disruption of protein kinase activity is associated with multiple pathways involved in tumor development. [ABSTRACT FROM AUTHOR]

Chronic restraint stress (CRS) is a widely used stimulus to induce anxiety- and depression-like behaviors, linked to alterations in tryptophan-kynurenine (TRP-KYN) metabolism in animals. This study assessed the effects of different CRS periods on anxiety- or depression-like behaviors and TRP-KYN metabolism along brain-gut axis in C57BL/6N mice. Results showed that one-week CRS decreased the open arm entries of mice in elevated plus maze and delayed latency of feeding in novelty suppressed feeding test. Four-week CRS reduced sucrose preference, increases forced swimming immobility time, and also induced anxiety-like behaviors of mice. UPLC-MS/MS analysis revealed decreased levels of the neurotoxic 3-hydroxykynurenine (3-HK) and quinolinic acid (QA), and an increase in the neuroprotective kynurenic acid (KA) in the hippocampus of one-week CRS mice; meanwhile, four-week CRS mice displayed a reduction in KA and increases in 3-HK and QA. In the colon, both one-week and four-week CRS mice exhibited significant reductions in 3-HK and QA, with a marked increase of KA exclusively in four-week CRS mice. Briefly, one-week CRS only induced anxiety-like behaviors with hippocampal neuroprotection in TRP-KYN metabolism, whereas four-week CRS caused anxiety- and depression-like behaviors with neurotoxicity. In the colon, during both CRS periods, KYN was metabolized in the direction of NAD+ production. However, four-week CRS triggered intestinal inflammation risk with increased KA. Summarily, slightly short-term stress has beneficial effects on mice, while prolonged chronic stress can lead to pathological changes. This study offers valuable insights into stress-induced emotional disturbances. [Display omitted] • This paper reported the effect of CRS periods on mice behaviors and TRP-KYN metabolism along the brain-gut axis at first time. • One-week CRS only induced anxiety-like behaviors, while four-week CRS produced anxiety- and depression-like behaviors. • One-week CRS increases neuroprotective KA in hippocampus of mice, while four-week CRS increases neurotoxic QA and 3-HK. • The colonic KYN were directed to QA both in one- and four-week CRS mice; but enterotoxic KA signally increased in the latter. • Based on TRP-KYN, slightly short CRS may be beneficial to mice, while long time CRS can cause mice pathological changes. [ABSTRACT FROM AUTHOR]

Spinal cord injury (SCI) can lead to severe motor, sensory and autonomic nervous dysfunction, cause serious psychosomatic injury to patients. There is no effective treatment for SCI at present. In recent years, exciting evidence has been obtained in the application of cell-based therapy in basic research. These studies have revealed the fact that cells transplanted into the host can exert the pharmacological properties of treating and repairing SCI. Olfactory ensheathing cells (OECs) are a kind of special glial cells. The application value of OECs in the study of SCI lies in their unique biological characteristics, that is, they can survive and renew for life, give full play to neuroprotection, immune regulation, promoting axonal regeneration and myelination formation. The function of producing secretory group and improving microenvironment. This provides an irreplaceable treatment strategy for the repair of SCI. At present, some researchers have explored the possibility of treatment of OECs in clinical trials of SCI. Although OECs transplantation shows excellent safety and effectiveness in animal models, there is still lack of sufficient evidence to prove the effectiveness of their clinical application in clinical trials. There has been an obvious stagnation in the transformation of OECs transplantation into routine clinical practice, and clinical trials of cell therapy in this field are still facing major challenges and many problems that need to be solved. Therefore, this paper summarized and analyzed the clinical trials of OECs transplantation in the treatment of SCI, and discussed the problems and challenges of OECs transplantation in clinical trials. [ABSTRACT FROM AUTHOR]

Sirtuins (SIRTs) were originally characterized by yeast Sir2 as a lifespan regulator that is conserved in all three structural domains of bacteria, archaea and eukaryotes and belong to histone deacetylases consisting of seven members (SIRT1-SIRT7). Surprisingly, SIRTs have been shown to play important regulatory roles in almost all cellular functions, including mitochondrial biogenesis, oxidative stress, inflammation, cell growth, energy metabolism, neural function, and stress resistance. Among the SIRT members, sirtuin 3 (SIRT3) is one of the most important deacetylases that regulates the mitochondrial acetylation and plays a role in pathological processes, such as metabolism, DNA repair, oxidative stress, apoptosis and ferroptosis. Therefore, SIRT3 is considered as a potential target for the treatment of a variety of pathological diseases, including metabolic diseases, neurodegenerative diseases, age-related diseases and others. Furthermore, the isolation, screening, and development of SIRT3 signaling agonists, especially from natural products, have become a widely investigated objective. This paper describes the structure of SIRT3 protein, discusses the pathological process of SIRT3-mediated acetylation modification, and reviews the role of SIRT3 in diseases, SIRT3 activators and its related disease studies. [ABSTRACT FROM AUTHOR]

Abstract: This paper appears in a special issue of the European Journal of Pharmacology that commemorates the retirement of Professor Willem Hendrik Gispen as distinguished professor of Utrecht University and as editor of the European Journal of Pharmacology. The paper provides an overview of a research line on the impact of diabetes on cognition that we started together 20 years ago, and that continues to this day. I will report how we more or less stumbled upon this topic, that was understudied, but proved to be of definite clinical relevance. I will discuss how we tried to establish animal models, how developments from clinical and experimental studies from around the world led us to reconsider our concepts, and how findings from research on diabetic neuropathy, insulin signaling in the brain, Alzheimer′s disease and dementia, and vascular disease and stroke converged and helped to create new ideas and refute others. This voyage has not ended yet, because the ultimate goal is to offer patients with diabetes treatment that can protect them against accelerated cognitive decline. Although this could take another 20 years, the research from Willem Hendrik and his group brought us an important step in the right direction. [Copyright &y& Elsevier]

