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Evidence-Based Medicine has little consideration for mechanisms and philosophers of science and medicine have recently made pleas to increase the place of mechanisms in the medical evidence hierarchy. However, in this debate the notions of mechanisms seem to be limited to 'mechanistic processes' and 'complex-systems mechanisms,' understood as 'componential causal systems'. I believe that this will not do full justice to how mechanisms are used in biological, psychological and social sciences and, consequently, in a more biopsychosocial approach to medicine. Here, I propose, following (Kuorikoski, 2009), to pay more attention to 'abstract forms of interaction' mechanisms. The present work scrutinized review articles on depression and medically unexplained pain, which are considered to be of multifactorial pathogenesis, for their use of mechanisms. In review articles on these disorders there seemed to be a range of uses between more 'abstract forms of interaction' and 'componential causal system' mechanisms. I therefore propose to expand the notions of mechanisms considered in medicine to include that of more 'abstract forms of interaction' to better explain and manage biopsychosocial disorders., Competing Interests: Declaration of competing interest None., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Iron is essential for all organisms and cells. Diseases of iron imbalance affect billions of patients, including those with iron overload and other forms of iron toxicity. Excess iron load is an adverse prognostic factor for all diseases and can cause serious organ damage and fatalities following chronic red blood cell transfusions in patients of many conditions, including hemoglobinopathies, myelodyspasia, and hematopoietic stem cell transplantation. Similar toxicity of excess body iron load but at a slower rate of disease progression is found in idiopathic haemochromatosis patients. Excess iron deposition in different regions of the brain with suspected toxicity has been identified by MRI T2* and similar methods in many neurodegenerative diseases, including Alzheimer's disease and Parkinson's disease. Based on its role as the major biological catalyst of free radical reactions and the Fenton reaction, iron has also been implicated in all diseases associated with free radical pathology and tissue damage. Furthermore, the recent discovery of ferroptosis, which is a cell death program based on free radical generation by iron and cell membrane lipid oxidation, sparked thousands of investigations and the association of iron with cardiac, kidney, liver, and many other diseases, including cancer and infections. The toxicity implications of iron in a labile, non-protein bound form and its complexes with dietary molecules such as vitamin C and drugs such as doxorubicin and other xenobiotic molecules in relation to carcinogenesis and other forms of toxicity are also discussed. In each case and form of iron toxicity, the mechanistic insights, diagnostic criteria, and molecular interactions are essential for the design of new and effective therapeutic interventions and of future targeted therapeutic strategies. In particular, this approach has been successful for the treatment of most iron loading conditions and especially for the transition of thalassemia from a fatal to a chronic disease due to new therapeutic protocols resulting in the complete elimination of iron overload and of iron toxicity.

Abstract Due to the heterogeneous nature of depression, the underlying etiological mechanisms greatly differ among individuals, and there are no known subtype-specific biomarkers to serve as precise targets for therapeutic efficacy. The extensive research efforts over the past decades have not yielded much success, and the currently used first-line conventional antidepressants are still ineffective for close to 66% of patients. Most clinicians use trial-and-error treatment approaches, which seem beneficial to only a fraction of patients, with some eventually developing treatment resistance. Here, we review evidence from both preclinical and clinical studies on the pathogenesis of depression and antidepressant treatment response. We also discuss the efficacy of the currently used pharmacological and non-pharmacological approaches, as well as the novel emerging therapies. The review reveals that the underlying mechanisms in the pathogenesis of depression and antidepressant response, are not specific, but rather involve an interplay between various neurotransmitter systems, inflammatory mediators, stress, HPA axis dysregulation, genetics, and other psycho-neurophysiological factors. None of the current depression hypotheses sufficiently accounts for the interactional mechanisms involved in both its etiology and treatment response, which could partly explain the limited success in discovering efficacious antidepressant treatment. Effective management of treatment-resistant depression (TRD) requires targeting several interactional mechanisms, using subtype-specific and/or personalized therapeutic modalities, which could, for example, include multi-target pharmacotherapies in augmentation with psychotherapy and/or other non-pharmacological approaches. Future research guided by interaction mechanisms hypotheses could provide more insights into potential etiologies of TRD, precision biomarker targets, and efficacious therapeutic modalities.

Abstract Objectives Analyse reported processes of co-design and co-production in the context of health and social care to explore the underlying mechanisms that enable inclusive and reciprocal engagement. Search strategy Peer review research was obtained from a prior scoping review searching eight databases consisting of all methodologies relevant to co-design or co-production in the context of health and social care services and involving service-users. Methods of selection Articles were included for synthesis if they reported a process of dialogue, with mutuality, insight and clarification in their engagement process. Ninety-three peer-review articles informed our programme theory development. Analysis Data relating to co-design and co-production processes were extracted and analysed through inductive, abductive, and deductive analysis leading to the development of an initial programme theory. Main results This realist synthesis finds that co-design and co-production can occur at different times, in part or all of the research and participatory process. There is an over reliance on the term ‘co-design’ or ‘co-production’ to convey complex engagement or participatory processes. We identified six mechanisms (intention, assets, dialogue, documentation, interpretation and understanding). Interaction between these six identified mechanisms in context, even if only brief, is important for supporting meaningful engagement, alignment and agreement within a co-design or co-production process. Implications for practice The initial programme theory presented in this article provides clarity by identifying essential mechanisms which can guide the design and implementation of a range of participatory approaches. Rather than relying on a single label to convey complex participatory methods or processes, the values and principles of co-design or co-production, in combination with this programme theory, could be applied to guide implementation and reporting of specific activities within a range of research or participatory methods. Patient and public contribution The initial programme theory was presented and piloted in a series of collaborative workshops between May 2023 and March 2024 with patient and public contributors, health professionals and researchers. This engagement process is currently underway to refine the programme theory and it is anticipated that this next phase will be completed in September 2024.

The severe acute respiratory syndrome coronavirus 2 （SARS-CoV-2） is still spreading widely around the world， and it is estimated that there are more than 760 million confirmed cases of SARS-CoV-2 infection （COVID-19）. Although most of the infected patients can be cured， there are still many patients who experience persistent clinical symptoms such as dizziness， fatigue， weakness， coughing and chest pain， etc. at two to three months or even longer after being infected with SARS-CoV-2. Internationally， this type of discomforts is referred to as long COVID. The emergence of long COVID has brought a new crisis to people’s health， which not only affects the quality of life and work of patients， but also brings great pressure on the health care of the society. Continuously exploring the impact of long COVID and its underlying mechanism， developing health management strategies for long COVID， and better prevention and treatment of long COVID are still the focus of research worldwide. The article introduces the definition of long COVID and reviews recent research progress in its underlying mechanism， common systemic clinical manifestations， risk factors， and health management of long COVID， aiming to provide more ideas for deepening clinicians’ understanding of long COVID.

The development of omics technologies and sequencing has significantly expanded the understanding of the role of microorganisms that inhabit various human organs and collectively make up its microbiota in the development of cancer. The extensive literature of recent years devoted to various aspects of the participation of the microbiota in carcinogenesis substantiates the relevance of analyzing the impact of its features on the processes of carcinogenesis in various human organs.Purpose of the study. Analysis of literature data on the key issues of the relationship between the human microbiome and the risk of cancer and explore possible prospects for its use in the diagnosis, therapy and prevention of cancer.Materials and methods. A literature search was carried out in the databases NCBI MedLine (PubMed), Scopus, Web of Science, based on an extended list of keywords that included all the localizations of malignant neoplasms (MNs) considered in the review. Original studies, meta-analyses, randomized controlled trials, and reviews published in recent years were used.Results. Recent studies using omics technologies have shown significant differences in the composition of microbial communities of healthy and tumor tissues and have made it possible to characterize the potential tumor microbiota in some types of cancer. The microbiota present in the various organs of the human body forms a network through which it interacts via migration or by forming metabolic axes between organs. Dysbiosis plays an important role in carcinogenesis, and its presence in one organ can negatively affect the condition of other distant organs and contribute to the development of pathological conditions in them.Conclusion. Numerous studies conducted over the past decade have revealed a complex relationship between microorganisms, tumors, and the host, reflecting the diverse effects of the microbiota on various organ- specific types of MNs. Gastrointestinal tract tumors, as well as sites outside it with significant bacterial associations, have been identified for a better understanding of the multifaceted mechanisms by which the microbiota influences cancer. The data obtained so far complement the emerging possibilities of using the microbiota in clinical practice, which represents a new approach to the prevention and treatment of malignant neoplasms.

