Basis For Action Research Articles

Targeting Sphingosine-1-Phosphate Signaling in Breast Cancer.

In recent years, newly emerging therapies, such as immune checkpoint inhibitors and antibody-drug conjugates, have further improved outcomes for breast cancer patients. However, recurrent and metastatic breast cancer often eventually develops resistance to these drugs, and cure is still rare. As such, the development of new therapies for refractory breast cancer that differ from conventional mechanisms of action is necessary. Sphingosine-1-phosphate (S1P) is a key molecule with a variety of bioactive activities, including involvement in cancer cell proliferation, invasion, and metastasis. S1P also contributes to the formation of the cancer microenvironment by inducing surrounding vascular- and lymph-angiogenesis and regulating the immune system. In this article, we outline the basic mechanism of action of S1P, summarize previous findings on the function of S1P in cancer cells and the cancer microenvironment, and discuss the clinical significance of S1P in breast cancer and the therapeutic potential of targeting S1P signaling.

Withaferin A and Celastrol Overwhelm Proteostasis.

Withaferin A (WA) and celastrol (CEL) are major bioactive components of plants that have been widely employed in traditional medicine. The pleiotropic activities of plant preparations and the isolated compounds in vitro and in vivo have been documented in hundreds of studies. Both WA and CEL were shown to have anticancer activity. Although WA and CEL belong to different chemical classes, our synthesis of the available information suggests that the compounds share basic mechanisms of action. Both WA and CEL bind covalently to numerous proteins, causing the partial unfolding of some of these proteins and of many bystander proteins. The resulting proteotoxic stress, when excessive, leads to cell death. Both WA and CEL trigger the activation of the unfolded protein response (UPR) which, if the proteotoxic stress persists, results in apoptosis mediated by the PERK/eIF-2/ATF4/CHOP pathway or another UPR-dependent pathway. Other mechanisms of cell death may play contributory or even dominant roles depending on cell type. As shown in a proteomic study with WA, the compounds appear to function largely as electrophilic reactants, indiscriminately modifying reachable nucleophilic amino acid side chains of proteins. However, a remarkable degree of target specificity is imparted by the cellular context.

Exploration on the mechanism of TCM treatment for systemic sclerosis based on intestinal flora

Systemic sclerosis (SSc) is a rare chronic disease, it is characterized by immune dysregulation, vascular lesions, and skin and multi-organ fibrosis. The disease is difficult to cure and it is important to find safe and effective complementary therapies.TCM is one of the important complementary therapies of SSc, however, the specific mechanism of action is unclear. In recent years, studies on intestinal flora have provided new ideas for the pathogenesis and treatment of diseases. Intestinal flora has been shown to influence the function of the immune system and play an important role in the development of autoimmune diseases. Modifying intestinal flora disorders and regulating inflammation-associated cytokines may be the basic mechanism of action of TCM for disease treatment. This review combines SSc, intestinal flora, and TCM to explore the mechanism of TCM's therapeutic effect on SSc by regulating intestinal flora, to provide a reference for subsequent studies, and offer new ideas for clinical treatment.

Education Aimed at Patient Safety Management of Chemotherapy Conducted at University Education Sites

The School Education Law was revised in 2006, and the university pharmacy education system and the national pharmacist examination system were changed. In line with the advancement of medical technology and the division of labor, 16 years have passed since the length of undergraduate pharmacy education was extended from 4 to 6 years in order to foster highly qualified pharmacists. During this period, the curriculum for practical training has been revised, and lectures and exercises focused on clinical education have been incorporated to foster pharmacists who can be useful in the medical field. In the area of cancer drug therapy, the university provides students with opportunities to learn about the basic mechanisms of action and side effects of anticancer drugs, but there is little coverage of clinical guidelines and pharmacological management of the latest therapies, such as cancer immunotherapy. Prior to my arrival at Hoshi University, I was involved in clinical work and clinical research at an oncology hospital for 13 years. Since my arrival, I have been exploring the gap between oncology pharmacotherapy and pharmacy education, and have been working to fill it. We have incorporated new curricula, such as exercises in formulation suggestions, lectures to deepen understanding of guidelines and supportive care, and information on the latest cancer drug therapies, such as cancer immunotherapy. This paper outlines the pharmacy education required to produce pharmacists who can practice safe cancer drug therapy.

