Possible Target For Therapy Research Articles

CD36 deficiency protects lipopolysaccharide-induced sepsis via inhibiting CerS6-mediated endoplasmic reticulum stress

The type 2 scavenger receptor CD36 functions not only as a long chain fatty acid transporter, but also as a pro-inflammatory mediator. Ceramide is the simple N-acylated form of sphingosine and exerts distinct biological activity depending on its acyl chain length. Six ceramide synthases (CerS) in mammals determine the chain length of ceramide species, and CerS6 mainly produces C16-ceramide. Endotoxin-induced septic shock shows high mortality, but the pathophysiologic role of sphingolipids involved in this process has been hardly investigated. This paper aims to highlight the different role of CerS isoforms in endotoxin-induced inflammatory responses and the regulatory role of CD36 in CerS6 protein degradation with an emphasis as the potential therapeutic candidates in humans. Lipopolysaccharide (LPS), the endotoxin of the Gram-negative bacterial cell wall, was treated to induce endotoxin-induced inflammation both in vitro and in vivo. CerS6-derived C16-ceramide propagated LPS-induced inflammatory responses activating various intracellular signaling pathways, such as mitogen-activated protein kinase and nuclear factor-κB, resulting in the formation of inflammasome complex and pro-inflammatory cytokines. Mechanistically, CerS6-derived C16-ceramide augmented inflammatory responses via endoplasmic reticulum stress, and CerS6 protein stability was regulated by CD36. Finally, CerS6 protein expression and LPS-induced lethality were strikingly reduced in CD36 knockout mice. Collectively, our findings show that CerS6-derived C16-ceramide plays a pivotal role in endotoxin-induced inflammation and suggest CerS6 and its regulator CD36 as possible targets for therapy under life-threatening inflammation such as septic shock.

Hypercholesterolemia and inflammation-Cooperative cardiovascular risk factors.

Maintaining low concentrations of plasma low-density lipoprotein cholesterol (LDLc) over time decreases the number of LDL particles trapped within the artery wall, slows the progression of atherosclerosis and delays the age at which mature atherosclerotic plaques develop. This substantially reduces the lifetime risk of atherosclerotic cardiovascular disease (ASCVD) events.In this context, plaque development and vulnerability result not only from lipid accumulation but also from inflammation. Changes in the composition of immune cells, including macrophages, dendritic cells, T cells, B cells, mast cells and neutrophils, along with altered cytokine and chemokine release, disrupt the equilibrium between inflammation and anti-inflammatory mechanisms at plaque sites. Considering that it is not a competition between LDLc and inflammation, but instead that they are partners in crime, the present narrative review aims to give an overview of the main inflammatory molecular pathways linked to raised LDLc concentrations and to describe the impact of lipid-lowering approaches on the inflammatory and lipid burden. Although remarkable changes in LDLc are driven by the most recent lipid lowering combinations, the relative reduction in plasma C-reactive protein appears to be independent of the magnitude of LDLc lowering. Identifying clinical biomarkers of inflammation (e.g. interleukin-6) and possible targets for therapy holds promise for monitoring and reducing the ASCVD burden in suitable patients.

Comprehensive Investigation of Natural Ligands as Inhibitors of β Secretase to Identify Alzheimer's Disease Therapeutics.

Alzheimer's disease (AD) is an alarmingly prevalent worldwide neurological disorder that affects millions of people and has severe effects on cognitive functions. The amyloid hypothesis, which links AD to Aβ (amyloid beta) plaque aggregation, is a well-acknowledged theory. The β-secretase (BACE1) is the main cause of Aβ production, which makes it a possible target for therapy. FDA-approved therapies for AD do exist, but none of them explicitly target BACE1, and their effectiveness is constrained and accompanied by adverse effects. We determined the essential chemical components of medicinal herbs by conducting a thorough literature research for BACE1. Computational methods like molecular docking, ADMET (Absorption, distribution, metabolism, excretion, toxicity) screening, molecular dynamic simulations, and MMPBSA analysis were performed in order to identify the most promising ligands for β-secretase. The results suggested that withasomniferol, tinosporide, and curcumin had better binding affinity with BACE1, suggesting their potential as therapeutic candidates against Alzheimer's disease. Herbal therapeutics have immense applications in the treatment of chronic diseases like Alzheimer's disease, and there is an urgent need to assess their efficacy as therapeutics.

