Search

Abstract Background Chronic inflammation is an increasing global healthcare challenge with limited effective treatment options. Developing medications for chronic diseases requires high financial investment and a long duration. Given these challenges, alternative strategies are needed. Here, we focus on one such strategy that holds great promise: drug repurposing, which involves identifying new therapeutic uses for existing drugs. Main body Here, we discuss the importance of two key transcription factors: nuclear factor kappa B (NF-κB) and activator protein 1 (AP-1), in orchestrating complex pathophysiological signaling networks involved in chronic inflammatory diseases. Dysregulation of the NF-κB and AP1 signaling pathways have been associated with various diseases, such as cancer, inflammatory disease, and autoimmune disorders. This review emphasized that repurposed small-molecule inhibitors of these pathways have proven successful as therapeutic interventions. These compounds exhibit high degrees of specificity and efficacy in modulating NF-κB or AP-1 signaling, making them appealing candidates for treating chronic inflammatory conditions. This review discusses the therapeutic potential and action mechanisms of several repurposed small-molecule inhibitors for combating diseases caused by abnormal activation or inhibition of NF-κB and AP-1. Conclusion This concise review highlights the potential of repurposing small-molecule inhibitors targeting the NF-κB and AP-1 pathways as effective therapies for various chronic inflammatory diseases. While further experimental validation is needed, drug repurposing offers a promising strategy to bypass the existing lengthy and expensive new drug development processes, providing a faster and more economical route to novel treatments.

Background Although they are fast‐growing populations in the United States, little is known about survival outcomes of Hispanic and Asian patients after in‐hospital cardiac arrest. Methods and Results In Get With The Guidelines–Resuscitation, we identified Asian, Hispanic, and White adults with in‐hospital cardiac arrest during 2005 to 2023. Using multivariable models, we compared rates of survival to discharge separately for Asian and Hispanic patients versus White patients, as well as rates of sustained return of spontaneous circulation for ≥20 minutes and favorable neurologic survival as secondary outcomes. Of 189 557 in‐hospital cardiac arrests, 167 640 (88.4%), 16 800 (8.9%), and 5117 (2.7%) patients were White, Hispanic, and Asian, respectively. Compared with the survival rate to discharge for White patients (22.0%), rates were lower for Hispanic (19.4%; adjusted odds ratio [OR], 0.93 [95% CI, 0.89–0.97]; P

Background: How frequently out-of-hospital cardiac arrest (OHCA) occurs within a reasonable walking distance to the nearest public automated external defibrillator (AED) has not been well studied. Methods: As Kansas City, Missouri has a comprehensive city-wide public AED registry, we identified adults with an OHCA in Kansas City during 2019–2022 in the Cardiac Arrest Registry to Enhance Survival. Using AED location data from the registry, we computed walking times between OHCAs and the nearest registered AED using the Haversine formula, a mapping algorithm to calculate walking distance in miles from one location to another. Results were stratified by OHCA location (home vs. public) and by whether the patient received bystander cardiopulmonary resuscitation (CPR). Results: Of 1,522 OHCAs, 1,291 (84.8%) occurred at home and 231 (15.2%) in public. Among at-home OHCAs, 634 (49.1%) received bystander CPR and no patients had an AED applied even as 297 (23.0%) were within a 4-minute walk to the closest public AED. Among OHCAs in public, 108 (46.8%) were within a 4-minute walk to the closest public AED. For public OHCAs within a 4-minute walk, bystanders applied an AED in 13 (12.0%) of these cases and in 24.5% (13/53) of those who received bystander CPR. Conclusion: In one U.S. city with a publicly available AED registry, there were no instances in which a bystander accessed a public AED for an OHCA at home. For OHCAs in public, nearly half occurred within a 4-minute walk to the closest AED but bystander use of an AED was low.