Metformin Inducing the Change of Functional and Exhausted Phenotypic Tumor-Infiltrated Lymphocytes and the Correlation with JNK Signal Pathway in Triple-Negative Breast Cancer.

Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer. Metformin has been shown to have the potential to inhibit the proliferation of malignant cells. This study aimed to investigate the regulatory effect of metformin on phenotypic tumor-infiltrated lymphocytes (TILs) and mechanisms in TNBC. Microarray analysis was performed on 4T1 cells post metformin treatment. BALB/c mice were inoculated with 4T1 cells with knockdown/overexpression of C-Jun N-terminal kinase (JNK), and administered with metformin. Phenotypic TILs in the tumor microenvironment (TME) were visualized by immunofluorescence staining. Metformin inhibited 4T1 cell proliferation and increased expression of JNK by 21% in vitro. In vivo, Metformin increased cell counts of CD4+ and CD8+TILs by 100% and 85%, respectively, and the increase of TILs was associated with JNK pathway. Cell counts of CD4+/PD-1+ and CD8+/PD-1+TILs were reduced by 64% and 58%, respectively, post metformin treatment, but the reduction of exhausted TILs was not associated with JNK pathway. Metformin induced a 11% and 20% reduction of IL-6 and TNF-α level in the TNBC model. Our study demonstrated that metformin increased the functional phenotype of TILs and associated with JNK pathway, and suppressed the exhausted phenotype of TILs independently to JNK pathway in TNBC microenvironment. Further studies are needed to explore the basic mechanism of action of the drug. Metformin has potentially enhanced efficacy when used in combination with immunotherapy against TNBC.

Molecular Mechanisms of Antifungal Resistance in Mucormycosis.

Mucormycosis is one among the life-threatening fungal infections with high morbidity and mortality. It is an uncommon and rare infection targeting people with altered immunity. This lethal infection induced by fungi belonging to the Mucorales family is very progressive in nature. The incidence has increased in recent decades owing to the rise in immunocompromised patients. Disease management involves a multimodal strategy including early administration of drugs and surgical removal of infected tissues. Among the antifungals, azoles and amphotericin B remain the gold standard drugs of choice for initial treatment. The order Mucorales are developing a high level of resistance to the available systemic antifungal drugs, and the efficacy still remains below par. Deciphering the molecular mechanisms behind the antifungal resistance in Mucormycosis would add vital information to our available antifungal armamentarium and design novel therapies. Therefore, in this review, we have discussed the mechanisms behind Mucormycosis antifungal resistance. Moreover, this review also highlights the basic mechanisms of action of antifungal drugs and the resistance landscape which is expected to augment future treatment strategies.

Roles of Regulatory T Cell-Derived Extracellular Vesicles in Human Diseases.

Regulatory T (Treg) cells play crucial roles in maintaining immune self-tolerance and immune homeostasis, and closely associated with many human diseases. Recently, Treg cells-derived extracellular vesicles (Treg-EVs) have been demonstrated as a novel cell-contact independent inhibitory mechanism of Treg cells. Treg-EVs contain many specific biological molecules, which are delivered to target cells and modulate immune responses by inhibiting T cell proliferation, inducing T cell apoptosis, and changing the cytokine expression profiles of target cells. The abnormal quantity or function of Treg-EVs is associated with several types of human diseases or conditions, such as transplant rejection, inflammatory diseases, autoimmune diseases, and cancers. Treg-EVs are promising novel potential targets for disease diagnosis, therapy, and drug transport. Moreover, Treg-EVs possess distinct advantages over Treg cell-based immunotherapies. However, the therapeutic potential of Treg-EVs is limited by some factors, such as the standardized protocol for isolation and purification, large scale production, and drug loading efficiency. In this review, we systematically describe the structure, components, functions, and basic mechanisms of action of Treg-EVs and discuss the emerging roles in pathogenesis and the potential application of Treg-EVs in human diseases.

Ivermectin: A Controversial Focal Point during the COVID-19 Pandemic.

The SARS-CoV-2 pandemic has confirmed the apocalyptic predictions that virologists have been making for several decades. The challenge the world is facing is that of trying to find a possible treatment, and a viable and expedient option for addressing this challenge is the repurposing of drugs. However, in some cases, although these drugs are approved for use in humans, the mechanisms of action involved are unknown. In this sense, to justify its therapeutic application to a new disease, it is ideal, but not necessary, to know the basic mechanisms of action involved in a drug’s biological effects. This review compiled the available information regarding the various effects attributed to Ivermectin. The controversy over its use for the treatment of COVID-19 is demonstrated by this report that considers the proposal unfeasible because the therapeutic doses proposed to achieve this effect cannot be achieved. However, due to the urgent need to find a treatment, an exhaustive and impartial review is necessary in order to integrate the knowledge that exists, to date, of the possible mechanisms through which the treatment may be helpful in defining safe doses and schedules of Ivermectin.