Somatic Variants Acquired Later in Life Associated with Thoracic Aortic Aneurysms: JAK2 V617F.

The JAK2 V617F somatic variant is a well-known driver of myeloproliferative neoplasms (MPN) associated with an increased risk for athero-thrombotic cardiovascular disease. Recent studies have demonstrated its role in the development of thoracic aortic aneurysm (TAA). However, limited clinical information and level of JAK2 V617F burden have been provided for a comprehensive evaluation of potential confounders. A retrospective genotype-first study was conducted to identify carriers of the JAK2 V617F variant from an internal exome sequencing database in Yale DNA Diagnostics Lab. Additionally, the overall incidence of somatic variants in the JAK2 gene across various tissue types in the healthy population was carried out based on reanalysis of SomaMutDB and data from the UK Biobank (UKBB) cohort to compare our dataset to the population prevalence of the variant. In our database of 12,439 exomes, 594 (4.8%) were found to have a thoracic aortic aneurysm (TAA), and 12 (0.049%) were found to have a JAK2 V617F variant. Among the 12 JAK2 V617F variant carriers, five had a TAA (42%), among whom four had an ascending TAA and one had a descending TAA, with a variant allele fraction ranging from 11.2% to 20%. Among these five patients, 60% were female, and average age at diagnosis was 70 (49-79). The mean ascending aneurysm size was 5.05 cm (range 4.6-5.5 cm), and four patients had undergone surgical aortic replacement or repair. UKBB data revealed a positive correlation between the JAK2 V617F somatic variant and aortic valve disease (effect size 0.0086, p = 0.85) and TAA (effect size = 0.004, p = 0.92), although not statistically significant. An unexpectedly high prevalence of TAA in our dataset (5/594, 0.84%) is greater than the prevalence reported before for the general population, supporting its association with TAA. JAK2 V617F may contribute a meaningful proportion of otherwise unexplained aneurysm patients. Additionally, it may imply a potential JAK2-specific disease mechanism in the developmental of TAA, which suggests a possible target of therapy that warrants further investigation.

Evaluation of secretome biomarkers in glioblastoma cancer stem cells: A bioinformatics analysis.

Glioblastoma (GBM) is a malignant brain tumor that frequently occurs alongside other central nervous system (CNS) conditions. The secretome of GBM cells contains a diverse array of proteins released into the extracellular space, influencing the tumor microenvironment. These proteins can serve as potential biomarkers for GBM due to their involvement in key biological processes, exploring the secretome biomarkers in GBM research represents a cutting-edge strategy with significant potential for advancing diagnostic precision, treatment monitoring, and ultimately improving outcomes for patients with this challenging brain cancer. This study was aimed to investigate the roles of secretome biomarkers and their pathwayes in GBM through bioinformatics analysis. Using data from the Gene Expression Omnibus and the Cancer Genome Atlas datasets-where both healthy and cancerous samples were analyzed-we used a quantitative analytical framework to identify differentially expressed genes (DEGs) and cell signaling pathways that might be related to GBM. Then, we performed gene ontology studies and hub protein identifications to estimate the roles of these DEGs after finding disease-gene connection networks and signaling pathways. Using the GEPIA Proportional Hazard Model and the Kaplan-Meier estimator, we widened our analysis to identify the important genes that may play a role in both progression and the survival of patients with GBM. In total, 890 DEGs, including 475 and 415 upregulated and downregulated were identified, respectively. Our results revealed that SQLE, DHCR7, delta-1 phospholipase C (PLCD1), and MINPP1 genes are highly expressed, and the Enolase 2 (ENO2) and hexokinase-1 (HK1) genes are low expressions. Hence, our findings suggest novel mechanisms that affect the occurrence of GBM development, growth, and/or establishment and may also serve as secretory biomarkers for GBM prognosis and possible targets for therapy. So, continued research in this field may uncover new avenues for therapeutic interventions and contribute to the ongoing efforts to combat GBM effectively.