Abstract Soft sensors that can discriminate shear and normal force could help provide machines the fine control desirable for safe and effective physical interactions with people. A capacitive sensor is made for this purpose, composed of patterned elastomer and containing both fixed and sliding pillars that allow the sensor to deform and buckle, much like skin itself. The sensor differentiates between simultaneously applied normal force and shear using summation and differences of signals from four deformable capacitors. Cross talk from shear to normal force is less than 2.5%, and between shear axes is less than 10%. Normal and shear stress sensitivity is 0.49 kPa and 0.31 kPa respectively, with a minimum displacement resolution of 40 μm. In addition, finger proximity is detectable at a range of up to 15 mm. The operation is demonstrated on a simple gripper holding a cup. The combination of features and the straightforward fabrication method make this sensor a candidate for implementation as a sensing skin for humanoid robotics applications.

Objective: Endovascular repair of chronic dissecting aortoiliac aneurysms is challenging given the rigid septum, compressed true lumen (TL), and target vessels frequently originating in the false lumen. We have used transcatheter electrosurgical aortic septotomy (TEAS) before stent graft implantation under intravascular ultrasound (IVUS) and fusion guidance. The purpose of this study is to assess the outcomes of TEAS during complex endovascular repair of dissecting aneurysms. Methods: From 2021 to 2023, 17 patients underwent TEAS. The primary end point was technical success, with secondary end points of proximal and distal seals, target vessel instability, aortic and iliac TL and cross-sectional area (CSA) expansion, and aortic-related death. During the procedure, the aortic septum is crossed through a pre-existing entry or via electrocautery-activated 0.018-in. Astato XS20 wire (Asahi-Intecc) under IVUS and fusion guidance. The penetrated wire is then snared in the false lumen and pulled through the ipsilateral femoral access. A 1-cm length of the middle of the Astato wire coating is kinked in a three-sided polygonal configuration, denuded the inner surface of the wire using a no. 15 blade, and positioned at the apex of the septum. Both ends of the Astato wire are insulated with 0.018-in. microcatheters, and the back end of the wire is denuded and connected to cautery. Gentle traction is applied to the wire, and short bursts of electrocautery cutting are applied at 60 to 80 W. Results: The technical success of the septotomy was 100%. No incidence of visceral or lower extremity malperfusion, vascular injury, or distal embolization occurred. Of the 17 patients, 4 underwent thoracic endovascular aneurysm repair, 2 underwent endovascular aortic repair, and 11 underwent fenestrated/branched endovascular aneurysm repair after septotomy. All target vessels were successfully stented. A distal landing zone seal with exclusion of the false lumen was achieved in 16 of the 17 patients (94.1%). One patient required embolization of the false lumen of the celiac artery after septotomy. The TL mean diameter and CSA of the descending thoracic aorta after septotomy was expanded by 7.01 ± 1.9 mm (relative mean diameter expansion, 42.3%; P < .0001) and 2.71 ± 0.4 cm2 (relative mean CSA expansion, 57.3%, P

Macrophages play a central role in initiating, maintaining, and terminating inflammation. For that, macrophages respond to various external stimuli in changing environments through signaling pathways that are tightly regulated and interconnected. This process involves, among others, autoregulatory loops that activate and deactivate macrophages through various cytokines, stimulants, and other chemical mediators. Adaptor proteins play an indispensable role in facilitating various inflammatory signals. These proteins are dynamic and flexible modulators of immune cell signaling and act as molecular bridges between cell surface receptors and intracellular effector molecules. They are involved in regulating physiological inflammation and also contribute significantly to the development of chronic inflammatory processes. This is at least partly due to their involvement in the activation and deactivation of macrophages, leading to changes in the macrophages’ activation/phenotype. This review provides a comprehensive overview of the 20 adaptor molecules and proteins that act as negative regulators of inflammation in macrophages and effectively suppress inflammatory signaling pathways. We emphasize the functional role of adaptors in signal transduction in macrophages and their influence on the phenotypic transition of macrophages from pro-inflammatory M1-like states to anti-inflammatory M2-like phenotypes. This endeavor mainly aims at highlighting and orchestrating the intricate dynamics of adaptor molecules by elucidating the associated key roles along with respective domains and opening avenues for therapeutic and investigative purposes in clinical practice.