FFA4 (Free Fatty Acid receptor 4, previously known as GPR120) is a G protein-coupled receptor that acts as a sensor of long-chain fatty acids, modulates metabolism, and whose dysfunction participates in endocrine disturbances. FFA4 is known to be phosphorylated and internalized in response to agonists and protein kinase C activation. In this paper report the modulation of this fatty acid receptor by activation of receptor tyrosine kinases. Cell-activation with growth factors (insulin, epidermal growth factor, insulin-like growth factor-I, and platelet-derived growth factor) increases FFA4 phosphorylation in a time- and concentration-dependent fashion. This effect was blocked by inhibitors of protein kinase C and phosphoinositide 3-kinase, suggesting the involvement of these kinases in it. FFA4 phosphorylation did not alter agonist-induced FFA4 calcium signaling, but was associated with decreased ERK 1/2 phosphorylation. In addition, insulin, insulin-like growth factor-I, epidermal growth factor, and to a lesser extent, platelet-derived growth factor, induce receptor internalization. This action of insulin, insulin-like growth factor I, and epidermal growth factor was blocked by inhibitors of protein kinase C and phosphoinositide 3-kinase. Additionally, cell treatment with these growth factors induced FFA4-β-arrestin coimmunoprecipitation. Our results evidenced cross-talk between receptor tyrosine kinases and FFA4 and suggest roles of protein kinase C and phosphoinositide 3-kinase in such a functional interaction. Image 1 [ABSTRACT FROM AUTHOR]

The cytokine storm includes a clinically heterogeneous set of life-threatening conditions that are manifested by extremely elevated serum cytokine levels and related symptoms (e.g., septic shock) and is devilishly mediated by Toll-like receptor (TLR) agonists in most situations. A tyrosine kinase inhibitor (TKIs), sunitinib, was screened in our group previously and showed antagonistic activity for cytokine release in a TLR7 stimulation model. In this paper, we further studied its mechanisms on interesting phenomena. In vitro , nearly all of the eleven TKIs decreased the TNF-α levels induced by the TLR7 agonist, especially sunitinib. Furthermore, sunitinib displayed potent inhibition of the cytokine levels triggered by several types of TLR ligands, including TLR3, TLR4, TLR7/8 and TLR9, in mouse spleen lymphocytes, mouse BMDCs and human PBMCs. The in vivo results showed that sunitinib efficiently depressed the LPS-induced cytokine storm, i.e., rapid and intense production of TNF-α and IL-6. Sunitinib further increased the survival time and decreased damage to mice. As for the immunosuppressive mechanisms of sunitinib, at least the PDGFR-activated ERK and p38 pathways were critical, although we could not rule out the possibility of other pathways being involved. In conclusion, our study demonstrated the inhibitory actions of TKIs on the cytokine storm induced by TLR ligands, primarily through PDGFR pathways, which could be potentially used to reduce cytokine storms in septic shock. Image 1 [ABSTRACT FROM AUTHOR]

Abstract COPD is a chronic lung disease characterized by persistent respiratory symptoms and airflow limitation due to airway and/or alveolar abnormalities. Furthermore, COPD is often characterized by extrapulmonary manifestations and comorbidities worsening COPD progression and quality of life. A neglected comorbidity in COPD management is mental health impairment defined by anxiety, depression and cognitive problems. This paper summarizes the evidence for impaired mental health in COPD and focuses on current pharmacological intervention strategies. In addition, possible mechanisms in impaired mental health in COPD are discussed with a central role for inflammation. Many comorbidities are associated with multi-organ-associated systemic inflammation in COPD. Considering the accumulative evidence for a major role of systemic inflammation in the development of neurological disorders, it can be hypothesized that COPD-associated systemic inflammation also affects the function of the brain and is an interesting therapeutic target for nutra- and pharmaceuticals. [ABSTRACT FROM AUTHOR]

Mitochondrial autophagy plays an important role in maintaining the complexity of mitochondrial functions and removing damaged mitochondria, of which the PINK1-Parkin signal pathway is one of the most classical pathways. Thus, a comprehensive and in-depth interpretation of the PINK1-Parkin signal pathway might deepen our understanding on the impacts of mitochondrial autophagy. Alzheimer's disease (AD) is a classical example of neurodegenerative disease. Research on the pathogenesis and treatments of AD has been a focus of scientific research because of its complexity and the limitations of current drug therapies. It was reported that the pathogenesis of AD might be related to mitochondrial autophagy due to excessive deposition of Aβ protein and aggravation of the phosphorylation of Tau protein. Two key proteins in the PINK1-Parkin signaling pathway, PINK1 and Parkin, have important roles in the folding and accumulation of Aβ protein and the phosphorylation of Tau protein. In addition, the intermediate signal molecules in the PINK1-Parkin signal pathway also have certain effects on AD. In this paper, we first described the role of PINK1-Parkin signal pathway on mitochondrial autophagy, then discussed and analyzed the effect of the PINK1-Parkin signal pathway in AD and other metabolic diseases. Our aim was to provide a theoretical direction to further elucidate the pathogenesis of AD and highlight the key molecules related to AD that could be important targets used for AD drug development. [ABSTRACT FROM AUTHOR]