Abstract Recently, research on the human microbiome, especially concerning the bacteria within the digestive system, has substantially advanced. This exploration has unveiled a complex interplay between microbiota and health, particularly in the context of disease. Evidence suggests that the gut microbiome plays vital roles in digestion, immunity and the synthesis of vitamins and neurotransmitters, highlighting its significance in maintaining overall health. Conversely, disruptions in these microbial communities, termed dysbiosis, have been linked to the pathogenesis of various diseases, including digestive system cancers. These bacteria can influence cancer progression through mechanisms such as DNA damage, modulation of the tumour microenvironment, and effects on the host’s immune response. Changes in the composition and function within the tumours can also impact inflammation, immune response and cancer therapy effectiveness. These findings offer promising avenues for the clinical application of intratumoral bacteria for digestive system cancer treatment, including the potential use of microbial markers for early cancer detection, prognostication and the development of microbiome-targeted therapies to enhance treatment outcomes. This review aims to provide a comprehensive overview of the pivotal roles played by gut microbiome bacteria in the development of digestive system cancers. Additionally, we delve into the specific contributions of intratumoral bacteria to digestive system cancer development, elucidating potential mechanisms and clinical implications. Ultimately, this review underscores the intricate interplay between intratumoral bacteria and digestive system cancers, underscoring the pivotal role of microbiome research in transforming diagnostic, prognostic and therapeutic paradigms for digestive system cancers.

Abstract Radiation‐induced tissue injury (RITI) is the most common complication in clinical tumor radiotherapy. Due to the heterogeneity in the response of different tissues to radiation (IR), radiotherapy will cause different types and degrees of RITI, which greatly limits the clinical application of radiotherapy. Efforts are continuously ongoing to elucidate the molecular mechanism of RITI and develop corresponding prevention and treatment drugs for RITI. Single‐cell sequencing (Sc‐seq) has emerged as a powerful tool in uncovering the molecular mechanisms of RITI and for identifying potential prevention targets by enhancing our understanding of the complex intercellular relationships, facilitating the identification of novel cell phenotypes, and allowing for the assessment of cell heterogeneity and spatiotemporal developmental trajectories. Based on a comprehensive review of the molecular mechanisms of RITI, we analyzed the molecular mechanisms and regulatory networks of different types of RITI in combination with Sc‐seq and summarized the targeted intervention pathways and therapeutic drugs for RITI. Deciphering the diverse mechanisms underlying RITI can shed light on its pathogenesis and unveil new therapeutic avenues to potentially facilitate the repair or regeneration of currently irreversible RITI. Furthermore, we discuss how personalized therapeutic strategies based on Sc‐seq offer clinical promise in mitigating RITI.

Introduction: Chalcones, are a group of organic compounds containing two aromatic rings bridged by a three-carbon -a, ?; unsaturated carbonyl system. This attracted much attention because of their versatility in pharmacological profiles. Aims & Objectives: To investigate the therapeutic efficacy of a particular chalcone derivative, namely (E)-1-(4- bromophenyl)-3-(4-chlorophenyl) prop-2-ene-1-one. Place and Duration of Study: It was conducted in the Pharmacology Laboratory of the Institute of Basic Medical Sciences, Khyber Medical University, Peshawar, and the University of Malakand for about one year. Material & Method: This was a lab-based experimental study. The therapeutic efficacy of a chalcone derivative, (E)-1- (4-bromophenyl)-3-(4-chlorophenyl) prop-2-ene-1-one was assessed through an experiment on pain and inflammation in mice. Claisen-Schmidt condensation reaction and spectroscopic tools were used. Results: Pharmacological data proved a significant decrease in pain and inflammation as compared to Diclofenac Sodium. Reduction of 75.20% in acetic acid-induced writhing as compared to 84.4% with Diclofenac. After 3 hours, there was 67.08% reduction in edema. Conclusion: This study provides evidence that chalcone derivatives in moderation may be effective and safer than present-day drugs that address pain and inflammation. This result may need to be further clinically related to potentially translate them in different patient populations in terms of efficacy and safety.

BackgroundOpinion leadership, educational outreach visiting, and innovation championing are commonly used strategies to address barriers to implementing innovations and evidence-based practices in healthcare settings. Despite voluminous research, ambiguities persist in how these strategies work and under what conditions they work well, work poorly, or work at all. The current paper develops middle-range theories to address this gap.MethodsConceptual articles, systematic reviews, and empirical studies informed the development of causal pathway diagrams (CPDs). CPDs are visualization tools for depicting and theorizing about the causal process through which strategies operate, including the mechanisms they activate, the barriers they address, and the proximal and distal outcomes they produce. CPDs also clarify the contextual conditions (i.e., preconditions and moderators) that influence whether, and to what extent, the strategy's causal process unfolds successfully. Expert panels of implementation scientists and health professionals rated the plausibility of these preliminary CPDs and offered comments and suggestions on them.FindingsTheoretically, opinion leadership addresses potential adopters' uncertainty about likely consequences of innovation use (determinant) by promoting positive attitude formation about the innovation (mechanism), which results in an adoption decision (proximal outcome), which leads to innovation use (intermediate outcome). As this causal process repeats, penetration, or spread of innovation use, occurs (distal outcome). Educational outreach visiting addresses knowledge barriers, attitudinal barriers, and behavioral barriers (determinants) by promoting critical thinking and reflection about evidence and practice (mechanism), which results in behavioral intention (proximal outcome), behavior change (intermediate outcome), and fidelity, or guideline adherence (distal outcome). Innovation championing addresses organizational inertia, indifference, and resistance (determinants) by promoting buy-in to the vision, fostering a positive implementation climate, and increasing collective efficacy (mechanisms), which leads to participation in implementation activities (proximal outcome), initial use of the innovation with increasing skill (intermediate outcome) and, ultimately, greater penetration and fidelity (distal outcomes). Experts found the preliminary CPDs plausible or highly plausible and suggested additional mechanisms, moderators, and preconditions, which were used to amend the initial CPD.DiscussionThe middle-range theories depicted in the CPDs furnish testable propositions for implementation research and offer guidance for selecting, designing, and evaluating these social influence implementation strategies in both research studies and practice settings.

Abstract Freeze-thaw cycles and compactness are two critical factors that significantly affect the engineering properties and safety of building foundations, especially in seasonally frozen regions. This paper investigated the effects of freeze-thaw cycles on the shear strength of naturally strongly chlorine saline soil with the compactness of 85%, 90% and 95%. Three soil samples with different compactness were made. Size and mass changes were measured and recorded during freeze-thaw cycles. Shear strength under different vertical pressures was determined by direct shear tests, and the cohesion and friction angle were measured and discussed. Microstructure characteristic changes of saline soil samples were observed using scanning electron microscopy under different freeze-thaw cycles. Furthermore, numerical software was used to calculate the subsoil-bearing capacity and settlement of the electric tower foundation in the Qarhan Salt Lake region under different freeze-thaw cycles. Results show that the low-density soil shows thaw settlement deformation, but the high-density soil shows frost-heaving deformation with the increase in freeze-thaw cycles. The shear strength of the soil samples first increases and then decreases with the increase in freeze-thaw cycles. After 30 freeze-thaw cycles, the friction angle of soil samples is 28.3%, 29.2% and 29.6% lower than the soil samples without freeze-thaw cycle, the cohesion of soil samples is 71.4%, 60.1% and 54.4% lower than the samples without freeze-thaw cycle, and the cohesion and friction angle of soil samples with different compactness are close to each other. Microstructural changes indicate that the freeze-thaw cycle leads to the breakage of coarse particles and the aggregation of fine particles. Correspondingly, the structure type of soil changes from a granular stacked structure to a cemented-aggregated system. Besides, the quality loss of soil samples is at about 2% during the freeze-thaw cycles. Results suggest that there may be an optimal compactness between 90 and 95%, on the premise of meeting the design requirements and economic benefits. This study can provide theoretical guidance for foundation engineering constructions in seasonally frozen regions.