Abstract The role of TIRAP (toll/interleukin-1 receptor (TIR) domain-containing adapter protein) in macrophage inflammatory signalling has been significantly evolved since its discovery in 2001 due to its dynamic nature and subcellular localization to regulate multiple signaling through several protein–protein interactions (PPIs). Structural analysis of these interactions can reveal a better understanding of their conformational dynamics and the nature of their binding. Tyrosine phosphorylation in the TIR domain of TIRAP is very critical for its function. In toll-like receptor (TLR) 4/2 signalling, Bruton's tyrosine kinase (BTK) and Protein kinase C delta (PKCδ) are known to phosphorylate the Y86, Y106, Y159, and Y187 of TIRAP which is crucial for the downstream function of MAPKs (mitogen-activated protein kinases) activation. The objective of this study is to understand the interaction of TIRAP with p38 MAPK through molecular docking and identify the importance of TIRAP tyrosine phosphorylation in p38 MAPK interaction. In this structural study, we performed an in-silico molecular docking using HADDOCK 2.4, pyDockWEB, ClusPro 2.0, and ZDOCK 3.0.2 tools to unravel the interaction between TIRAP and p38 MAPK. Further, manual in-silico phosphorylations of TIRAP tyrosines; Y86, Y106, Y159, and Y187 was created in the Discovery Studio tool to study the conformational changes in protein docking and their binding affinities with p38 MAPK in comparison to non-phosphorylated state. Our molecular docking and 500 ns of molecular dynamic (MD) simulation study demonstrates that the Y86 phosphorylation (pY86) in TIRAP is crucial in promoting the higher binding affinity (∆Gbind) with p38 MAPK. The conformational changes due to the tyrosine phosphorylation mainly at the Y86 site pull the TIRAP closer to the active site in the kinase domain of p38 MAPK and plays a significant role at the interface site which is reversed in its dephosphorylated state. The heatmap of interactions between the TIRAP and p38 MAPK after the MD simulation shows that the TIRAP pY86 structure makes the highest number of stable hydrogen bonds with p38 MAPK residues. Our findings may further be validated in an in-vitro system and would be crucial for targeting the TIRAP and p38 MAPK interaction for therapeutic purposes against the chronic inflammatory response and associated diseases.

We report our initial experience using Fiber Optic RealShape (FORS), an innovative real-time three-dimensional visualization technology that uses light instead of radiation, to achieve upper extremity (UE) access during fenestrated/branched endovascular aortic aneurysm repair (FBEVAR). An 89-year-old male patient with a type III thoracoabdominal aortic aneurysm, unfit for open aortic repair, underwent FBEVAR. Dual fluoroscopy, intravascular ultrasound, and three-dimensional fusion overlay were used, in addition to FORS. All target artery catheterizations were successfully accomplished using FORS, from UE access, without radiation. Our experience demonstrates that FBEVAR with FORS using UE access can be used for target artery catheterization without radiation.

We report the case of a 23-year-old female pedestrian who had been struck by a car and had presented with axillary artery transection in the setting of scapulothoracic dissociation. The initial endovascular repair was compromised by her shoulder instability and had required the addition of bridging stent placement. Caution is advised with endovascular repair in this clinical scenario because of possible stent separation.