Uncontrolled inflammation leads to nonspecific destruction and remodeling of tissues and can contribute to many human pathologies, including pulmonary diseases. Stimulation of inflammatory resolution is considered an important process that protects against the progression of chronic inflammatory diseases. Resolvins generated from essential omega-3 polyunsaturated fatty acids have been demonstrated to be signaling molecules in inflammation with important pro-resolving and anti-inflammatory capabilities. By binding to specific receptors, resolvins can modulate inflammatory processes such as neutrophil migration, macrophage phagocytosis and the presence of pro-inflammatory mediators to reduce inflammatory pathologies. The discovery of these pro-resolving mediators has led to a shift in drug research from suppressing pro-inflammatory molecules to investigating compounds that promote resolution to treat inflammation. The exploration of inflammatory resolution also provided the opportunity to further understand the pathophysiology of pulmonary diseases. Alterations of resolution are now linked to both the development and exacerbation of diseases such as asthma, chronic obstructive pulmonary disease, cystic fibrosis, acute respiratory distress syndrome, cancer and COVID-19. These findings have resulted in the rise of novel design and testing of innovative resolution-based therapeutics to treat diseases. Hence, this paper reviews the generation and mechanistic actions of resolvins and investigates their role and therapeutic potential in several pulmonary diseases that may benefit from resolution-based pharmaceuticals. [ABSTRACT FROM AUTHOR]

Cardiovascular diseases have been closely linked to abnormal epigenetic regulation. In the context of epigenetic regulation, BRG1, a pivotal SWI/SNF chromatin remodeling enzyme, emerges as a key epigenetic regulator with significant impact on the development and progression of cardiovascular disorders. From the perspective of epigenetic regulation of cardiovascular diseases, BRG1 emerges as a pivotal SWI/SNF chromatin remodeling enzyme, functioning as a key epigenetic regulator. It exerts substantial influence on the development and progression of cardiovascular disorders by exerting precise control over gene expression and protein levels. Therefore, a comprehensive understanding of BRG1's epigenetic regulatory role in cardiovascular disease is essential for unraveling its underlying pathophysiological mechanisms. This paper summarizes and discusses the function of BRG1 in the epigenetic regulation of cardiovascular diseases. [ABSTRACT FROM AUTHOR]

Depression is a profound mental disorder that dampens the mood and undermines volition, which exhibited an increased incidence over the years. Although drug-based interventions remain the primary approach for depression treatment, the available medications still can't satisfy the patients. In recent years, the newly discovered therapeutic targets such as N-methyl-D-aspartate (NMDA) receptor, α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) receptor, and tyrosine kinase B (TrkB) have brought new breakthroughs in the development of antidepressant drugs. Moreover, it has come to light that certain anesthetics possess pharmacological mechanisms intricately linked to the aforementioned therapeutic targets for depression. At present, numerous preclinical and clinical studies have explored the therapeutic effects of anesthetic drugs such as ketamine, isoflurane, N 2 O, and propofol, on depression. These investigations suggested that these drugs can swiftly ameliorate patients' depression symptoms and engender long-term effects. In this paper, we provide a comprehensive review of the research progress and potential molecular mechanisms of various anesthetic drugs for depression treatment. By shedding light on this subject, we aim to facilitate the development and clinical implementation of new antidepressant drugs based on anesthetic medications. [ABSTRACT FROM AUTHOR]

MicroRNA (miRNA)-mediated gene silencing is a method of RNA interference in which a miRNA binds to messenger RNA sequences and regulates target gene expression. MiRNA-based therapeutics have shown promise in treating a variety of central nervous system diseases, as verified by results from diverse preclinical model organisms. Over the last decade, several miRNA-based therapeutics have entered clinical trials for various kinds of diseases, such as tumors, infections, and inherited diseases. However, such clinical trials for central nervous system diseases are scarce, and many central nervous system diseases, including hemorrhagic stroke, ischemic stroke, traumatic brain injury, intractable epilepsy, and Alzheimer's disease, lack effective treatment. Considering its effectiveness for central nervous system diseases in preclinical experiments, microRNA-based intervention may serve as a promising treatment for these kinds of diseases. This paper reviews basic principles and recent progress of miRNA-based therapeutics and summarizes general procedures to develop such therapeutics for treating central nervous system diseases. Then, the current obstacles in drug development are discussed. This review also provides a new perspective on possible solutions to these obstacles in the future. [ABSTRACT FROM AUTHOR]

Quantitative techniques improve our understanding of tumor volume data for combination treatments and its translation across in vivo models and species. The focus of this paper is therefore on understanding in vivo data, highlighting key structural elements of pharmacodynamic tumor models, and challenging these methods from a translational point of view. We introduce the concept of Tumor Static Exposure (TSE) both for single and multiple combined anticancer agents. The TSE curve separates all possible exposure combinations into regions of tumor growth and tumor shrinkage. Moreover, the degree of curvature of the TSE curve indicates the degree of synergy or antagonism. We demonstrate the TSE approach by two case studies. The first examines a combination of the drugs cetuximab and cisplatin. The TSE curve associated with this combination reveals a weak synergistic effect, suggesting only modest gains from combination therapy. The second case study examines combinations of ionizing radiation and a radiosensitizing agent. In this case, the TSE curve exhibits a pronounced curvature, indicating a strong synergistic effect; tumor regression can be achieved at significantly lower exposure levels and/or radiation doses. Finally, an allometric approach to human dose prediction demonstrates the translational power of the model and the TSE concept. We conclude that the TSE approach, which embodies model-based measures of both drug (potency) and target properties (tumor growth rate), has a strong potential for ranking of compounds, supporting compound selection, and translating preclinical findings to humans. [ABSTRACT FROM AUTHOR]

Pharmacology is one of the cornerstones in health sciences curricula as well as research-oriented biomedical programs in higher education. New educational insights and scientific developments in teaching and learning, as well as exciting discoveries in pharmacology research, must prompt pharmacology teachers to regularly rethink and adjust their teaching. Reflecting on pharmacology education, this paper touches upon some educational issues that might inspire readers of this journal who are involved in pharmacology teaching. [ABSTRACT FROM AUTHOR]