Previous research has established that polyphenols increase lifespan and stress resistance in C. elegans. However, the effects of timing of exposure on the extension of lifespan and the mechanisms involved are not completely understood. This study aims to clarify the influence of the timing of polyphenol-rich sugarcane extract (PRSE) administration on the lifespan of Caenorhabditis elegans. C. elegans worms were subjected to a diet containing PRSE powder at various larval stages until their death. The optimal concentration for lifespan extension was found to be 5 mg/mL PRSE, which increased the lifespan of N2 worms by 18.12% compared to the control group. Mutant strains were also tested, and worm thermotolerance assays were used to assess age-related health at different life stages. Lifespan was notably extended when PRSE was introduced at the first larval stage and 15 h thereafter. No significant extension of lifespan was observed when introduced later in life. The lifespan of DAF-16 and DAF-2 mutants remained unaffected by PRSE. Improved thermotolerance was observed, especially in young and middle-aged worms. Early initiation and sustained intake of PRSE might improve the heat stress and lifespan, implicating the insulin/IGF-1 signaling pathway as a likely mediator in C. elegans.

Abstract Primary angle closure disease (PACD) is a major cause of blindness worldwide. It has a high prevalence in East Asia, especially in China, which leads to a higher incidence of blindness than open-angle glaucoma. The aim of this study was to directly observe the circumlental space (CLS) in laser peripheral iridotomized eyes with PACD and to determine whether this structure plays a role in the pathogenesis of PACD. Fifty eyes of 50 patients with PACD, who had received laser peripheral iridotomy performed with neodymium:yttrium–aluminum-garnet were recruited from glaucoma clinics from March 2021 to May 2022, including 17 primary angle closure suspect (PACS), 16 primary angle closure (PAC) and 17 primary angle closure glaucoma (PACG). They were classified into two groups based on whether the ciliary process and the crystalline lens equator were in contact using slit-lamp photograph: the attached group and the unattached group. The demographic, clinical characteristics and anterior segment parameters measured from ultrasound biomicroscopy were compared between the attached group and the unattached group. Thirty-three eyes were assigned to the attached group and 17 eyes belonged to the unattached group. In the unattached group, the mean CLS was 0.10 ± 0.07 mm. No significant differences were identified between the different diagnosis groups in age, sex, best-corrected visual acuity, intraocular pressure, white-to-white, axial length, central corneal thickness, anterior chamber depth, flat keratometry, steep keratometry or iridotomy diameter (p > 0.05). The unattached group had shorter trabecular-ciliary process distance (p = 0.021) and larger ciliary process area (p = 0.001) compared with the attached group. Small CLS and its potential effect (partial ciliary block) might be considered as one of the mechanisms of PACD.

Background/Objectives: The current Bordetella bronchiseptica (Bb) vaccine, when adjuvanted with alum, does not elicit adequate robust cellular immunity or effective antibody defense against Bb attacks. Unfortunately, antibiotic treatment generally represents an ineffective strategy due to the development of resistance against a broad range of antibiotics. Methods: The present study was designed to investigate the immune response, protective capabilities and underlying mechanisms of a plant oil-based adjuvant E515 formulated with inactivated Bb antigen as a potential vaccine candidate against Bordetella bronchiseptica. Results: Immunization studies revealed that a combination of SO, VE and GS (E515) exhibited a good synergistic adjuvant effect. The E515 adjuvanted Bb vaccine was proven to be highly efficacious and induced a mixed Th1/Th2/Th17 immune response in mice, leading to a significant increase in Bb-specific IgG, IgG1 and IgG2a antibodies, proliferative lymphocyte responses and cytokine levels (by lymphocytes and serum) and effectively induced responses by CD4+ TE, TM cells and B cells. The E515 adjuvant significantly enhanced the immune protection provided by the Bb vaccine in a mice model, as indicated by a reduced bacterial burden in the lungs. Multi-omics sequencing analysis revealed that E515 functions as an adjuvant by modulating critical pathways, including cytokine–cytokine receptor interaction, the IL-17 signaling pathway and the chemokine signaling pathway. This modulation also included interactions with beneficial species of bacteria including Alistipes, Odoribacter and Colidextribacter, as well as energy and lipid-related metabolites, thus highlighting its role as an immunomodulatory agent. Conclusion: Collectively, our results demonstrate the huge potential of E515-Bb vaccine candidates, thus highlighting the vegetable oil original adjuvant E515 as a promising agent for the development of new veterinary vaccines.

Background: Aluminum adjuvants, renowned for their safety and efficacy, act as excellent adsorbents and vaccine immunogen enhancers, significantly contributing to innate, endogenous, and humoral immunity. An ideal adjuvant not only boosts the immune response but also ensures optimal protective immunity. Aluminum adjuvants are the most widely used vaccine adjuvants and have played a crucial role in both the prevention of existing diseases and the development of new vaccines. With the increasing emergence of new vaccines, traditional immune adjuvants are continually being researched and upgraded. The future of vaccine development lies in the exploration and integration of novel adjuvant technologies that surpass the capabilities of traditional aluminum adjuvants. One promising direction is the incorporation of nanoparticles, which offer precise delivery and controlled release of antigens, thereby enhancing the overall immune response. Conclusions: This review summarizes the types, mechanisms, manufacturers, patents, advantages, disadvantages, and future prospects of aluminum adjuvants. Although aluminum adjuvants have certain limitations, their contribution to enhancing vaccine immunity is significant and cannot be ignored. Future research should continue to explore their mechanisms of action and address potential adverse reactions to achieve improved vaccine efficacy.

Background Social prescribing involves connecting individuals to community groups and activities, often to support their mental health and well-being. It has received increasing support in recent years across the NHS. There is a strong evidence base for the benefits of different types of community activities, including exercise groups, arts groups and nature interventions, on mental health outcomes, however, less is known about how these groups impact mental health and well-being. This study explores through what individual-level mechanisms (the ‘how’) these groups support psychosocial well-being. Methods An ethnographic study was conducted over 12-months to explore key shared, individual-level mechanisms across 4 social prescribing community groups: football, singing, gardening and reading. This study focused mostly on those with severe mental illness, whereas previously most social prescribing studies have focused on mild to moderate mental health problems. To frame the findings, a ‘multi-level theoretical framework of mechanisms of action’ of leisure activities was used. Results Key shared psychological mechanisms were: increased self-confidence and self-esteem, increased purpose/meaning, increased sense of achievement, experience of pleasure; social mechanisms included: increased social support, formation of friendships and reduced loneliness, enhanced sense of community and belonging; behavioural mechanisms were: increased independence and openness to experience, reduction in addictive behaviours and building healthier habits, increased work-seeking behaviour, and provision of structure & routine. Conclusions It is hoped that the findings of this study can help referring professionals increase their understanding of exactly how such groups support individuals’ mental health, thus enhancing referring practices.