Atherosclerosis is a chronic inflammatory disease characterized by plaque build-up in the arteries, leading to the obstruction of blood flow. Macrophages are the primary immune cells found in the atherosclerotic lesions and are directly involved in atherosclerosis progression. Macrophages are derived from extravasating blood monocytes. The monocytic CD40 receptor is important for monocyte recruitment on the endothelium expressing the CD40 ligand (CD40L). Thus, targeting monocyte/macrophage interaction with the endothelium by inhibiting CD40-CD40L interaction may be a promising strategy for attenuating atherosclerosis. Monoclonal antibodies have been used against this target but shows various complications. We used an array of computer-aided drug discovery tools and molecular docking approaches to design a therapeutic inhibitory peptide that could efficiently bind to the critical residues (82Y, 84D, and 86N) on the CD40 receptor essential for the receptor's binding to CD40L. The initial screen identified a parent peptide with a high binding affinity to CD40, but the peptide exhibited a positive hepatotoxicity score. We then designed several novel peptidomimetic derivatives with higher binding affinities to CD40, good physicochemical properties, and negative hepatotoxicity as compared to the parent peptide. Furthermore, we conducted molecular dynamics simulations for both the apo and complexed forms of the receptor with ligand, and screened peptides to evaluate their stability. The designed peptidomimetic derivatives are promising therapeutics targeting the CD40-CD40L interaction and may potentially be used to attenuate atherosclerosis.

Abstract Human coronavirus NL63 (HCoV-NL63) mainly affects young children and immunocompromised patients, causing morbidity and mortality in a subset of patients. Since no specific treatment is available, this study aims to explore the anti-SARS-CoV-2 agents including favipiravir and remdesivir for treating HCoV-NL63 infection. We first successfully modelled the 3D structure of HCoV-NL63 RNA-dependent RNA polymerase (RdRp) based on the experimentally solved SARS-CoV-2 RdRp structure. Molecular docking indicated that favipiravir has similar binding affinities to SARS-CoV-2 and HCoV-NL63 RdRp with LibDock scores of 75 and 74, respectively. The LibDock scores of remdesivir to SARS-CoV-2 and HCoV-NL63 were 135 and 151, suggesting that remdesivir may have a higher affinity to HCoV-NL63 compared to SARS-CoV-2 RdRp. In cell culture models infected with HCoV-NL63, both favipiravir and remdesivir significantly inhibited viral replication and production of infectious viruses. Overall, remdesivir compared to favipiravir is more potent in inhibiting HCoV-NL63 in cell culture. Importantly, there is no evidence of resistance development upon long-term exposure to remdesivir. Furthermore, combining favipiravir or remdesivir with the clinically used antiviral cytokine interferon-alpha resulted in synergistic effects. These findings provided a proof-of-concept that anti-SARS-CoV-2 drugs, in particular remdesivir, have the potential to be repurposed for treating HCoV-NL63 infection.

Abstract Cotton leaf curl disease (CLCuD), caused by begomoviruses in combination with betasatellite molecule, has adversely affected cotton industry of Indian subcontinent. To devise a CLCuD-control strategy, RNAi-mediated approach was followed in this study. Gossypium hirsutum cv. HS6 plants were transformed with intron-hairpin RNAi (ihpRNAi-C4) construct carrying silencing suppressor C4 gene of Cotton leaf curl Multan virus (CLCuMuV). Efficacy of the construct in imparting CLCuD resistance was evaluated in transgenic (T0, T1) cotton lines. Accumulation of CLCuMuV/betasatellite and attenuation of CLCuD symptoms in the transgenic lines were monitored at different times interval after virus inoculation. Northern hybridization revealed the expression of C4-gene derived siRNA. Expression of the ihpRNAi transcript was recorded higher in transgenic lines expressing siRNA which supposedly targeted the C4 gene. A significant delay in detection of virus as well as betasatellite was observed in the transgenic lines. At 30 days post inoculation (dpi), none of the lines tested positive. At 45 dpi, however, it could be detected in few lines having much lower titre as compared to non-transformed control plants. Notably, till 60 dpi, no significant progression of the virus/betasatellite DNA was observed and the plants did not exhibit any characteristic CLCuD symptoms. A tolerance phenomenon leading to escape of CLCuD symptoms in the transformed cotton was described.