Vitamin E – Known or Unknown?

Vitamin E was described in 1922 and its basic mechanism of action was elucidated in 1931. However, some new compounds with vitamin E activity have been discovered, and some unknown mechanisms of action of this vitamin in vivo have been described in a research conducted in the last 20 years. Therefore, the present review provides a comprehensive, current view of vitamin E.

Guide to radiation therapy use in companion animals

Background: Radiation therapy (RT) is an important component of a multimodality approach to treating cancer in companion animals. Many owners that receive a cancer diagnosis for their pet never get to consult with a veterinary oncologist, and so it is important that clinicians involved in cancer diagnosis or treatment (whether a general practitioner, internal medicine clinician, surgical specialist or neurologist) have a basic understanding of the equipment used, the basic mechanism of action, the indications, as well as the expected side effects of RT.Aim of the article: This article provides an updated review of veterinary RT. This is particularly timely, given the current investment in RT facilities in the UK, which will revolutionise the incorporation of RT into veterinary medicine in the near future.

Superior Enhancement of Cutaneous Microcirculation Due to "Cyclic" Application of a Negative Pressure Wound Therapy Device in Humans - Local and Remote Effects.

ObjectivesDespite a common utilization of “Negative Pressure Wound Therapy” (NPWT) Devices in a wide range of specialties, some of the basic mechanisms of action of the techniques are still on debate. Conflicting results from prior studies demonstrate our lack of understanding how wound-bed perfusion or cutaneous microcirculation is affected by NPWT.MethodsWe conducted a prospective randomized study which included 45 healthy subjects to further investigate the acute effects of NPWT on cutaneous microcirculation underneath the applied dressing. Three modes of application, namely, continuous, intermittent, cyclic, were tested. Amongst others, measurements of elicited surface pressure and a comprehensive microcirculatory analysis were carried out by utilizing an O2C-device. For the detection of (systemic) remote effects, perfusion changes of the contra-lateral thigh were evaluated.ResultsAll three tested modes of application led to a significant (p < 0.05) improvement in local tissue perfusion with an increased blood flow of max +151% and tissue oxygen saturation of +28.2% compared to baseline values. Surface pressure under the dressing significantly increased up to 29.29 mmHg due to the activation of the NPWT device. Continuous, intermittent, and cyclic application of negative pressure were accurately sensed by participants, resulting in reported pain values that mirrored the different levels of applied suction. Although the cyclic application mode showed the most pronounced effects regarding microcirculatory changes, no statistical significance between groups was observed.ConclusionWe could demonstrate a significant improvement of cutaneous microcirculation under an applied NPWT dressing with favorable effects due to cyclic mode of application. An increased surface pressure leads to a better venous drainage of the tissue, which was shown to increase arterial inflow with a consecutive improvement of oxygen supply. Further research is warranted to evaluate our findings regarding wound bed perfusion in the clinical field with respect to formation of granulation tissue and wound healing.

Effects of Bacillus subtilis CF-3 volatile organic compounds on the transcriptome and proteome of Monilinia fructicola reveal a potential mechanism of action

Monilinia fructicola is the causal agent of brown rot disease in several species of fruit crops. Volatile organic compounds (VOCs) produced by some microorganisms have been shown to inhibit postharvest disease development in fruit crops and are being explored for use in disease management. Our previous studies have shown that Bacillus subtilis, strain CF-3 VOCs can inhibit the growth of M. fructicola [ACCC 36262]. In the present study, the effect of B. subtilis CF-3 VOCs on M. fructicola was subjected to transcriptomic and proteomic analyses to provide a theoretical basis for the mechanism of action of CF-3 VOCs. A total of 1,602 differentially expressed genes (DEGs) and 1,008 differentially expressed proteins (DEPs) were identified by quantitative transcriptome (RNA-sequencing) and quantitative proteomics (Tandem Mass Tag, TMT). The DEGs and DEPs were mainly associated with the GO and KEGG categories cell wall, cell membrane, extracellular enzyme, energy metabolism, and ribosome biosynthesis. Our results indicate that CF-3 VOCs influence both the growth and pathogenicity of M. fructicola and provide a theoretical basis for the potential mechanism of action of B. subtilis CF-3 in the protection of fruits against M. fructicola and perhaps other pathogens.