As the use of radiation technology for nuclear warfare or for the benefits of mankind (e.g. in radiotherapy or radio-diagnosis) is increasing tremendously, the risk of associated side effects is becoming a cause of concern. These effects, ranging from nausea/vomiting to death, may result from accidental or deliberate exposure and begin in seconds. Through this review paper, efforts have been done to critically review different compounds which have been investigated as radioprotectors and radiation mitigators. Radioprotectors are compounds which are administered just before or at the time of irradiation so as to minimize the radiation induced damage to normal tissues. And radiation mitigators are the compounds which can even minimize or ameliorate post irradiaion-toxicity provided they are administered before the onset of toxic symptoms. A variety of agents have been investigated for their preventive and ameliorative potential against radiation induced toxic effects. This review article has focused on various aspects of the promising representative agents belonging to different classes of radioprotectors and mitigators. Many compounds have shown promising results, but till date only amifostine and palifermin are clinically approved by FDA. To fill this void in pharmacological armamentarium, focus should be shifted towards novel approaches. [ABSTRACT FROM AUTHOR]

Dopaminergic neurons play an important role on central regulatory mechanisms of feeding behavior. Dopamine receptors are distributed within the hypothalamus and densely localized in the paraventricular hypothalamic nucleus (PVN). From these ideas we postulated that PVN D 1 receptors may play a role in regulating the food intake behavioral process. In this paper, we considered the effects of SKF38393, a D 1 receptor agonist, and the D 1 receptor antagonist (SCH23390), on food intake of conscious rats deprived of food for 24 h. Our findings revealed that intraparaventricular injections of SKF383993 (0.3–5 µg) stimulated food intake behavior in a dose dependent manner. This stimulatory effect of SKF3833 persisted over 2 h of the monitoring period. The PVN injections of D 1 receptor antagonist were associated with dose-dependent inhibition of food intake. SCH23390 (0.01 µg) was also administered 5 min before intraparaventricular injection of SKF3833. The results showed that SCH23390 suppressed stimulated food intake induced by SKF38393 (1.2 µg). In conclusion, endogenous dopamine impact PVN D 1 receptors and may be a factor in regulating the food intake behavioral process. [ABSTRACT FROM AUTHOR]

Dysregulation of nucleocytoplasmic shuttling impairs cellular homeostasis and promotes cancer development. KPNB1 is a member of karyopherin β family, mediating the transportation of proteins from the cytoplasm to the nucleus. In a variety of cancers, the expression of KPNB1 is upregulated to facilitate tumor growth and progression. Both downregulation of KPNB1 level and inhibition of KPNB1 activity prevent the entry of cancer-related transcription factors into the nucleus, subsequently suppressing the proliferation and metastasis of cancer cells. Currently, five KPNB1 inhibitors have been reported and exhibited good efficacy against cancer. This paper provides an overview of the role and mechanism of KPNB1 in different cancers and KPNB1-targeted anticancer compounds which hold promise for the future. [ABSTRACT FROM AUTHOR]

Glaucoma is a chronic and progressive neurodegenerative disease characterized by the loss of retinal ganglion cells and visual field defects, and currently affects around 1% of the world's population. Elevated intraocular pressure (IOP) is the best-known modifiable risk factor and a key therapeutic target in hypertensive glaucoma. The trabecular meshwork (TM) is the main site of aqueous humor outflow resistance and therefore a critical regulator of IOP. Fibrosis, a reparative process characterized by the excessive deposition of extracellular matrix components and contractile myofibroblasts, can impair TM function and contribute to the pathogenesis of primary open-angle glaucoma (POAG) as well as the failure of minimally invasive glaucoma surgery (MIGS) devices. This paper provides a detailed overview of the current anti-fibrotic therapeutics targeting the TM in glaucoma, along with their anti-fibrotic mechanisms, efficacy as well as the current research progress from pre-clinical to clinical studies. [ABSTRACT FROM AUTHOR]

Non-alcoholic fatty liver disease (NAFLD) is a clinicopathological syndrome characterized by fatty lesions and fat accumulation in hepatic parenchymal cells, which is in the absence of excessive alcohol consumption or definite liver damage factors. The exact pathogenesis of NAFLD is not fully understood, but it is now recognized that oxidative stress, insulin resistance, and inflammation are essential mechanisms involved in the development and treatment of NAFLD. NAFLD therapy aims to stop, delay or reverse disease progressions, as well as improve the quality of life and clinical outcomes of patients with NAFLD. Gasotransmitters are produced by enzymatic reactions, regulated through metabolic pathways in vivo, which can freely penetrate cell membranes with specific physiological functions and targets. Three gasotransmitters, nitric oxide, carbon monoxide, and hydrogen sulfide have been discovered. Gasotransmitters exhibit the effects of anti-inflammatory, anti-oxidant, vasodilatory, and cardioprotective agents. Gasotransmitters and their donors can be used as new gas-derived drugs and provide new approaches to the clinical treatment of NAFLD. Gasotransmitters can modulate inflammation, oxidative stress, and numerous signaling pathways to protect against NAFLD. In this paper, we mainly review the status of gasotransmitters research on NAFLD. It provides clinical applications for the future use of exogenous and endogenous gasotransmitters for the treatment of NAFLD. [Display omitted] [ABSTRACT FROM AUTHOR]