The nitric oxide synthases (NOS; EC 1.14.13.39) use L-arginine as a substrate to produce nitric oxide (NO) as a by-product in the tissue microenvironment. NOS1 represents the predominant NO-producing enzyme highly enriched in the brain and known to mediate multiple functions, ranging from learning and memory development to maintaining synaptic plasticity and neuronal development, Alzheimer’s disease (AD), psychiatric disorders and behavioral deficits. However, accumulating evidence indicate both canonical and non-canonical roles of NOS1-derived NO in several other tissues and chronic diseases. A better understanding of NOS1-derived NO signaling, and identification and characterization of NO-metabolites in non-neuronal tissues could become useful in diagnosis and prognosis of diseases associated with NOS1 expression. Continued investigation on the roles of NOS1, therefore, will synthesize new knowledge and aid in the discovery of small molecules which could be used to titrate the activities of NOS1-derived NO signaling and NO-metabolites. Here, we address the significance of NOS1 and its byproduct NO in modifying pathophysiological events, which could be beneficial in understanding both the disease mechanisms and therapeutics.

With the rapid growth of the COVID-19 (coronavirus disease 2019) pandemic across the globe, therapeutic attention must be directed to fight the novel severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2). However, developing new antiviral drugs and vaccines is time-consuming, so one of the best solutions to tackle this virus at present is to repurpose ready-to-use drugs. This paper proposes the repurposing of the Food and Drug Administration (FDA)-approved, purchasable, and naturally occurring drugs for preventive and therapeutic use. We propose to design a dual-inhibitor for the SARS-CoV-2 cysteine proteases—3 Chemotrypsin-like protease or main protease (3CLpro or Mpro) and Papain-like protease (PLpro) responsible for processing the translated polyprotein chain from the viral RNA yielding functional viral proteins. For virtual screening, an unbiased blind docking was performed from which the top nine dual-targeting inhibitors for 3CLpro and PLpro were selected. The nine repurposed drugs, block the catalytic dyad (His41 and Cys145) of 3CLpro as well as the catalytic triad (Cys111, His272, and Asp286) of PLpro. Repurposing known drugs will not only pave the way for rapid in-vitro and in-vivo studies to battle the SARS-CoV-2 but will also expedite the quest for a potent anti-coronaviral drug.

Abstract Background Breast tumor initiating cells (BTIC) are stem-like cells that initiate and sustain tumor growth, and drive disease recurrence. Identifying therapies targeting BTIC has been hindered due primarily to their scarcity in tumors. We previously reported that BTIC frequency ranges between 15% and 50% in multiple mammary tumors of 3 different transgenic mouse models of breast cancer and that this frequency is maintained in tumor cell populations cultured in serum-free, chemically defined media as non-adherent tumorspheres. The latter enabled high-throughput screening of small molecules for their capacity to affect BTIC survival. Antagonists of several serotonin receptors (5-HTRs) were among the hit compounds. The most potent compound we identified, SB-699551, selectively binds to 5-HT5A, a Gαi/o protein coupled receptor (GPCR). Methods We evaluated the activity of structurally unrelated selective 5-HT5A antagonists using multiple orthogonal assays of BTIC frequency. Thereafter we used a phosphoproteomic approach to uncover the mechanism of action of SB-699551. To validate the molecular target of the antagonists, we used the CRISPR-Cas9 gene editing technology to conditionally knockout HTR5A in a breast tumor cell line. Results We found that selective antagonists of 5-HT5A reduced the frequency of tumorsphere initiating cells residing in breast tumor cell lines and those of patient-derived xenografts (PDXs) that we established. The most potent compound among those tested, SB-699551, reduced the frequency of BTIC in ex vivo assays and acted in concert with chemotherapy to shrink human breast tumor xenografts in vivo. Our phosphoproteomic experiments established that exposure of breast tumor cells to SB-699551 elicited signaling changes in the canonical Gαi/o-coupled pathway and the phosphoinositide 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) axis. Moreover, conditional mutation of the HTR5A gene resulted in the loss of tumorsphere initiating cells and BTIC thus mimicking the effect of SB-699551. Conclusions Our data provide genetic, pharmacological and phosphoproteomic evidence consistent with the on-target activity of SB-699551. The use of such agents in combination with cytotoxic chemotherapy provides a novel therapeutic approach to treat breast cancer.