Препараты гинкго билоба: по пути открытий в клинической нейрофармакологии

В статье приведены наиболее актуальные и современные данные об основных механизмах действия экстракта гинкго билоба: нейромедиаторных, нейрометаболических и вазотропных эффектах. Популярность экстракта гинкго билоба в неврологии связана с его эффективностью и безопасностью.

Adjunctive Therapies to Optimize Closed-loop Glucose Control.

Closed-loop insulin delivery systems are fast becoming the standard of care in the management of type 1 diabetes and have led to significant improvements in diabetes management. Nevertheless, there is still room for improvement for the closed-loop systems to optimize treatment and meet target glycemic control. Adjunct treatments have been introduced as an alternative method to insulin-only treatment methods to overcome diabetes treatment challenges and improve clinical and patient reported outcomes during closed-loop treatment. The adjunct treatment agents mostly consist of medications that are already approved for type 2 diabetes treatment and aim to complete the missing physiologic factors, such as the entero-endocrine system, that regulate glycemia in addition to insulin. This paper will review many of these adjunct therapies, including the basic mechanisms of action, potential benefits, side effects, and the evidence supporting their use during closed-loop treatment.

The Effects of Statins on Neurotransmission and Their Neuroprotective Role in Neurological and Psychiatric Disorders.

Statins are among the most widely used drug classes in the world. Apart from their basic mechanism of action, which is lowering cholesterol levels, many pleiotropic effects have been described so far, such as anti-inflammatory and antiatherosclerotic effects. A growing number of scientific reports have proven that these drugs have a beneficial effect on the functioning of the nervous system. The first reports proving that lipid-lowering therapy can influence the development of neurological and psychiatric diseases appeared in the 1990s. Despite numerous studies about the mechanisms by which statins may affect the functioning of the central nervous system (CNS), there are still no clear data explaining this effect. Most studies have focused on the metabolic effects of this group of drugs, however authors have also described the pleiotropic effects of statins, pointing to their probable impact on the neurotransmitter system and neuroprotective effects. The aim of this paper was to review the literature describing the impacts of statins on dopamine, serotonin, acetylcholine, and glutamate neurotransmission, as well as their neuroprotective role. This paper focuses on the mechanisms by which statins affect neurotransmission, as well as on their impacts on neurological and psychiatric diseases such as Parkinson’s disease (PD), Alzheimer’s disease (AD), vascular dementia (VD), stroke, and depression. The pleiotropic effects of statin usage could potentially open floodgates for research in these treatment domains, catching the attention of researchers and clinicians across the globe.

Hormonally Active Contraceptives Part I: Risks Acknowledged and Unacknowledged.

We reviewed the effect of hormonal contraceptives on women's health. A number of potential side effects were noted including increased risks of breast cancer, cervical cancer, inflammatory bowel disease, lupus, multiple sclerosis, cystitis, bone fractures, depression, mood disorders and suicides, fatty weight gain, and female sexual dysfunction. With the long-acting injectable contraceptives there is an increased risk of getting HIV. Misleading prescribing information regarding the risks of heart attacks, strokes and blood clotting problems were also noted. Women seeking birth control have a right to know about how to avoid these risks by using effective hormone-free Fertility Awareness Methods.

Study of anti-free radical action of phytopreparations and their effectiveness on animals

With industrial technologies of animal husbandry, the state of the animal’s body is characterized by the presence of metabolic disorders considered as oxidative stress. Currently, in animal husbandry, characterized by stressful content in industrial complexes, the use of adaptogenic drugs is required; however, among their abundance, phytobiotics are the most effective in terms of optimizing metabolic processes. Phytobiotics are herbal preparations that are sources of biologically active substances. The work shows the results of studying anti-free radicals of phytobiotics (nettle, germinated wheat sprouts, clover, licorice, marsh cinquefoil and cranberry) in the POL-AOS model system and the results of the application of the developed method of antioxidant protection for high-yielding cows kept under stressful conditions under industrial dairy management. cattle breeding. The basic mechanism of action of phytopreparations based on nettle, germinated sprouts of wheat, clover, licorice, marsh cinquefoil and cranberry in the correction and prevention of biochemical disorders caused by stress is inhibition of free radical oxidation and activation of endogenous antioxidants.