Abstract Cancer poses a significant global health challenge, with predictions of increasing prevalence in the coming years due to limited prevention, late diagnosis, and inadequate success with current therapies. In addition, the high cost of new anti-cancer drugs creates barriers in meeting the medical needs of cancer patients, especially in developing countries. The lengthy and costly process of developing novel drugs further hinders drug discovery and clinical implementation. Therefore, there has been a growing interest in repurposing approved drugs for other diseases to address the urgent need for effective cancer treatments. The aim of this comprehensive review is to provide an overview of the potential of approved non-oncology drugs as therapeutic options for cancer treatment. These drugs come from various chemotherapeutic classes, including antimalarials, antibiotics, antivirals, anti-inflammatory drugs, and antifungals, and have demonstrated significant antiproliferative, pro-apoptotic, immunomodulatory, and antimetastatic properties. A systematic review of the literature was conducted to identify relevant studies on the repurposing of approved non-oncology drugs for cancer therapy. Various electronic databases, such as PubMed, Scopus, and Google Scholar, were searched using appropriate keywords. Studies focusing on the therapeutic potential, mechanisms of action, efficacy, and clinical prospects of repurposed drugs in cancer treatment were included in the analysis. The review highlights the promising outcomes of repurposing approved non-oncology drugs for cancer therapy. Drugs belonging to different therapeutic classes have demonstrated notable antitumor effects, including inhibiting cell proliferation, promoting apoptosis, modulating the immune response, and suppressing metastasis. These findings suggest the potential of these repurposed drugs as effective therapeutic approaches in cancer treatment. Repurposing approved non-oncology drugs provides a promising strategy for addressing the urgent need for effective and accessible cancer treatments. The diverse classes of repurposed drugs, with their demonstrated antiproliferative, pro-apoptotic, immunomodulatory, and antimetastatic properties, offer new avenues for cancer therapy. Further research and clinical trials are warranted to explore the full potential of these repurposed drugs and optimize their use in treating various cancer types. Repurposing approved drugs can significantly expedite the process of identifying effective treatments and improve patient outcomes in a cost-effective manner.

Bacillus thuringiensis (Bt) toxins are potential alternatives to synthetic insecticides for the control of lepidopteran pests. However, the evolution of resistance in some insect pest populations is a threat and can reduce the effectiveness of Bt toxins. In this review, we summarize the results of 161 studies from 20 countries reporting field and laboratory-evolved resistance, cross-resistance, and inheritance, mechanisms, and fitness costs of resistance to different Bt toxins. The studies refer mainly to insects from the United States of America (70), followed by China (31), Brazil (19), India (12), Malaysia (9), Spain (3), and Australia (3). The majority of the studies revealed that most of the pest populations showed susceptibility and a lack of cross-resistance to Bt toxins. Factors that delay resistance include recessive inheritance of resistance, the low initial frequency of resistant alleles, increased fitness costs, abundant refuges of non-Bt, and pyramided Bt crops. The results of field and laboratory resistance, cross-resistance, and inheritance, mechanisms, and fitness cost of resistance are advantageous for predicting the threat of future resistance and making effective strategies to sustain the effectiveness of Bt crops.

Claviceptaceous endophytic fungi in the genus Epichloë mostly form a symbiotic relationship with cool-season grasses. Epichloë spp. are capable of producing bioactive alkaloids such as peramines, lolines, ergot alkaloids, and indole-diterpenes, which protect the host plant from herbivory by animals, insects, and nematodes. The host also benefits from enhanced tolerance to abiotic stresses, such as salt, drought, waterlogging, cold, heavy metals, and low nitrogen stress. The bioactive alkaloids produced can have both direct and indirect effects towards plant parasitic nematodes. Direct interaction with nematodes’ motile stages can cause paralysis (nematostatic effect) or death (nematicidal effect). Indirectly, the metabolites may induce host immunity which inhibits feeding and subsequent nematode development. This review highlights the different mechanisms through which this interaction and the metabolites produced have been explored in the suppression of plant parasitic nematodes and also how the specific interactions between different grass genotypes and endophyte strains result in variable suppression of different nematode species. An understanding of the different grass–endophyte interactions and their successes and failures in suppressing various nematode species is essential to enable the proper selection of grass–endophyte combinations to identify the alkaloids produced, concentrations required, and determine which nematodes are sensitive to which specific alkaloids.

Abstract Metformin is a well-known anti-diabetic drug that has been repurposed for several emerging applications, including as an anti-cancer agent. It boasts the distinct advantages of an excellent safety and tolerability profile and high cost-effectiveness at less than one US dollar per daily dose. Epidemiological evidence reveals that metformin reduces the risk of cancer and decreases cancer-related mortality in patients with diabetes; however, the exact mechanisms are not well understood. Energy metabolism may be central to the mechanism of action. Based on altering whole-body energy metabolism or cellular state, metformin’s modes of action can be divided into two broad, non-mutually exclusive categories: “direct effects”, which induce a direct effect on cancer cells, independent of blood glucose and insulin levels, and “indirect effects” that arise from systemic metabolic changes depending on blood glucose and insulin levels. In this review, we summarize an updated account of the current knowledge on metformin antitumor action, elaborate on the underlying mechanisms in terms of the hallmarks of cancer, and propose potential applications for repurposing metformin for cancer therapeutics.

Background Accumulating data suggest antiviral effects of povidone-iodine against the Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus. This narrative review aims to examine the antiviral mechanisms of povidone-iodine, efficacy of povidone-iodine against the SARS-CoV-2 virus, and safety of povidone-iodine to human epithelial cells and thyroid function.Methods We searched the electronic databases PubMed, Embase, Cochrane Library, ClinicalTrials.gov and World Health Organization’s International Clinical Trials Registry Platform for articles containing the keywords “povidone-iodine”, “SARS-CoV-2” and “COVID-19” from database inception till 3 June 2021.Results Despite in vitro data supporting the anti-SARS-CoV-2 effects of povidone-iodine, findings from clinical studies revealed differences in treatment response depending on study settings (healthy vs. hospitalized individuals), treatment target (nasal vs. oral vs. pharynx), method of administration (oral rinse vs. gargle vs. throat spray) and choice of samples used to measure study endpoints (nasopharyngeal vs. saliva). One large-scale clinical trial demonstrated reduction in the incidence of SARS-CoV-2 infection among participants who administered povidone-iodine 3 times daily during an active outbreak. Povidone-iodine is also used to disinfect the oro-pharyngeal space prior to dental or otolaryngology procedures. Although existing data suggest minimal impact of povidone-iodine on thyroid function, high-quality safety data are presently lacking.Conclusions Povidone-iodine application to the oropharyngeal space could complement existing non-pharmacological interventions to reduce SARS-CoV-2 infection especially in high exposure settings.Key messagesAccumulating data suggest antiviral effects of povidone-iodine against the SARS-CoV-2 virus.Findings from clinical studies reveal differences in treatment response depending on study settings, treatment target, method of administration and choice of samples used to measure study endpoints. One large-scale clinical trial observed reduction in the incidence of SARS-CoV-2 infection among participants who administered povidone-iodine 3 times daily during an active outbreak.Povidone-iodine application to the oropharyngeal space could complement existing non-pharmacological interventions to reduce SARS-CoV-2 infection especially in high exposure settings.

Circular RNA is a kind of RNA molecule with special covalent closed circular structure. The existing research results showed that circular RNA zinc finger RNA binding protein (circRNA-ZFR) was abnormally expressed in many malignant tumors, and its expression level was closely related to tumor clinical stage, cell metastasis and patient prognosis. circRNA-ZFR could participate in the regulation of tumor occurrence and development through endogenous competitive adsorption of miRNA, regulation of cell cycle and activation of multiple signal pathways. Further study on the expression and mechanisms of circRNA-ZFR in malignant tumors may support early diagnosis, targeted therapy of related tumors and patients' prognosis.

Abstract Severe acute respiratory syndrome-associated coronavirus-2 (SARS-CoV-2) is the causal agent of coronavirus disease-2019 (COVID-19), a systemic illness characterized by variably severe pulmonary symptoms, cardiac conduction abnormalities, diarrhea, and gastrointestinal bleeding, as well as neurologic deficits, renal insufficiency, myalgias, endocrine abnormalities, and other perturbations that reflect widespread microvascular injury and a pro-inflammatory state. The mechanisms underlying the various manifestations of viral infection are incompletely understood but most data suggest that severe COVID-19 results from virus-driven perturbations in the immune system and resultant tissue injury. Aberrant interferon-related responses lead to alterations in cytokine elaboration that deplete resident immune cells while simultaneously recruiting hyperactive macrophages and functionally altered neutrophils, thereby tipping the balance from adaptive immunity to innate immunity. Disproportionate activation of these macrophages and neutrophils further depletes normal activity of B-cells, T-cells, and natural killer (NK) cells. In addition, this pro-inflammatory state stimulates uncontrolled complement activation and development of neutrophil extracellular traps (NETS), both of which promote the coagulation cascade and induce a state of “thrombo-inflammation”. These perturbations have similar manifestations in multiple organ systems, which frequently show pathologic findings related to microvascular injury and thrombosis of large and small vessels. However, the pulmonary findings in patients with severe COVID-19 are generally more pronounced than those of other organs. Not only do they feature inflammatory thromboses and endothelial injury, but much of the parenchymal damage stems from failed maturation of alveolar pneumocytes, interactions between type 2 pneumocytes and non-resident macrophages, and a greater degree of NET formation. The purpose of this review is to discuss the pathogenesis underlying organ damage that can occur in patients with SARS-CoV-2 infection. Understanding these mechanisms of injury is important to development of future therapies for patients with COVID-19, many of which will likely target specific components of the immune system, particularly NET induction, pro-inflammatory cytokines, and subpopulations of immune cells.