Abstract Background and objective Coronavirus disease (COVID-19) is an ongoing pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Due to the incessant spread of the disease with substantial morbidity and mortality rates, there is an urgent demand for effective therapeutics and vaccines to control and diminish this pandemic. A critical step in the crosstalk between the virus and the host cell is the binding of SARS-CoV-2 spike protein to the angiotensin-converting enzyme 2 (ACE2) receptor present on the surface of the host cells. Hence, inhibition of this interaction could be a promising strategy to combat the SARS-CoV-2 infection. Methods Docking and Molecular Dynamics (MD) simulation studies revealed that designed peptide maintains their secondary structure and provide a highly specific and stable binding (blocking) to SARS-CoV-2. Results We have designed a novel peptide that could inhibit SARS-CoV-2 spike protein interaction with ACE2, thereby blocking the cellular entry of the virus. Conclusion Our findings suggest that computationally developed inhibitory peptide may be developed as an anti-SARS-CoV-2 agent for the treatment of SARS-CoV-2 infection. We further plan to pursue the peptide in cell-based assays and eventually for clinical trials.

The outbreak of the coronavirus disease 2019 caused by the severe acute respiratory syndrome coronavirus 2 triggered a global pandemic where control is needed through therapeutic and preventive interventions. This study aims to identify natural compounds that could affect the fusion between the viral membrane (receptor-binding domain of the severe acute respiratory syndrome coronavirus 2 spike protein) and the human cell receptor angiotensin-converting enzyme 2. Accordingly, we performed the enzyme-linked immunosorbent assay-based screening of 10 phytochemicals that already showed numerous positive effects on human health in several epidemiological studies and clinical trials. Among these phytochemicals, epigallocatechin gallate, a polyphenol and a major component of green tea, could effectively inhibit the interaction between the receptor-binding domain of the severe acute respiratory syndrome coronavirus 2 spike protein and the human cell receptor angiotensin-converting enzyme 2. Alternately, in silico molecular docking studies of epigallocatechin gallate and angiotensin-converting enzyme 2 indicated a binding score of −7.8 kcal/mol and identified a hydrogen bond between R393 and angiotensin-converting enzyme 2, which is considered as a key interacting residue involved in binding with the severe acute respiratory syndrome coronavirus 2 spike protein receptor-binding domain, suggesting the possible blocking of interaction between receptor-binding domain and angiotensin-converting enzyme 2. Furthermore, epigallocatechin gallate could attenuate severe acute respiratory syndrome coronavirus 2 infection and replication in Caco-2 cells. These results shed insight into identification and validation of severe acute respiratory syndrome coronavirus 2 entry inhibitors.