Genetically Predicted Higher Levels of Caffeic Acid Are Protective Against Ulcerative Colitis: A Comprehensive Metabolome Analysis

Abstract Background It is crucial to pinpoint the metabolites that cause Crohn’s disease (CD) and ulcerative colitis (UC) to comprehend their pathogenesis and identify possible targets for therapy. To achieve this goal, we performed the first metabolome-wide Mendelian randomization (MR) study of Japanese patients with CD and UC. Methods As exposure datasets, genetic instruments with blood-circulating metabolites were obtained from the Tohoku Medical Megabank Organization, which includes 204 metabolites from the genome-wide association study data of 7843 Japanese individuals. As outcome datasets, we enrolled Japanese patients with CD (n = 1803), Japanese patients with UC (n = 1992), and healthy controls (n = 2022). The main analysis utilized the inverse variance–weighted method, while stability of the findings was evaluated through sensitivity analyses. Results After single nucleotide polymorphism (SNP) filtering, 169 SNPs for 45 metabolites were available for MR. Genetically predicted elevated circulating trans-glutaconic acid and tryptophan were associated with a lower CD risk (odds ratio [OR], 0.68; P = 5.95 × 10−3; and OR, 0.64; P = 1.90 × 10−2, respectively). Genetically predicted elevated caffeic acid was associated with a lower UC risk (OR, 0.67; P = 4.2 × 10−4), which remained significant after multiple testing correction. We identified a causal link between UC and 3-hydroxybutyrate (OR, 2.21; P = 1.41 × 10−2), trans-glutaconic acid (OR, 0.72; P = 1.77 × 10−2), and 2-hydroxyvaleric acid (OR, 1.31; P = 4.23 × 10−2). There was no evidence of pleiotropy or reverse causal effects for these candidate metabolites. Conclusions In our metabolome-wide MR study, we discovered a notable protective effect of caffeic acid against UC.

A New Cell Type in Pulmonary Veins

Pulmonary veins (PVs) carry oxygenated blood from lungs back to the heart and may play an important role in preventing blood backflow from the left atrium. Previous studies show that large PVs exhibit spontaneously pulsatile contractions in cardiomyocyte-like manner. However, the contractions of small PVs have not been investigated. We hypothesized that Ca2+ signaling mechanisms in the myocytes mediate small PV contractions. Small, 4th-order PVs from C57BL6 mice were obtained and imaged. Pressurized PVs showed ryanodine receptor-dependent Ca2+ signals and spontaneous contractions. Light sheet fluorescence microscopy and immunostaining showed the expression of troponin C, a cardiomyocyte marker, in the myocyte layer of small PVs, which was not observed in the pulmonary arteries, vena cava, or mesenteric veins. Based on these results, we termed these cells cardiomyocyte-like (CML) cells. In the study of mice with Myh11 Cre-driven tdTomato expression, Myh11 expression was observed in CML cells in small PVs, which was not seen in the smooth muscle cells (SMC) of small PAs. Endothelial protrusions crossing the connective tissue layer into the CML layer were also observed in PVs. Previous studies showed PV remodeling in pulmonary hypertension (PH), and impaired Ca2+ signaling in PAs contribute to higher pulmonary arterial pressure in PH. We further hypothesized that ryanodine receptor (RyR) Ca2+ signals in CML cells are impaired in PH. Results show that RyR Ca2+ signaling was reduced in CML cells of PH mice (injected with Su5416, subjected to chronic hypoxic conditions). Overall, our findings identify a new cell type in small PVs. Moreover, our data show that RyR Ca2+ signals in CML cells underlie spontaneous contractions in small PV, and are impaired in PH. We propose that RyR signaling mechanisms in CML cells may be possible targets for therapy in pulmonary vascular disorders. This work was supported by funding from the National Institute of Health to Swapnil Sonkusare (R01:HL146914, R01:HL157407). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Type II Interleukin-4 Receptor Activation in Basal Breast Cancer Cells Promotes Tumor Progression via Metabolic and Epigenetic Modulation.