Objective To investigate the serological and molecular characteristics of HBsAg+ /HBV DNA non-reactive (NR) infections. Methods Samples tested as HBsAg+ and HBV DNA NR were confirmed by individual NAT repeat testing, viral particle concentration by PEG precipitation combined with in-house nested PCR and real-time quantitative PCR, anti-HBc testing, and HBsAg quantification. HBV sequences were compared with those from donors with chronic and occult infection as controls. Results A total of 792 195 samples were screened between January 2011 and December 2020, of which 53 (1: 14 947) were confirmed HBsAg+ /HBV DNA NR. HBV DNA was detected further in five (9.4%) samples; three S sequences and four Pre Core/Core sequences were obtained. Unique amino acid substitutions (P130T, P135Q/S, R151Q, G153S and S155F) were found in the Core protein that may affect virus packaging and replication. Conclusion Extremely low HBV DNA level was detected in plasmas of HBsAg+ /HBV DNA NR donors. Barely detectable HBV DNA might be associated with unusual mutations in the Pre Core/Core protein affecting viral replication. More sensitive HBV DNA and/or HBsAg assays may be considered to further reduce the potential HBV transfusion-transmission residual risk.

With the increasing application of rituximab (RTB) in hematological diseases and autoimmune diseases (AIDs), we have gradually increased our awareness of the adverse reaction of rituximab-associated neutropenia (RAN), but little is known about its true incidence rate, susceptibility risk factors and exact pathogenesis. At present, research groups have conducted a large number of studies on different populations. The team found that age (> 60), advanced disease, systemic lupus erythematosus (SLE) and combined cyclophosphamide therapy were independent risk factors for RAN. However, its exact mechanism is not completely clear. Several hypotheses have been put forward to solve this question, including the production of anti-neutrophil antibodies after RTB, the generation disorder and neutrophil maturation stagnation caused by abnormal B-cell reconstruction, and the amplification of T-large granular lymphocyte population that may induce neutrophil apoptosis. However, there are still many unsolved problems in all aspects of RAN. This article is an update of the incidence rate, risk factors and mechanisms of RAN.

Abstract Hydrocephalus is a serious condition that affects patients of all ages, resulting from a multitude of causes. While the etiologies of hydrocephalus are numerous, many of the acute and chronic symptoms of the condition are shared. These symptoms include disorientation and pain (headaches), cognitive and developmental changes, vision and sleep disturbances, and gait abnormalities. This collective group of symptoms combined with the effectiveness of CSF diversion as a surgical intervention for many types of the condition suggest that the various etiologies may share common cellular and molecular dysfunctions. The incidence rate of pediatric hydrocephalus is approximately 0.1–0.6% of live births, making it as common as Down syndrome in infants. Diagnosis and treatment of various forms of adult hydrocephalus remain understudied and underreported. Surgical interventions to treat hydrocephalus, though lifesaving, have a high incidence of failure. Previously tested pharmacotherapies for the treatment of hydrocephalus have resulted in net zero or negative outcomes for patients potentially due to the lack of understanding of the cellular and molecular mechanisms that contribute to the development of hydrocephalus. Very few well-validated drug targets have been proposed for therapy; most of these have been within the last 5 years. Within the last 50 years, there have been only incremental improvements in surgical treatments for hydrocephalus, and there has been little progress made towards prevention or cure. This demonstrates the need to develop nonsurgical interventions for the treatment of hydrocephalus regardless of etiology. The development of new treatment paradigms relies heavily on investment in researching the common molecular mechanisms that contribute to all of the forms of hydrocephalus, and requires the concerted support of patient advocacy organizations, government- and private-funded research, biotechnology and pharmaceutical companies, the medical device industry, and the vast network of healthcare professionals.

Objective To establish a stable cyclophosphamide(CTX) induced ovarian insufficiency rat model and to explore the mechanisms. Methods The survival curve of rats after intraperitoneal injection of different dosage of CTX was drawn and the optimal dose was determined. Sex hormone level, estrous cycle and ovarian histological change were further observed. The underlying mechanisms were explored by transcriptome sequencing. Results The mortality rate of medium and high dose in CTX group was high, so low dose CTX was chosen. After CTX exposure, E2 and AMH decreased(both P＜0.05),while FSH increased(P＜0.01). About half of the model rats showed irregular estrous cycles(P＜0.05). The preantral and antral follicles decreased(P＜0.01, P＜0.05), while atresia follicles increased (P＜0.01). Transcriptome sequencing analysis showed that differentially expressed genes (DEGs) between two groups functioned in channel activity and in transmembrane transporter activity. DEGs mainly enriched in neuroactive ligand-receptor interaction pathway, cAMP signal pathway and calcium signaling pathway, axon guidance. According to the protein-protein interaction network of DEGs,we screened out 14 hub genes. Among them, Leptin, Shh,Ntrk2,GRIN2A,CAMK2A,CaSR and Pvalb have been revealed to be closely related to ovarian function. Conclusions A POI rat model induced by CTX was successfully constructed; the neuroactive ligand-receptor interaction pathway, cAMP signal pathway, calcium signaling pathway and axon guidance pathway are enriched pathways. Lep, Shh, Ntrk2, GRIN2A, CAMK2A, CaSR and Pvalb are potentially key genes.

Abstract Lung cancer is the second cancer and the leading cause of tumor-related mortality worldwide. Angiogenesis is a crucial hallmark of cancer development and a promising target in lung cancer. However, the anti-angiogenic drugs currently used in the clinic do not achieve long-term efficacy and are accompanied by severe adverse reactions. Therefore, the development of novel anti-angiogenic therapeutic approaches for lung cancer is urgently needed. Non-coding RNAs (ncRNAs) participate in multiple biological processes in cancers, including tumor angiogenesis. Many studies have demonstrated that ncRNAs play crucial roles in tumor angiogenesis. This review discusses the regulatory functions of different ncRNAs in lung cancer angiogenesis, focusing on the downstream targets and signaling pathways regulated by these ncRNAs. Additionally, given the recent trend towards utilizing ncRNAs as cancer therapeutics, we also discuss the tremendous potential applications of ncRNAs as biomarkers or novel anti-angiogenic tools in lung cancer.