Different Point of View to the Autoimmune Diseases and Treatment with Acupuncture.

ObjectivesIt was aimed to investigate the basic action mechanism of the autoimmune diseases and common features of all diseases. Autoimmune disease are classified organ specific and systemic.MethodsThese diseases are seen systemic and disease start locations, origins seem differently. This makes learning and understanding difficult. Autoimmune diseases investigated for easier understanding. It was noticed that, autoimmune diseases’ starting places are specific and same all of them. This remarkable point is very important for acupuncture also. So; whole literatüre was researched and important point was found.ResultsWhole autoimmune diseases are attack to mesodermal layers and mesodermal origin organs of the body’s. The common property of all these disease are same; Diseases start from the mesoderm and mesodermal layer even though their organ origins’ belongs to different germ layer. From this point of view, we were able to classify autoimmune diseases simply and it was planned how can we effect body in this context with acupuncture.ConclusionAnd, when immunity comes into question, induction of adaptive immunity is depend on antigen presentation to T cells and this situation take place in the lymph node (LN) and also in the skin.When we sank the acupuncture needle into skin, signals create and start mesodermal contacts, during this time mesenchymal origin’ autoimmune cells are regulated with this signals.

Role of Indole Scaffolds as Pharmacophores in the Development of Anti-Lung Cancer Agents.

Lung cancer is the leading cause of death in men and women worldwide, affecting millions of people. Between the two types of lung cancers, non-small cell lung cancer (NSCLC) is more common than small cell lung cancer (SCLC). Besides surgery and radiotherapy, chemotherapy is the most important method of treatment for lung cancer. Indole scaffold is considered one of the most privileged scaffolds in heterocyclic chemistry. Indole may serve as an effective probe for the development of new drug candidates against challenging diseases, including lung cancer. In this review, we will focus on discussing the existing indole based pharmacophores in the clinical and pre-clinical stages of development against lung cancer, along with the synthesis of some of the selected anti-lung cancer drugs. Moreover, the basic mechanism of action underlying indole based anti-lung cancer treatment, such as protein kinase inhibition, histone deacetylase inhibition, DNA topoisomerase inhibition, and tubulin inhibition will also be discussed.

Partycypacja obywatelska w demokracji deliberacyjnej ku dobru wspólnemu

The author draws attention to the consideration of the complexity of civil participation in deliberative democracy, indicating that the legislator assumed that dialogue is to be a way of existence, and thus the basis of any social situation in the state. State authorities appointed to serve the people and the common good have to ask citizens about their position in the case, not in order to obtain the desired response, thus emphasizing the departure from the monologue culture in favor of dialogue and communication with the public. The author claims that the normative foundations of the community state are linked by the conviction that public values and purposes are established in the communication process. In this approach, it is important to achieve public purposes and the quality of their achievement, its constructive features are: network, multi-level management, conciliation, participation. The basic mechanisms of action of this type of state are: deliberation, compromise and arrangements are made in the social networks – the dominant type of management of public affairs in this model is co-management. Solicitude of the state as a common good obliges not only a citizen, but means that a citizen has the right to expect that public authority will act so that the Republic of Poland can be considered a common good by citizens. Referring to literature, the author notes that deliberative democracy and its concept put more emphasis on the importance of conversation, discussion and debate on democratic practice than on the importance of voting. Its supporters argue that the debate improves the quality of collective decisions and increases the chances of their acceptance. Varieties of deliberative democracy range from accentuating local representation to reinforcing the debate within representative legislative bodies. The article points out the differences between discourse and deliberation. Moreover, the forms of civic participation and civic participation techniques used in Poland are presented. We have come to live in times when communication, both traditional and with the help of modern media, plays a significant role in shaping societies. It is important to understand the basic laws guiding communication, the ability to properly form interpersonal relationships, cognize the factors affecting the quality of messages transmitted, the technique of freedom of expression, the skill of persuasion and argumentation. The correct perception of the essence of dialogue in a deliberative democracy is its foundation, especially when it concerns institutions aimed at turning natural and legal persons to public decision-making process. Considering the literature, it was found that new participative solutions, primarily the ability to dialogue, could prevent a democratic deficit and also indicated that that civic participation impacts on the creation of deliberative democracy.