Interleukin-4 (IL4) is a Th2 cytokine that can signal through two different receptors, one of which-the type II receptor-is overexpressed by various cancer cells. Previously, we have shown that type II IL4 receptor signaling increases proliferation and metastasis in mouse models of breast cancer, as well as increasing glucose and glutamine metabolism. Here, we expand on those findings to determine mechanistically how IL4 signaling links glucose metabolism and histone acetylation to drive proliferation in the context of triple-negative breast cancer (TNBC). We used a combination of cellular, biochemical, and genomics approaches to interrogate TNBC cell lines, which represent a cancer type where high expression of the type II IL4 receptor is linked to reduced survival. Our results indicate that type II IL4 receptor activation leads to increased glucose uptake, Akt and ACLY activation, and histone acetylation in TNBC cell lines. Inhibition of glucose uptake through the deletion of Glut1 ablates IL4-induced proliferation. Additionally, pharmacological inhibition of histone acetyltransferase P300 attenuates IL4-mediated gene expression and proliferation in vitro. Our work elucidates a role for type II IL4 receptor signaling in promoting TNBC progression, and highlights type II IL4 signaling, as well as histone acetylation, as possible targets for therapy.

The Role of Inflammation in Atherosclerosis: A Comprehensive Review of Mechanisms and Therapeutic Targets

In this review, we examine the evolving importance of inflammation in atherosclerosis, the root cause of heart attacks, and strokes. We analyze the complex processes by which inflammation drives all phases of atherosclerosis and closely assess possible targets for therapy within the inflammatory pathway. For researchers and health-care professionals seeking insight into the crucial role of inflammation in atherosclerosis and its potential for novel therapeutic approaches, this review offers a valuable resource.

Comparative structural studies on Bovine papillomavirus E6 oncoproteins: Novel insights into viral infection and cell transformation from homology modeling and molecular dynamics simulations.

Bovine papillomavirus (BPV) infects cattle cells worldwide, leading to hyperproliferative lesions and the potential development of cancer, driven by E5, E6, and E7 oncoproteins along with other cofactors. E6 oncoprotein binds experimentally to various proteins, primarily paxillin and MAML1, as well as hMCM7 and CBP/p300. However, the molecular and structural mechanisms underlying BPV-induced malignant transformation remain unclear. Therefore, we have modeled the E6 oncoprotein structure from non-oncogenic BPV-5 and compared them with oncogenic BPV-1 to assess the relationship between structural features and oncogenic potential. Our analysis elucidated crucial structural aspects of E6, highlighting both conserved elements across genotypes and genotype-specific variations potentially implicated in the oncogenic process, particularly concerning primary target interactions. Additionally, we predicted the location of the hMCM7 binding site on the N-terminal of BPV-5 E6. This study enhances our understanding of the structural characteristics of BPV E6 oncoproteins and their interactions with host proteins, clarifying structural differences and similarities between high and low-risk BPVs. This is important to understand better the mechanisms involved in cell transformation in BPV infection, which could be used as a possible target for therapy.

Immunoexpression of Claudins -3, -4 and -7 in prostate adenocarcinomas.