The variability inherent in animal models and the methods used to define drug response can lead to highly divergent results when evaluating new drug candidates. Several guidelines exist for high-quality and comprehensive reporting of experiments with animals. The present survey makes a quantitative demonstration of whether compliance with good preclinical practice guidelines can affect the results and reduce risk of over- or underestimation of treatment benefit. This meta-analysis was performed on more than 400 animal studies concerning pulmonary hypertension, where a wide range of potential therapeutic agents have been recently positively assessed in preclinical experiments. The experiments were reviewed according to the selected methodological and statistical items being recommended to report in papers. A quantitative evaluation was performed of their impact on effect size, which defined the efficacy of particular drug candidates. In addition, the paper also examines whether the quality score calculated for the papers included in the analysis changed over the previous 25 years. In conclusion, some information in experimental studies is often missed or incomplete, which complicates the correct evaluation and comprehension of obtained results. This in turn could subsequently increase the potential hazards involved in translating positive experimental outcomes to possible clinical benefits in patients. [Display omitted] [ABSTRACT FROM AUTHOR]

Recent years have seen the rise of invasive fungal infections, which are mostly due to the increase in patients. Three major opportunistic fungal species in human are Aspergillus fumigatus , Candida albicans , and Cryptococcus neoformans that pose the biggest concern for these immunocompromised patients’ mortality. The growing occurrence of opportunistic fungal infections has sparked the interest to understand defense mechanisms against pathogenic fungi. Toll-like receptors (TLRs), as a part of innate immune system, play an important role for recognizing the invading microorganisms and initiating sufficient immune responses. Recent studies have revealed an integrated role for TLR, signaling inactivating immune defense mechanisms against exact fungi. Among TLRs, TLR2 and TLR4 are the major participants in fungi recognition. The present paper highlights the role of TLR participants in fungal recognition as well as their mechanisms. [ABSTRACT FROM AUTHOR]

The renin-angiotensin system (RAS) is one of important systems among homeostatic mechanisms that control the function of cardiovascular, renal and adrenal systems. As RAS has a very complex nature, it has been also found as related to the control of cell migration and apoptosis. Angiotensin-converting enzyme inhibitors (ACEI) are drugs most commonly used in the modulation of RAS activity. ACEI have been extensively described as effective in the treatment of hypertension among adults, but also as drugs delaying progression in diabetic nephropathy and reducing mortality in left ventricular dysfunction and congestive heart failure. What is less obvious, ACEI are also widely used in pediatric nephrology and cardiology. Moreover, there are more and more reports showing evidence that ACEI can be beneficial in the treatment of many other diseases and the pleiotropic activity of ACEI is mainly based on their antioxidant properties. In this paper we focus on the less obvious possibilities of the clinical use of ACEI in neurological or oncological patients, discuss the role of ACE gene polymorphism and show the perspectives of potentially new applications of ACEI in contemporary pharmacotherapy. [ABSTRACT FROM AUTHOR]

Overexpression of FoxM1 was closely related to the proliferation, metastasis, chemo-resistance and poor prognosis of various cancers. FoxM1 was regarded as the Achilles’ heel of cancer and a potential target for anti-cancer drug discovery. We previously obtained several high affinity peptides from the phage random library against the DNA binding domain of FoxM1c (FoxM1c-DBD) protein. Here in this paper, we found that 9R-P201, one of the novel peptides, showed stronger inhibition to HepG2 cancer cells than those of DU145, HUVEC and L-02 cells with an IC 50 of 43.6 µg/ml (13.1 µM). The peptide was highly effective to liver cancer cells with an IC 50 for L-02 cells of 2855.9 µg/ml. We confirmed that 9R-P201 aggregated in the cell nucleus and the expression of FoxM1 was significantly down-regulated at both transcriptional and translational levels in HepG2 cells, leading to the suppression of cell proliferation, migration, angiogenesis, and induction of apoptosis. Whole genomic RNA sequencing analysis revealed that 357 genes were significantly and differentially expressed, most of them were enriched in cancer-associated biological processes. Finally, treatment of HepG2 xenografts with 9R-P201 resulted in growth inhibition and down-regulation of foxM1 expression in tumors. Collectively, our findings suggested that 9R-P201 could strongly inhibit the viability, proliferation and migration of liver cancer HepG2 cells and induce apoptosis by down-regulation of FoxM1 and regulation of related gene expression in signal transduction passways. Thus, 9R-P201 holds great potential as a lead anti-cancer drug targeting FoxM1. [ABSTRACT FROM AUTHOR]

Chronic pain affects patients' physical and psychological health and quality of life, entailing a tremendous public health challenge. Currently, drugs for chronic pain are usually associated with a large number of side effects and poor efficacy. Chemokines in the neuroimmune interface combine with their receptors to regulate inflammation or mediate neuroinflammation in the peripheral and central nervous system. Targeting chemokines and their receptor-mediated neuroinflammation is an effective means to treat chronic pain. In recent years, growing evidence has shown that the expression of chemokine ligand 2 (CCL2) and its main chemokine receptor 2 (CCR2) is involved in its occurrence, development and maintenance of chronic pain. This paper summarises the relationship between the chemokine system, CCL2/CCR2 axis, and chronic pain, and the CCL2/CCR2 axis changes under different chronic pain conditions. Targeting chemokine CCL2 and its chemokine receptor CCR2 through siRNA, blocking antibodies, or small molecule antagonists may provide new therapeutic possibilities for managing chronic pain. • Summarize the current situation and pathogenesis of chronic pain. • Explain the neuroimmune interface-chemokine-CCL2/CCR2 axis relationship with chronic pain. • Introduce the function of CCL2/CCR2 axis and its tissue/cell distribution in pain related sites. • Summarize the experimental study on CCL2/CCR2 axis under different types of chronic pain. • Propose possible methods to treat chronic pain according to CCL2/CCR2 axis. [ABSTRACT FROM AUTHOR]