Published reports from the CDC’s Autism and Development Disabilities Monitoring Networks have shown that an average of 1 in every 44 (2.3%) 8-year-old children were estimated to have ASD in 2018. Many of the ASDs exhibiting varying degrees of autism-like phenotypes have chromosomal anomalies in the Chr15q11–q13 region. Numerous potential candidate genes linked with ASD reside in this chromosomal segment. However, several clinical, in vivo, and in vitro studies selected one gene more frequently than others randomly and unbiasedly. This gene codes for UBE3A or Ubiquitin protein ligase E3A [also known as E6AP ubiquitin-protein ligase (E6AP)], an enzyme involved in the cellular degradation of proteins. This gene has been listed as one of the several genes with a high potential of causing ASD in the Autism Database. The gain of function mutations, triplication, or duplication in the UBE3A gene is also associated with ASDs like Angelman Syndrome (AS) and Dup15q Syndrome. The genetic imprinting of UBE3A in the brain and a preference for neuronal maternal-specific expression are the key features of various ASDs. Since the UBE3A gene is involved in two main important diseases associated with autism-like symptoms, there has been widespread research going on in understanding the link between this gene and autism. Additionally, since no universal methodology or mechanism exists for identifying UBE3A-mediated ASD, it continues to be challenging for neurobiologists, neuroscientists, and clinicians to design therapies or diagnostic tools. In this review, we focus on the structure and functional aspects of the UBE3A protein, discuss the primary relevance of the 15q11–q13 region in the cause of ASDs, and highlight the link between UBE3A and ASD. We try to broaden the knowledge of our readers by elaborating on the possible mechanisms underlying UBE3A-mediated ASDs, emphasizing the usage of UBE3A as a prospective biomarker in the preclinical diagnosis of ASDs and discuss the positive outcomes, advanced developments, and the hurdles in the field of therapeutic strategies against UBE3A-mediated ASDs. This review is novel as it lays a very detailed and comprehensive platform for one of the most important genes associated with diseases showing autistic-like symptoms. Additionally, this review also attempts to lay optimistic feedback on the possible steps for the diagnosis, prevention, and therapy of these UBE3A-mediated ASDs in the upcoming years.

A genetically-identical bacterial population is phenotypically heterogeneous, with phenotypic variants arising due to fluctuations in gene expression. Persister formation may be induced by environmental factors/stress such as antibiotic treatment, signalling molecule indole, quorum sensing molecules, nutrient starvation, oxidative stress, heat stress, hyperosmotic stress, and acid stress. Since persisters are clinically relevant, it is important to study the mechanisms responsible for persister formation so that therapies can be designed to curtail these infections.

Aim: systematization of knowledge about the pathobiochemical mechanisms of heart disease in alcoholic cardiomyopathy (ACMP) and the search for promising ways of cardiocytoprotection. Alcohol abuse is an important medical and social problem, risk factor for metabolic disorders, malnutrition, cancers, dementia, neuropathy, and others. Consumption of large amounts of ethanol increases a risk of sudden cardiac death and cardiac arrhythmias. The term “alcoholic cardiomyopathy” describes a heart disease in people with a history of long-term alcohol use. ACMP is characterized by left ventricular dilatation, decreased wall thickness and (at the later stages) decreased left ventricular ejection fraction (less than 40 %). Analysis of literature data about the mechanisms of alcohol-induced cardiotoxicity revealed trigger factors for myocardial damage. Negative effect of ethanol on the heart is realized through induction of oxidative-nitrosative stress, apoptosis, inflammation, fibrogenesis, hypoenergetic state and ion pump dysfunction, development of endothelial dysfunction, impaired ribosomal synthesis. In-depth study of biochemical mechanisms and identification of new molecular targets, integrated into the pathogenesis of ACMP, will optimize the pharmacotherapy for this pathology. Hydrogen sulfide (H2S), is a metabolic factor involved in the regulation of cardiovascular activity. Use of exogenous H2S has potent cardioprotective properties in cardio-vascular diseases. Donors of H2S and H2S-releasing drugs (hybrid molecules – H2S-aspirin, H2S-NO) show a powerful cardioprotective role in various pathological conditions. Therefore, it is advisable to further study the role of H2S system in the pathogenesis of ACMP to develop new approaches to more effective treatment of this disease. Conclusions. Modulation of the H2S level in the organism may be a predictor of the severity of myocardial damage, as well as a promising vector in pharmacotherapy, including alcoholic cardiomyopathy.

Chronic inflammatory demyelinating polyneuropathy (CIDP) is an acquired immune-mediated inflammatory disorder of the peripheral nervous system. This clinically heterogeneous neurological disorder is closely related to Guillain–Barré syndrome and is considered the chronic counterpart of that acute disease. Currently available treatments are mostly empirical; they include corticosteroids, intravenous immunoglobulins, plasma exchange and chronic immunosuppressive agents, either alone or in combination. Recent advances in the understanding of the underlying pathogenic mechanisms in CIDP have brought a number of novel ways of possible intervention for use in CIDP. This review summarizes selected pre-clinical and clinical findings, highlights the importance of using adapted animal models to evaluate the efficacy of novel treatments, and proposes the outlines of future directions to ameliorate the conditions of patients with CIDP.

Introduction and purpose: Chimeric antigen receptor‐T (CAR‐T) cells have achieved inspiring outcomes in the treatment for lymphoid malignancies, especially diffuse large B-cell lymphoma (DLBCL) and acute lymphoblastic leukemia (ALL), providing alternative therapeutic options for patients who failed to respond to conventional treatments. CAR-T are based on the patient's T lymphocytes, which through genetic modification, gain new abilities to detect and fight cancer cells. Although the percentage of complete remissions after standard treatment of B-cell malignancies is quite high, methods that could have an even better result regarding patient survival by reducing the side effects of treatment are still being sought to improve the quality of patients' lives. CAR-T is a culmination of many years of research in the dynamically developing area of immunotherapy as a revolutionary therapy of hematological cancers treatments. State of knowledge: In order to explore the topic, analysis included research available in the PubMed database. The research focused on the possibility of using CAR-T cell therapy in selected hematological cancers. Conclusion: CAR-T is one of the most advanced and personalized methods of immunotherapy. Despite the side effects of this method, there is still scope for improvement. Our overview summarizes all the issues that have been overcome in designing this therapy, as well as highlighting all the challenges that still need to be addressed.

Abstract Background and Aims Cryptozoospermia is an extreme oligozoospermia with an unsatisfactory treatment effect, with an incidence rate of approximately 8.73% in male infertility, whose effective solution has become the call of the times. Western Medicine has achieved certain effects through drugs, surgery, and assisted reproductive therapy, but this is still not ideal. Traditional Chinese medicine (TCM) has made many achievements in other disciplines; however, there is still a lack of evidence‐based medical evidence to improve sperm production. Methods The relevant literatures from the China National Knowledge Internet (CNKI) and PubMed in the past 10 years were collected in this article, of which the mechanisms, advantages, or current controversies of various treatment methods of Western Medicine and TCM were analyzed, to find new treatment methods and research directions. Results With the development of modern science and technology, medical treatments for cryptozoospermia have become increasingly abundant; however, there is still no universally recognized unified and effective guiding plan. Although TCM has not been fully verified by evidence‐based medicine, most TCM combined with Western Medicine can achieve unexpected results. Conclusion The combination of TCM and Western Medicine may become a bane for cryptozoospermia and bring good news to infertile men worldwide.

Abstract Pulmonary fibrosis is the end stage of a broad range of heterogeneous interstitial lung diseases and more than 200 factors contribute to it. In recent years, the relationship between virus infection and pulmonary fibrosis is getting more and more attention, especially after the outbreak of SARS-CoV-2 in 2019, however, the mechanisms underlying the virus-induced pulmonary fibrosis are not fully understood. Here, we review the relationship between pulmonary fibrosis and several viruses such as Human T-cell leukemia virus (HTLV), Human immunodeficiency virus (HIV), Cytomegalovirus (CMV), Epstein–Barr virus (EBV), Murine γ-herpesvirus 68 (MHV-68), Influenza virus, Avian influenza virus, Middle East Respiratory Syndrome (MERS)-CoV, Severe acute respiratory syndrome (SARS)-CoV and SARS-CoV-2 as well as the mechanisms underlying the virus infection induced pulmonary fibrosis. This may shed new light on the potential targets for anti-fibrotic therapy to treat pulmonary fibrosis induced by viruses including SARS-CoV-2.