Claudins are a family of essential tight junction proteins, abnormally expressed in human carcinomas. The studies that indicated the involvement of claudins in tumor biology and progression suggest the possibility of their utility as markers for diagnosis or prognosis, but also as possible targets for therapy. We investigated 50 prostate adenocarcinomas (PAs) for which we followed the expression of Claudins -3, -4 and -7 in relation to International Society of Urological Pathology (ISUP) grades. We observed the positivity for Claudin-3, Claudin-4, and Claudin-7 in 76%, 74% and 46% of cases. Analysis of the immunoexpression pattern revealed the cytoplasmic and nuclear translocation for Claudins -3 and -4, and only cytoplasmic for Claudin-7. For all claudins investigated, we noted a final staining score with significantly higher values or at the limit of statistical significance for PA belonging to ISUP groups 1-4. The internalization of Claudins -3, -4 and -7 expression, regardless of the degree of PA, indicates their involvement in prostate carcinogenesis. In addition, the similar immunoexpression patterns of the three investigated claudins and their positive linear correlation suggest a coordinated regulation and indicate the possibility of a targeted treatment strategy.

Down-regulated MiRNA 29-b as a diagonistic marker in colorectal cancer and its correlation with ETV4 and Cyclin D1 immunohistochemical expression.

Colorectal cancer (CRC) is the most common malignant tumor of the gastrointestinal tract with unfavorable prognosis. Therefore, novel biomarkers that may be used for new diagnostic strategies and drug-targeting therapy should be developed. To investigate the expression of miR-29b in CRC and its association with ETV4 and cyclin D1 expression. Moreover, the current work aims to investigate the association between them and the clinicopathological features of CRC. The expression of miR-29b and ETV4 (by qRT-PCR) and ETV4 and cyclin D1 (immunohistochemistry) was investigated in 65 cases of colon cancer and surrounding healthy tissues. MiR-29b down-regulated and ETV4 and Cyclin D1 up-regulated significantly in colon cancer tissues compared to normal nearby colonic tissues. In addition, significant associations between ETV4 and cyclin D1 expressions and progressive stage and lymph node (LN) metastasis (P< 0.001 for each) were found. Furthermore, there was a negative correlation between miR-29b gene expression and ETV4 gene expression (r=-0.298, P<0.016). Down-regulation of miR-29b and over-expression of ETV4 and cyclin D1 may be utilized as early diagnostic marker for development of colon cancer. ETV4 and cyclin D1 correlate with poor prognostic indicators and considered as a possible target for therapy in colon cancer.

Abstract P4-08-22: Expression of Dual Specific Phosphatase-7 (DUSP7/PYST2) and it’s Connection with Salt Inducible Kinases (SIKs) and Downstream MKKs in breast cancer