In 1957, cyclic adenosine monophosphate (cAMP) was identified as the first secondary messenger, and the first signaling cascade discovered was the cAMP-protein kinase A (PKA) pathway. Since then, cAMP has received increasing attention given its multitude of actions. Not long ago, a new cAMP effector named exchange protein directly activated by cAMP (Epac) emerged as a critical mediator of cAMP's actions. Epac mediates a plethora of pathophysiologic processes and contributes to the pathogenesis of several diseases such as cancer, cardiovascular disease, diabetes, lung fibrosis, neurological disorders, and others. These findings strongly underscore the potential of Epac as a tractable therapeutic target. In this context, Epac modulators seem to possess unique characteristics and advantages and hold the promise of providing more efficacious treatments for a wide array of diseases. This paper provides an in-depth dissection and analysis of Epac structure, distribution, subcellular compartmentalization, and signaling mechanisms. We elaborate on how these characteristics can be utilized to design specific, efficient, and safe Epac agonists and antagonists that can be incorporated into future pharmacotherapeutics. In addition, we provide a detailed portfolio for specific Epac modulators highlighting their discovery, advantages, potential concerns, and utilization in the context of clinical disease entities. [ABSTRACT FROM AUTHOR]

In 2020 the whole world focused on antivirus drugs towards SARS-CoV-2. Most of the researchers focused on drugs used in other viral infections or malaria. We have not seen such mobilization towards one topic in this century. The whole situation makes clear that progress needs to be made in antiviral drug development. The first step to do it is to characterize the potential antiviral activity of new or already existed drugs on the market. Phenothiazines are antipsychotic agents used previously as antiseptics, anthelminthics, and antimalarials. Up to date, they are tested for a number of other disorders including the broad spectrum of viruses. The goal of this paper was to summarize the current literature on activity toward RNA-viruses of such drugs like chlorpromazine, fluphenazine, perphenazine, prochlorperazine, and thioridazine. We identified 49 papers, where the use of the phenothiazines for 23 viruses from different families were tested. Chlorpromazine, fluphenazine, perphenazine, prochlorperazine, and thioridazine possess anti-viral activity towards different types of viruses. These drugs inhibit clathrin-dependent endocytosis, cell-cell fusion, infection, replication of the virus, decrease viral invasion as well as suppress entry into the host cells. Additionally, since the drugs display activity at nontoxic concentrations they have therapeutic potential for some viruses, still, further research on animal and human subjects are needed in this field to verify cell base research. Diagrammatic summary of phenothiazine derivatives antiviral activity. All of the phenothiazines (chlorpromazine, fluphenazine, perphenazine, prochlorperazine, and thioridazine) possess antiviral activity towards RNA viruses. These drugs inhibit clathrin-dependent endocytosis, cell-cell fusion, infection, replication of the virus, decrease viral invasion as well as suppress entry into the host cells. Image 1 • Phenothiazines possess antiviral activity towards RNA viruses. • An antiviral activity can be achieved below toxic serum concentration. • Phenothiazines are characterized by multidirectional points of action. [ABSTRACT FROM AUTHOR]

Age-related frailty is a significant health and social care burden, with limited treatment options. There is a lack of suitable cell culture model for screening large numbers of test compounds to identify those which promote healthy skeletal muscle function. This paper describes the characterization of reactive oxygen and nitrogen species (RONS) signalling changes in young and aged myoblasts and myotubes using C 2 C 12 cells, and the application of aged cultures to assess the effect of dietary polyphenols on RONS signalling. Aged myoblasts and myotubes showed significantly increased reactive oxygen species (p < 0.01 and p < 0.001 respectively), nitric oxide (p < 0.05 for myoblasts and myotubes), and lipid peroxidation (p < 0.05 for myoblasts and myotubes). Nine polyphenols were assessed in aged myoblasts and myotubes using concentrations and incubation times consistent with known pharmacokinetic parameters for these compounds. Although several polyphenols were seen to reduce single markers of RONS signalling, only kaempferol and resveratrol significantly reduced multiple markers in both cell models. Modulation of enzymatic antioxidant activities was assessed as a possible mechanism of action, although superoxide dismutase and catalase activities were significantly reduced in aged (versus young) myotubes (p < 0.01 and p < 0.05 respectively), no effect of polyphenol treatment on these enzyme activities were observed. Overall, this research has shown the utility of the C 2 C 12 model (myoblasts and myotubes) for screening compounds in aged muscle, and that resveratrol and kaempferol (using pharmacokinetically-informed exposures) can modulate RONS signalling in skeletal muscle cells after an acute exposure. [ABSTRACT FROM AUTHOR]

Ischemic stroke (IS) is the leading cause of long-term disability in the world and characterized by high morbidity, recurrence, complications, and mortality. Due to the lack of early diagnostic indicators, limited therapeutic measures and inadequate prognostic indicators, the diagnosis and treatment of IS remains a particular challenge at present. It has recently been reported that exosomes (EXOs) play a significant role in the pathogenesis and treatment of IS. The purpose of this paper is to probe the role of EXOs in diagnostic biomarkers and therapeutic measures for IS and to provide innovative ideas for improving the prognosis of IS. [ABSTRACT FROM AUTHOR]

FXF is a third-generation antihistamine drug and osthole is assumed a natural antihistamine alternative. This paper compares peripheral blood mononuclear cell (PBMC) incubation with FXF and osthole, by studying FXF, osthole and histamine cytokine secretion in PBMC in vitro cultures. Mabtech kits determined the interleukins IL-1β, IL-4, IL-10, IL-13 and TNF-α. The influence of the above active substances on cytokine secretion in PBMC's and serum was assessed: cytokines were IL-1β, IL-4, IL-10, IL-13 and TNF-α; and cytokine levels secreted by untreated PBMCs in pure culture medium formed the absolute control (ctrl). We determined that osthole affects PBMC cytokine secretion to almost precisely the same extent as FXF (IL-1β, IL-4, IL-10 and TNF). In addition osthole had greater IL-13 blocking ability than FXF. Moreover, we observed significantly decreased IL-4 level in histamine/osthole theatment compared to histamine alone. Meanwhile, FXF not significantly decrease the level of IL-4 increased by histamine. This data indicates osthole's strong role in allergic inflamation. All results confirm our hypothesis that osthole is a natural histamine antagonist and therefore can be beneficially used in antihistamine treatment of conditions such as allergies. [ABSTRACT FROM AUTHOR]