For a long time, the role of an extensive neurological network in the gut (the little-brain) has been under-recognized because the enteric nervous system (ENS) is thought to have little impact beyond digestion. More recently, there has been a paradigm shift in understanding interactions between the gut and brain, i.e., the gut-brain axis, especially in clinical disorders termed functional gastrointestinal disorders (FGIDs). In a global epidemiology study commissioned by the Rome Foundation, among 70,000 adults, at least one FGID wasdiagnosed in 40.3% of internet surveys and 20.7% of household survey. FGIDs are perhaps the second most common consults in gastroenterology practice in Asia (the first being chronic liver disorders largely due to a high burden of viral hepatitis). These disorders include functional dyspepsia (FD) and irritable bowel syndrome (IBS). During the recent fourth iteration of the Rome diagnostic criteria, FGIDs have been relabeled as disorders of gut-brain interactions (DGBIs)

Stress, a disruption of homeostasis, is an unavoidable part of everyday life. In medical procedures, stress profoundly affects both operators and patients. Although the stress reaction has evolved to aid survival of physical trauma, it may also be harmful, by aggravating the baseline medical condition and/or creating new stress-related medical problems. Stress responses comprise several protective mechanisms that are particularly relevant in the clinical setting (e.g., a procoagulatory state and blood loss counteraction, preservation of blood perfusion pressure, prevention of hypoglycemia, enhanced immune response). Beneficial psychological effects prevent recurrence of traumatic memories, and promote patient compliance and positive lifestyle changes. In contrast, overt acute stress responses may lead to severe pathological conditions such as cytokine storm, post-traumatic stress disorder, takotsubo syndrome, deep venous thrombosis and pulmonary embolism, myocardial infarction, life-threatening arrhythmias and sudden cardiac death. There is also evidence that stress exposure may promote atherosclerosis and reduce long-term benefits from the intervention (increase in major adverse clinical events, in-stent restenosis, etc.). Insights into the role of stress on the operator’s performance have recently led to the introduction of counteractive measures such as simulation training. Conversely, very little is known about the effect of the patient’s periprocedural stress on the outcomes of cardiovascular procedures. Recent data show that the patient periprocedural stress affects the well-being of whole families. This review, focused on topics particularly relevant to cardiovascular interventions, provides a mechanistic insight into beneficial and harmful effects of periprocedural patient stress, including the array of available stress-relieving measures.

Fungal contamination of animal feed can severely affect the health of farm animals, and result in considerable economic losses. Certain filamentous fungi or molds produce toxic secondary metabolites known as mycotoxins, of which aflatoxins (AFTs) are considered the most critical dietary risk factor for both humans and animals. AFTs are ubiquitous in the environment, soil, and food crops, and aflatoxin B1(AFB1) has been identified by the World Health Organization (WHO) as one of the most potent natural group 1A carcinogen. We reviewed the literature on the toxic effects of AFB1 in humans and animals along with its toxicokinetic properties. The damage induced by AFB1 in cells and tissues is mainly achieved through cell cycle arrest and inhibition of cell proliferation, and the induction of apoptosis, oxidative stress, endoplasmic reticulum (ER) stress and autophagy. In addition, numerous coding genes and non-coding RNAs have been identified that regulate AFB1 toxicity. This review is a summary of the current research on the complexity of AFB1 toxicity, and provides insights into the molecular mechanisms as well as the phenotypic characteristics.

Obesity is a complex, multifactorial condition, a major public health problem with an increasing prevalence worldwide. Obesity is characterized by an excess of adipose tissue, a low degree of chronic inflammation and disorders in the synthesis of biologically active hormones and peptides which intervene in regulating appetite and energy balance, immunity, insulin sensitivity, angiogenesis, blood pressure, lipid metabolism and homeostasis of the body. The visceral adipose tissue accumulation is accompanied by metabolic disorders that have as a substrate subclinical inflammation and signaling by intracellular pathways that lead to irreversible cellular structural and functional changes. The long-term impact of overweight and obesity translates into shortening life expectancy and disability, due to association with severe comorbidities, such as cardiovascular diseases, diabetes, oncological conditions. Therefore, understanding the cellular mechanisms involved in obesity may facilitate the highlighting of new possible therapeutic targets.

Hereditary angioedema (HAE) with normal C1-inhibitor level is a rare potentially life-threatening disorder with autosomal dominant inheritance which was first described in 2000. Its clinical presentation is similar to HAE with C1-deficiency. The review is summarized data about its prevalence, mechanisms, genetics and diagnostic criteria. Different subtypes and treatment options (on demand, short term and long-term prophylaxis) are discussed. We describe family clinical cases of 2 female patients with normal C1-inhibitor and plasminogen gene mutation. Their features were late diagnosis (in 10 and 25 years after the onset of symptoms), family history (similar genetic mutation in 3 female members of the same family, including 1-asymtomatic) and combination of face, tongue, larynx and abdominal angioedema in patient and her sibling.

Introduction: The discovery of sodium-glucose co-transporter-2 inhibitors is attributed to phlorizin, which after oral administration caused the excretion of glucose in urine. Later studies showed that this effect was conditioned by SGLT-2 inhibition. However, this substance has not been used in the treatment of diabetes mellitus due to its non-selective action. Beeing also active against SGLT-1 transporters in alimentary tract, it causes osmotic diarrhea, dehydration and eventually malnutrition. Currently in Poland, gliflozins are used only in the treatment of diabetes mellitus, mainly type 2, especially with coexisting obesity and high cardio-vascular risk. However, as many human and animal studies show, the effect of SGLT2 inhibitors can be observed in many systems and organs.Results: The best known non-anti-diabetic action is the reduction of body fat and protection against fat accumulation following a high-calorie diet. These compounds reduce the production of endogenous fatty acids. Moreover, gliflozines lower the levels of cholesterol, triglycerides, uric acid and aminotransferases. They have a protective effect on the liver because they cause remission of nonalcoholic steatohepatitis (NASH), nonalcoholic fatty liver disease (NAFLD). They lower the cardiovascular risk and have an anti-inflammatory effect. Moreover, they inhibit vascular remodeling and improve hemodynamic conditions.Conclusions: According to many research, gliflozines have many collateral effects which can be used in the clinic as a treatment of diseases other than diabetes or coexisting with it. Obesity and cardiovascular diseases are among the most important health problems in the modern world. SGLT-2 inhibitors can prevent the above-mentioned diseases and reduce them.

Introduction: Bisphenol A (BPA) is a substance commonly used in industry for the production of everyday plastic products. It is also found in thermal paper. Global pollution of the environment by BPA results in constant exposure to its harmful effects. This substance penetrates the skin, respiratory tract and food into the body. BPA, due to its structure similar to estrogens, disturbs e.g. functioning of the endocrine system and increases the risk of certain cancers. Material and methods: The PubMed and Google Scholar databases were used to review the literature. Description of knowledge: Exposure of breast cancer cells to BPA results in increased aromatase synthesis and increased proliferation of ER + cells. Moreover, BPA stimulates the growth of neoplastic breast cancer cells not only at high doses but also at low doses (

Obesity represents a heavy burden for modern healthcare. The main challenge facing obesity research progress is the unknown underlying pathways, which limits our understanding of the pathogenesis and developing therapies. Obesity induces specific biochemical environments that impact the different cells and tissues. In this piece of writing, we suggest mimicking obesity-induced in vivo biochemical environments including pH, lipids, hormones, cytokines, and glucose within an in vitro environment. The concept is to reproduce such biochemical environments and use them to treat the tissue cultures, explant cultures, and cell cultures of different biological organs. This will allow us to clarify how the obesity-induced biochemistry impacts such biological entities. It would also be important to try different environments, in terms of the compositions and concentrations of the constitutive elements, in order to establish links between the effects (impaired regeneration, cellular inflammation, etc.) and the factors constituting the environment (hormones, cytokines, etc.) as well as to reveal dose-dependent effects. We believe that such approaches will allow us to elucidate obesity mechanisms, optimize animal models, and develop therapies as well as novel tissue engineering applications.