Abstract Background Breast tumor growth and recurrence are driven by an infrequent population of breast tumor-initiating cells (BTIC). We and others have reported that the frequency of BTIC is orders of magnitude higher when breast tumor cells are propagated in vitro as clonal spheres, termed tumorspheres, by comparison to adherent cells. We exploited the latter to screen > 35,000 small molecules to identify agents capable of targeting BTIC. We unexpectedly discovered that selective antagonists of serotonin signaling were among the hit compounds. To better understand the relationship between serotonin and BTIC we expanded our analysis to include monoamine oxidase-A (MAO-A), an enzyme that metabolizes serotonin. Methods We used the Nanostring technology and Western blotting to determine whether MAO-A is expressed in human breast tumor cell lines cultured as tumorspheres by comparison to those grown as adherent cells. We then determined whether MAO-A activity is required for tumorsphere formation, a surrogate in vitro assay for BTIC, by assessing whether selective MAO-A inhibitors affect the frequency of tumorsphere-forming cells. To learn whether MAO-A expression in breast tumor cells is associated with other reported properties of BTIC such as anticancer drug resistance or breast tumor recurrence, we performed differential gene expression analyses using publicly available transcriptomic datasets. Results Tumorspheres derived from human breast tumor cell lines representative of every breast cancer clinical subtype displayed increased expression of MAO-A transcripts and protein by comparison to adherent cells. Surprisingly, inhibition of MAO-A activity with selective inhibitors reduced the frequency of tumorsphere-forming cells. We also found that increased MAO-A expression is a common feature of human breast tumor cell lines that have acquired anticancer drug resistance and is associated with poor recurrence-free survival (RFS) in patients that experienced high-grade, ER-negative (ER−) breast tumors. Conclusions Our data suggests that MAO-A activity is required for tumorsphere formation and that its expression in breast tumor cells is associated with BTIC-related properties. The discovery that a selective MAO-A inhibitor targets tumorsphere-forming cells with potencies in the nanomolar range provides the first evidence of this agent’s anticancer property. These data warrant further investigation of the link between MAO-A and BTIC.

The Toll-interleukin-1 Receptor (TIR) domain-containing adaptor protein (TIRAP) represents a key intracellular signalling molecule regulating diverse immune responses. Its capacity to function as an adaptor molecule has been widely investigated in relation to Toll-like Receptor (TLR)-mediated innate immune signalling. Since the discovery of TIRAP in 2001, initial studies were mainly focused on its role as an adaptor protein that couples Myeloid differentiation factor 88 (MyD88) with TLRs, to activate MyD88-dependent TLRs signalling. Subsequent studies delineated TIRAP’s role as a transducer of signalling events through its interaction with non-TLR signalling mediators. Indeed, the ability of TIRAP to interact with an array of intracellular signalling mediators suggests its central role in various immune responses. Therefore, continued studies that elucidate the molecular basis of various TIRAP-protein interactions and how they affect the signalling magnitude, should provide key information on the inflammatory disease mechanisms. This review summarizes the TIRAP recruitment to activated receptors and discusses the mechanism of interactions in relation to the signalling that precede acute and chronic inflammatory diseases. Furthermore, we highlighted the significance of TIRAP-TIR domain containing binding sites for several intracellular inflammatory signalling molecules. Collectively, we discuss the importance of the TIR domain in TIRAP as a key interface involved in protein interactions which could hence serve as a therapeutic target to dampen the extent of acute and chronic inflammatory conditions.

Cardiovascular diseases (CVDs) are one of the main reasons of death and morbidity in the world. Both women and men have high rates of cardiovascular morbidity and mortality, although gender-related differences in mortality and morbidity rates are observed in different age groups of the population. In the large cohort of cardiovascular disease, ischemic heart disease (IHD), heart failure (HF), systemic hypertension, and valvular heart disease are particularly common in the population. CVDs caused by atherosclerosis are in the first place in terms of frequency, that is why society is particularly interested in this problem. The development and course of atherosclerotic processes associated with lipid and other metabolic changes are characterized by a long latent period, the clinical manifestation is often an acute vascular catastrophe, which can lead to human disability and death. Differences associated with sex are observed in the clinical course and manifestations, which raises the suspicion that gender influences processes related to atherosclerosis. Atherosclerotic cardiovascular disease (ACD) includes two main most dangerous clinical manifestations: IHD and cerebrovascular disease (mainly ischemic stroke). Other less common clinical manifestations of atherosclerosis include aortic atherosclerosis and peripheral vascular disease. Gender-related differences were also identified concerning these diseases. The present review discusses the effects of gender and age on atherosclerotic processes, disease development, and clinical manifestations. The metabolic basis for the development of atherosclerosis appears to be related to sex hormones. Thus this issue is interesting and useful for doctors of different specialties.