Abstract Expression of Dual Specific Phosphatase-7 (DUSP7/PYST2) and it’s Connection with Salt Inducible Kinases (SIKs) and Downstream MKKs in breast cancer Wenxiao Ji1, Emily Ling Xin1,2, Lin Ye1, Eleri Davies3, Wen G. Jiang1, Tracey A. Martin1 1CCMRC, Cardiff University School of Medicine, Cardiff, Wales, UK 2Breast Centre, Peking University First Hospital, Xicheng District, Beijing, China 3Wales Breast Centre, University Llandough Hospital, Cardiff CF64 2XX, UK Introduction. DUSP7 is a member of the large Dual specific phosphatase family, able to regulate the phosphorylation of both tyrosine and serine/threonine protein kinases. The role of DUSP7 in cancer is not clear, however, it has been identified as a possible target for therapy in cancers including breast cancer. It has also been reported as having value in prognosis of certain cancers, such as haematological malignancies, breast cancer and certain types of gynaecological cancer. The signalling network for DUSP7 is not fully established but is known to connect to ERKs and MAP2Ks. DUSP7 also appears to be linked with salt inducible kinases (SIKs), a small family of kinases linked with progression and response to therapies in breast cancer. Thus, DUSP7 and salt inducible kinases may interact with each other and with the downstream kinases including MAP2Ks and STK11 to influence the clinical course of breast cancer. The present study explored if the pattern of DUSP7 together with salt inducible kinases and the downstream MKKs in breast cancer. Methods. The expression of DUSP7 was quantified in a cohort of breast cancer tissues (both normal mammary tissues and breast cancer tissues). The expression of the potential downstream kinases including MKK1, MKK2, MKK3, MKK4 and STK11 was also quantified. The expression profile of these molecule, together with the salt inducible kinases reported to be aberrant in our previous studies, were analysed against clinical and outcome information. Results. Breast cancer tissues expressed high levels of DUSP7 compared with normal mammary tissues, although not statistically significant. When we explored the relationship between DUSP7 and other potential related molecules in the database of the cohort, we found a highly significant correlation between DUSP7 and SIK1 (r=0.385, p&amp;lt; 0.001), SIK2 (r=0.590, p&amp;lt; 0.001), but not SIK3 (r=0.158, p&amp;gt;0.05). Together with SIK1 and SIK2 (known to link to drug sensitivity), DUSP7, MKK1 (MAP2K1) and MKK3 (MAP2K3) appear to form a gene signature that is of significant value in predicting the overall survival of the patients (ROC 0.723, p=0.001). This allowed us to significantly distinguish between those with good OS and poor OS (p&amp;lt; 0.001, Hazard Ration (HR) =1.443 (95%CI 1.154-1.804)). Multivariate analysis has shown that this signature is independent in predicting overall survival (p=0.013, HR=1.432). The signature is more significant in predicting OS in ER(-) tumours (p&amp;lt; 0.001) than ER(+) tumours (p=0.61). The same is seen when predicting OS with triple negative breast cancers (TNBC) (p&amp;lt; 0.001) than non-TNBC tumours (p=0.044). The gene signature also predicted disease free outcome (p=0.007, HR=1.266 (95% CI 1.065-1.504)). Conclusion. The dual specific phosphatase DUSP7 together with potentially correlated salt inducible kinases (SIK-1 and SIK-2) and downstream MKKs (MKK-1 and MKK3) have important clinical value in breast cancer. This provides support that DUSP7 may be a valuable therapeutic target in breast cancer. Citation Format: WENXIAO JI, Ling Xin, Eleri Davies, Wen G. Jiang, Lin Ye. Expression of Dual Specific Phosphatase-7 (DUSP7/PYST2) and it’s Connection with Salt Inducible Kinases (SIKs) and Downstream MKKs in breast cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P4-08-22.

Bicarbonate transporter SLC4A7 promotes EMT and metastasis of HNSCC by activating the PI3K/AKT/mTOR signaling pathway.

Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide. Currently, therapeutic modalities such as surgery, chemotherapy, radiotherapy, and immunotherapy are being used to treat HNSCC. However, the treatment outcomes of most patients are dismal because they are already in middle or advanced stage by the time of diagnosis and poorly responsive to treatments. It is therefore of great interest to clarify mechanisms that contribute to the metastasis of cells to identify possible targets for therapy. In this study, we identified the Na+ -coupled bicarbonate transporter, SLC4A7, play essential roles in the metastasis of HNSCC. Our results showed that the relative expression of SLC4A7 messengerRNA was highly expressed in HNSCCs samples from TCGA, and compared with precancerous cells of human oral mucosa (DOK), SLC4A7 was highly expressed in HNSCC cell lines. In vitro and in vivo experiments showed that dysregulation of SLC4A7 had minor influence on the proliferation of HNSCC but impacted HNSCC's migration and invasion. Meanwhile, SLC4A7 could promote epithelial-mesenchymal transition (EMT) in HNSCC. RNA-seq, KEGG pathway enrichment analysis and Western blot further revealed that downregulation of SLC4A7 in HNSCC cells inhibited the PI3K/AKT pathway. These findings were further validated via rescue experiments using a small molecule inhibitor of PI3K/mTOR (GDC-0980). Our findings suggest that SLC4A7 promotes EMT and metastasis of HNSCC through the PI3K/AKT/mTOR signaling pathway, which may be a valuable predictive biomarker and potential therapeutic target in HNSCC.