In this paper, we synthesized three fluorine-substituted mono-carbonyl curcumin analogs and evaluated their cytotoxicity against several cancer cells by the MTT assay. The results exhibited that all the three compounds were more active than the leading curcumin. Especially, 2,2′-F mono-carbonyl curcumin, 1a , surfaced as an important lead compound displaying almost 4-fold cytotoxicity relative to curcumin. More importantly, 1a was more stable in (RPMI)-1640 medium and more massive uptake than curcumin, which may be relationship to their cytotoxicity, apoptotic acitivity and reactive oxygen species generation. And then, the generation of reactive oxygen species can disrupt the intracellular redox balance, induce lipid peroxidation, cause the collapse of the mitochondrial membrane potential and ultimately lead to apoptosis. The results not only suggest that 2,2′-F mono-carbonyl curcumin ( 1a ) may cause cancer cells apoptosis through reactive oxygen species-Mediated pathway, but also gives us an important information for design of mono-carbonyl curcumin analog. [ABSTRACT FROM AUTHOR]

Since its clinical inception, tamoxifen (TAM) has proved to be a powerful tool in treating estrogen receptor-positive breast cancers while exhibiting manageable side effects. Although TAM was synthesized as an estrogen receptor antagonist, reports have found that a significant fraction of women with estrogen receptor-negative cancers have benefitted from TAM treatment, suggesting the possibility of an alternate anti-cancer mechanism. In this paper, we present a review of recent and past literature in an attempt to clarify how TAM inhibits cell proliferation and induces apoptosis in cells lacking the estrogen receptor. Our analysis indicates that micromolar concentrations of TAM selectively elevate intracellular calcium concentrations in malignant cells, possibly by inversely agonizing cannabinoid receptors, producing considerable mitochondrial distress followed by the rapid production of reactive oxygen species. In response, cytoplasmic proteins such as JNK1 are activated, which mediates the activation of caspase-8. Fyn kinase auto phosphorylates in response to increased reactive oxygen species and directs the ubiquitin ligase c-Cbl to tag growth factor receptors for ubiquitination, potentially abrogating constitutively active survival pathways that are hallmarks of cancer progression. We attempt to differentiate the effect that TAM has on purified Protein Kinase C (PKC) compared to that in an intact cell, suggesting that low micromolar concentrations of TAM indirectly inhibit PKC by inducing EGFR destruction and high micromolar concentrations of TAM inhibits PKC through a direct binding mechanism. [ABSTRACT FROM AUTHOR]

Nuclear factor erythroid 2-related factor (Nrf2), a key transcription factor triggers the expression of antioxidant and detoxification genes thereby providing cellular protective functions against oxidative stress-mediated disorders. Recent research has identified that pharmacological activation of Nrf2 also regulates the largest cluster of genes associated with lipid metabolism. With this background, this paper highlights the anti-hyperlipidemic and anti-peroxidative role of pterostilbene (PTS), an Nrf2 activator, in streptozotocin (STZ)-induced diabetic model. PTS administration to diabetic mice for 5 weeks significantly regulated blood glucose levels through the elevation of insulin secretion. The circulatory and liver lipid profiles of total cholesterol (TC), triglycerides (TG) and non-esterified fatty acids (NEFA) were maintained to normal levels upon PTS treatment. Moreover, PTS administration also normalized the circulatory levels of very low-, low- and high density lipoprotein cholesterols (VLDL-, LDL-, HDL-C) and also reduced lipid peroxidation in STZ-induced diabetic mice. In addition, Nrf2 and its downstream targets, superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) enzyme activities and glutathione (GSH) levels were significantly elevated in liver tissues of diabetic mice upon PTS administration. Further, H&E staining of diabetic mouse liver showed collapse in hepatic microvesicles due to altered lipid metabolism. Both structural and functional alterations were attenuated by PTS indicating its role in diabetic dyslipidemia through Nrf2-mediated mechanism that could be considered as a promising therapeutic agent. [ABSTRACT FROM AUTHOR]

L3, an analog of curcumin, is a compound isolated from a traditional Chinese medicine Turmeric. In this paper, we aims to explore the efficacy of L3 on diabetic atherosclerosis and the related mechanism. The effect of L3 was studied on glucose and lipid metabolism, antioxidant status, atherosclerosis-related indexes and pathological changes of main organs in the mice model of diabetes induced by streptozotocin and high-fat diet. The results showed that L3 treatment could meliorate dyslipidemia and hyperglycemia, reduce oxidative stress, enhance the activity of antioxidases, increase the nitric oxide level in plasma and aortic arch, decrease the production of reactive oxygen species in pancreas and lectin-like oxidized low-density lipoprotein receptor-1 expression in aortic arch, and meliorate the fatty and atherosclerotic degeneration in aortic arch, thereby preventing the development of diabetes and its complications. These results suggested that L3 can alleviate the diabetic atherosclerosis by multiple effects. This study provided scientific basis for the further research and clinical application of L3. [ABSTRACT FROM AUTHOR]