Abstract Background Despite the increased utilization of clinical pathways (CPWs) as a strategy to improve patient and system outcomes in hospitals, there remain ongoing challenges with their conceptualization, implementation, and evaluation. Theories that explain how CPWs work in hospitals are lacking, making it difficult to identify important factors for sustaining changes arising from CPWs implemented in hospitals. The objective of this realist review is to develop a program theory for CPWs in hospitals. Methods This is a protocol for a realist review. The review will use a six-step iterative process to develop a program theory for CPWs in hospitals: (1) development of a preliminary program theory; (2) search strategy and literature search; (3) study selection and appraisal; (4) data extraction; (5) data analysis and synthesis; and (6) stakeholder engagement. In addition to searching the gray literature and contacting authors, we will search electronic databases such as MEDLINE, NHSEED, CINAHL EBSCO, HMIC, and PsycINFO. Studies will be included based on their ability to provide data that test some aspect of the program theory. Two independent reviewers will select, screen, and extract data related to the program theory from all relevant sources. A realist logic of analysis will be used to identify all context-mechanism-outcome heuristics that explains how CPWs implemented in hospitals translates to better health system outcomes. Discussion Overall, the review aims to develop a program theory for CPWs in hospitals and to explore how, why, to what extent, and in what contexts does the implementation of CPWs in hospitals contribute to better health system outcomes. As a result, the review will provide a theoretical framework of how CPWs work in hospitals. Systematic review registration PROSPERO CRD42018103220

Abstract MicroRNAs (miRNAs) are small non-coding RNAs with a length of about 19–25 nt, which can regulate various target genes and are thus involved in the regulation of a variety of biological and pathological processes, including the formation and development of cancer. Drug resistance in cancer chemotherapy is one of the main obstacles to curing this malignant disease. Statistical data indicate that over 90% of the mortality of patients with cancer is related to drug resistance. Drug resistance of cancer chemotherapy can be caused by many mechanisms, such as decreased antitumor drug uptake, modified drug targets, altered cell cycle checkpoints, or increased DNA damage repair, among others. In recent years, many studies have shown that miRNAs are involved in the drug resistance of tumor cells by targeting drug-resistance-related genes or influencing genes related to cell proliferation, cell cycle, and apoptosis. A single miRNA often targets a number of genes, and its regulatory effect is tissue-specific. In this review, we emphasize the miRNAs that are involved in the regulation of drug resistance among different cancers and probe the mechanisms of the deregulated expression of miRNAs. The molecular targets of miRNAs and their underlying signaling pathways are also explored comprehensively. A holistic understanding of the functions of miRNAs in drug resistance will help us develop better strategies to regulate them efficiently and will finally pave the way toward better translation of miRNAs into clinics, developing them into a promising approach in cancer therapy.

In type 2 diabetes, ecological and lifecourse factors may interact with the host microbiota to influence expression of his/her genomes causing perturbation of interconnecting biological pathways with diverse clinical course. Metformin is a plant-based or plant-derived medicinal product used for the treatment of type 2 diabetes for over 60 years and is an essential drug listed by the World Health Organization. By reducing mitochondrial oxidative phosphorylation and adenosine triphosphate (ATP) production, metformin increased AMP (adenosine monophosphate)-activated protein kinase (AMPK) activity and altered cellular redox state with reduced glucagon activity, endogenous glucose production, lipogenesis, and protein synthesis. Metformin modulated immune response by directly reducing neutrophil to lymphocyte ratio and improving the phagocytic function of immune cells. By increasing the relative abundance of mucin-producing and short-chain-fatty-acid-producing gut microbes, metformin further improved the host inflammatory and metabolic milieu. Experimentally, metformin promoted apoptosis and reduced proliferation of cancer cells by reducing their oxygen consumption and modulating the microenvironment. Both clinical and mechanistic studies support the pluripotent effects of metformin on reducing cardiovascular–renal events, infection, cancer, cognitive dysfunction, and all-cause death in type 2 diabetes, making this low-cost medication a fundamental therapy for individualization of other glucose-lowering drugs in type 2 diabetes. Further research into the effects of metformin on cognitive function, infection and cancer, especially in people without diabetes, will provide new insights into the therapeutic value of metformin in our pursuit of prevention and treatment of ageing-related as well as acute and chronic diseases beyond diabetes.

Adaptive immune response modulation has taken a central position in cancer therapy in recent decades. Treatment with immune checkpoint inhibitors (ICIs) is now indicated in many cancer types with exceptional results. The two major inhibitory pathways involved are cytotoxic T-lymphocyte-associated protein 4 (CTLA4) and programmed cell death protein 1 (PD-1). Unfortunately, immune activation is not tumor-specific, and as a result, most patients will experience some form of adverse reaction. Most immune-related adverse events (IRAEs) involve the skin and gastrointestinal (GI) tract; however, any organ can be involved. Cardiotoxicity ranges from arrhythmias to life-threatening myocarditis with very high mortality rates. To date, most treatments of ICI cardiotoxicity include immune suppression, which is also not cardiac-specific and may result in hampering of tumor clearance. Understanding the mechanisms behind immune activation in the heart is crucial for the development of specific treatments. Histological data and other models have shown mainly CD4 and CD8 infiltration during ICI-induced cardiotoxicity. Inhibition of CTLA4 seems to result in the proliferation of more diverse T0cell populations, some of which with autoantigen recognition. Inhibition of PD-1 interaction with PD ligand 1/2 (PD-L1/PD-L2) results in release from inhibition of exhausted self-recognizing T cells. However, CTLA4, PD-1, and their ligands are expressed on a wide range of cells, indicating a much more intricate mechanism. This is further complicated by the identification of multiple co-stimulatory and co-inhibitory signals, as well as the association of myocarditis with antibody-driven myasthenia gravis and myositis IRAEs. In this review, we focus on the recent advances in unraveling the complexity of the mechanisms driving ICI cardiotoxicity and discuss novel therapeutic strategies for directly targeting specific underlying mechanisms to reduce IRAEs and improve outcomes.

Potato late blight, one of the most devastating diseases in potato, is caused by the oomycete Phytophthora infestans. Over 20 resistance genes have been cloned including R1, R3a, and R3b. The distinctions between defense response mechanisms mediated by different resistance genes are still unclear. Here we performed transcriptome profiling in three transgenic lines, R1, R3a, and R3b, and wild-type Desiree under inoculation with two P. infestans isolates, 89148 (race 0) and CN152 (super race), using RNA-seq. Compared with wild type, specific differentially expressed genes (DEGs) were identified in the three transgenic lines. The highest number of DEGs occurred in transgenic R3b, with 779 DEGs in response to isolate 89148 and 864 DEGs in response to infection by CN152, followed by transgenic R1 lines with 408 DEGs for isolate 89148 and 267 DEGs for CN152. Based on gene ontology, the most common GO terms (15 for 89148 and 20 for CN152) were enriched in transgenic R3a and R3b lines. This indicates that the defense pathways mediated by R3a and R3b are more similar than those mediated by R1. Further separate GO analysis of up- or down-regulated DEGs showed that the down-regulated DEGs mainly functioned in mediating the resistance of potato to P. infestans 89148 by response to stress biological process and to CN152 by oxidation reduction biological process. KEGG pathways of DNA replication, plant-pathogen interaction and pentose and glucuronate interconversions are unique for transgenic R1, R3a, and R3b lines in incompatible interactions. Quantitative real-time PCR experimental validation confirmed the induced expression of DEGs in the late blight resistance signaling pathway. Our results will lay a solid foundation for further understanding the mechanisms of plant-pathogen interactions, and provide a theoretical reference for durable resistance in potato.

Systemic sclerosis is a chronic multisystem autoimmune disease that is associated with polyclonal B cell hyperreactivity. The CDR3 of BCRs is the major site of antigen recognition. Therefore, we analyzed the BCR repertoire of patients with SSc. The BCR repertoires in 12 subjects including eight SSc patients and four healthy controls were characterized by high-throughput sequencing, and bioinformatics analysis were studied. The average CDR3 length in the SSc group was significantly shorter. The SSc patient displayed more diverse BCR. Moreover, SSc patients with mild skin sclerosis, anti-Scl70, interstitial lung disease or female sex were more diversified. B cells from the SSc patients showed a differential V and J gene usage. SSc patients had distinct BCR repertoires.These findings reflected the differences of BCR repertoires between SSc patients and controls. The higher-usage genes for the BCR sequence might be potential biomarkers of B cell-targeted therapies or diagnosis for SSc.

The article discusses modern representation about the mechanisms of development, the results of recently completed and the background for new studies of methods for treating chronic heart failure with preserved ejection fraction according to the literature and authors' own works.