This review summarizes the main achievements in basic and clinical research of atherosclerosis. Focusing on desialylation as the first and the most important reaction of proatherogenic pathological cascade, we speak of how desialylation increases the atherogenic properties of low density lipoproteins and decreases the anti-atherogenic properties of high density lipoproteins. The separate sections of this paper are devoted to immunogenicity of lipoproteins, the enzymes contributing to their desialylation and animal models of atherosclerosis. In addition, we evaluate the available experimental and diagnostic protocols that can be used to develop new therapeutic approaches for atherosclerosis.

Breast tumors were the first tumors of epithelial origin shown to follow the cancer stem cell model. The model proposes that cancer stem cells are uniquely endowed with tumorigenic capacity and that their aberrant differentiation yields non-tumorigenic progeny, which constitute the bulk of the tumor cell population. Breast cancer stem cells resist therapies and seed metastases; thus, they account for breast cancer recurrence. Hence, targeting these cells is essential to achieve durable breast cancer remissions. We identified compounds including selective antagonists of multiple serotonergic system pathway components required for serotonin biosynthesis, transport, activity via multiple 5-HT receptors (5-HTRs), and catabolism that reduce the viability of breast cancer stem cells of both mouse and human origin using multiple orthologous assays. The molecular targets of the selective antagonists are expressed in breast tumors and breast cancer cell lines, which also produce serotonin, implying that it plays a required functional role in these cells. The selective antagonists act synergistically with chemotherapy to shrink mouse mammary tumors and human breast tumor xenografts primarily by inducing programmed tumor cell death. We hypothesize those serotonergic proteins of diverse activity function by common signaling pathways to maintain cancer stem cell viability. Here, we summarize our recent findings and the relevant literature regarding the role of serotonin in breast cancer.

Resveratrol (3, 4′, 5-trihydroxy-trans-stilbene) is a natural phytoalexin found in grapes and has long been thought to be the answer to the “French Paradox.” There is no shortage of preclinical and clinical studies investigating the broad therapeutic activity of resveratrol. However, in spite of many comprehensive reviews published on the bioactivity of resveratrol, there has yet to be a report focused on the variety and complexity of its structural binding properties, and its multi-targeted role. An improved understanding of disease mechanisms at the systems level has enabled targeted polypharmacology to mature into a rational drug discovery approach. Unlike traditional hit-to-lead campaigns that typically optimize activity and selectivity for a single target, polypharmacological drugs aim to selectively target multiple proteins, while avoiding critical off target interactions. This strategy bears promise of improved efficacy and reduced clinical attrition. This review seeks to investigate whether the bioactivity of resveratrol is due to a polypharmacological effect or promiscuity of the phenolic small molecule by examining the modes of binding with its diverse collection of protein targets. We focused on annotated targets, identified via the ChEMBL database, and matched these targets to a representative structure deposited in the Protein Data Bank (PDB), as crystal structures are most informative in understanding modes of binding at the atomic level. We discuss the structural aspects of resveratrol itself that permits binding to multiple proteins in various signaling pathways. Furthermore, we suggest that resveratrol’s bioactivity is a result of scaffold promiscuity rather than polypharmacology, and the variety of binding modes across targets display little similarity in the pattern of target interaction.

This study was conducted to examine the nature of the perception of organizational politics and its relation­ship with job satisfaction and bio-social variables. Using a questionnaire, data was collected on 142 super­visory personnel- The results indicate that the perception. of organizational politics consists of seven factor dusters. These are, impression management, clique behaviour, selection system, performance expectation, reward system, supervisory communication and ca-worker behaviour. The results -reconfirm the general finding of a negative relationship between job satisfaction and perception of organizational politics. Of the seven factors, impression management and supervisory communication contribute significantly to job satisfaction. While none of the bio-social variables showed any significant relationship with perception of organizational politics, on the whole, race, years of formal education and total years of experience showed significant differences/ relationships with the factors of performance expectation, co-worker behaviour and supervisory communication. These results are explained with reference to the Malaysian, context.