Mammalian tachykinins are a family of neuropeptides which are potent modulators of smooth muscle function with a significant contractile effect on human smooth muscle preparations. Tachykinins act via three distinct G protein-coupled neurokinin (NK) receptors, NK 1 , NK 2 and NK 3 , coded by the genes TACR1, TACR2 and TACR3 respectively. The purpose of this paper was to measure the mRNA and protein expression of these receptors and their isoforms in the clasp and sling fibers of the human lower esophageal sphincter complex and circular muscle from the adjacent distal esophagus and proximal stomach. We found differences in expression between the different receptors within these muscle types, but the rank order of the receptor expression did not differ between the different muscle types. The rank order of the mRNA expression was TACR2 (α isoform)>TACR2 (β isoform)>TACR1 (short isoform)>TACR1 (long isoform)>TACR3. The rank order of the protein expression was NK 2 >NK 1 >NK 3 . This is the first report of the measurement of the transcript and protein expression of the tachykinin receptors and their isoforms in the muscles of the human lower esophageal sphincter complex. The results provide evidence that the tachykinin receptors could contribute to the regulation of the human lower esophageal sphincter, particularly the TACR2 α isoform which encodes the functional isoform of the tachykinin NK 2 receptor was the most highly expressed of the tachykinin receptors in the muscles associated with the lower esophageal sphincter. [ABSTRACT FROM AUTHOR]

The anti-cancer effects of dioscin have been widely reported. However, its effect on laryngeal cancer remains unknown. In the present paper, our results showed that dioscin markedly caused cell apoptosis and DNA damage, increased reactive oxygen species (ROS) level, induced S-phase arrest, and inhibited invasion of human laryngeal cancer HEp-2 and TU212 cells. Mechanism investigation showed that dioscin markedly up-regulated p53 level, and down-regulated cyclin-dependent kinase 2 (CDK2) and Cyclin A levels. In addition, dioscin significantly down-regulated the levels of p-ERK, Bcl-2, up-regulated the levels of p-JNK, p-p38, Bax, cleaved caspase-3/-9, and caused Cytochrome c release. Furthermore, U0126, an ERK1/2 inhibitor, markedly down-regulated Bcl-2 level, up-regulated the levels of Bax, cleaved caspase-3/9, and enhanced Cytochrome c release inducted by dioscin. While, SP600125 (one JNK inhibitor) and SB203580 (one p38 inhibitor) markedly up-regulated Bcl-2 level, down-regulated the levels of Bax, cleaved caspase-3/9, and obviously boosted Cytochrome c release induced by dioscin. Interestingly, dioscin also markedly down-regulated the levels of MMP2 and MMP9 associated with tumor invasion. Taken together, our study indicated that dioscin suppressed laryngeal cancer cells growth via inducting cell-cycle arrest, MAPK-mediated mitochondrial- derived apoptosis and inhibiting tumor invasion, which could be used as one potential candidate for the treatment of laryngeal cancer in the future. [ABSTRACT FROM AUTHOR]

The present study was designed to investigate the antinociception of spirocyclopiperazinium salt compound LXM-10-M (2,4-dimethyl-9-β-m-hydroxyphenylethyl-3-oxo-6, 9-diazaspiro [5.5] undecane chloride) in thermal and chemical pain models, and further to explore the molecular target and potential signal pathway. We assessed the antinociception of LXM-10-M in hot-plate test, formalin test and acetic acid writhing test in mice. The possible changes of calcium/calmodulin-dependent protein kinase IIα (CaMKIIα)/cAMP response element-binding protein (CREB)/calcitonin gene related peptide (CGRP) signaling pathway were detected by Western Blot in mice. Administration of LXM-10-M produced significant antinociception in hot-plate test, formalin test and acetic acid writhing test in mice, with no obvious toxicity. The antinociceptive effects were blocked by pretreatment with methyllycaconitine citrate (MLA, α7 nicotinic receptor antagonist) or tropicamide (TRO, M4 muscarinic receptor antagonist). Western blot analysis showed that the upregulations of p-CaMKIIα, p-CREB and CGRP in the spinal cord were reduced by LXM-10-M in chemical pain model in mice, and the effects were blocked by MLA or TRO pretreatment. This is the first paper to report that LXM-10-M exerted significant antinociception, which may be attributed to the activation of α7 nicotinic receptor and M4 muscarinic receptor and thereby triggering the inhibition of CaMKIIα/CREB/CGRP signaling pathway in mice. [ABSTRACT FROM AUTHOR]

The zebrafish ( Danio rerio ) has recently become a powerful animal model for cardiovascular research and drug discovery due to its ease of maintenance, genetic manipulability and ability for high-throughput screening. Recent advances in imaging techniques and generation of transgenic zebrafish have greatly facilitated in vivo analysis of cellular events of cardiovascular development and pathogenesis. More importantly, recent studies have demonstrated the functional similarity of drug metabolism systems between zebrafish and humans, highlighting the clinical relevance of employing zebrafish in identifying lead compounds in Chinese herbal medicine with potential beneficial cardiovascular effects. This paper seeks to summarise the scope of zebrafish models employed in cardiovascular studies and the application of these research models in Chinese herbal medicine to date. [ABSTRACT FROM AUTHOR]

This paper compares results of peripheral blood mononuclear cell (PBMC) incubation with fexofenadine (FXF) and osthole. FXF is a third-generation antihistamine drug and osthole is assumed a natural antihistamine alternative. To our best knowledge, this is the first comparative study on FXF, osthole and histamine cytokine secretion and cytotoxicity in PBMC in vitro cultures using cell proliferation ELISA BrdU. The cultures were treated 12, 42, 48 and 72 h with FXF and osthole at 150, 300 and 450 ng/ml concentrations and histamine at 50, 100 and 200 ng/ml. Our study results confirm that FXF, osthole and histamine exert no cytotoxic effect on PBMCs and that IL-6, IL-10 and TNF-α cytokine secretion following osthole cell stimulation was similar to that by FXF stimulation.This confirms our hypothesis that osthole is a natural histamine antagonist, and can therefore be beneficially applied in antihistamine treatment. [ABSTRACT FROM AUTHOR]