Ion Channels of the Sarcolemma and Intracellular Organelles in Duchenne Muscular Dystrophy: A Role in the Dysregulation of Ion Homeostasis and a Possible Target for Therapy.

Duchenne muscular dystrophy (DMD) is caused by the absence of the dystrophin protein and a properly functioning dystrophin-associated protein complex (DAPC) in muscle cells. DAPC components act as molecular scaffolds coordinating the assembly of various signaling molecules including ion channels. DMD shows a significant change in the functioning of the ion channels of the sarcolemma and intracellular organelles and, above all, the sarcoplasmic reticulum and mitochondria regulating ion homeostasis, which is necessary for the correct excitation and relaxation of muscles. This review is devoted to the analysis of current data on changes in the structure, functioning, and regulation of the activity of ion channels in striated muscles in DMD and their contribution to the disruption of muscle function and the development of pathology. We note the prospects of therapy based on targeting the channels of the sarcolemma and organelles for the correction and alleviation of pathology, and the problems that arise in the interpretation of data obtained on model dystrophin-deficient objects.

Expression dynamics of ISGs and chemokines in maternal whole blood as an indicator of healthy embryonic implantation in buffalo

Successful pregnancy establishment has a major influence on reproductive efficiencies of dairy buffaloes. This success depends on coordinated communications between conceptus and maternally derived cells, and any disturbance in this communication network during this process leads to early embryonic losses. Since, early embryonic losses is one of the prime cause of pregnancy failure in dairy buffaloes, present investigation was aimed to understand the expression dynamics and correlation pattern of Interferon tau stimulated genes and chemokines during peri-implantation period in dairy buffaloes through transcriptional profiling followed by Principal Component Analysis. Our study revealed upregulation of all the candidate genes in maternal whole blood across the parity, emphasizing the involvement of immune responses as signatures for healthy pregnancy. Understanding these embryo-maternal communication signals offers potential to prevent incidences of early embryonic losses and can provide insights on possible targets for therapy too.

Intradiscal injection of human recombinant BMP-4 does not reverse intervertebral disc degeneration induced by nuclectomy in sheep.

BackgroundIntervertebral disc (IVD) degeneration is suggested as a major cause of chronic low back pain (LBP). Intradiscal delivery of growth factors has been proposed as a promising strategy for IVD repair and regeneration. Previously, BMP-4 was shown to be more potent in promoting extracellular matrix (ECM) production than other BMPs and TGF-β in human nucleus pulposus (NP) cells, suggesting its applicability for disc regeneration.MethodsThe effects of BMP-4 on ECM deposition and cell proliferation were assessed in sheep NP and annulus fibrosus (AF) cells in a pellet culture model. Further, a nuclectomy induced sheep lumbar IVD degeneration model was used to evaluate the safety and effects of intradiscal BMP-4 injection on IVD regeneration. Outcomes were assessed by magnetic resonance imaging, micro-computed tomography, histological and biochemical measurements.ResultsIn vitro, BMP-4 significantly increased the production of proteoglycan and deposition of collagen type II and proliferation of NP and AF cells. Collagen type I deposition was not affected in NP cells, while in AF cells it was high at low BMP-4 concentrations, and decreased with increasing concentration of BMP-4. Intradiscal injection of BMP-4 induced extradiscal new bone formation and Schmorl's node-like changes in vivo. No regeneration in the NP nor AF was observed.ConclusionOur study demonstrated that although BMP-4 showed promising regenerative effects in vitro, similar effects were not observed in a large IVD degeneration animal model.The Translational Potential of This ArticleThe contradictory results of using BMP-4 on IVD regeneration between in vitro and in vivo demonstrate that direct BMP-4 injection for disc degeneration-associated human chronic low back pain should not be undertaken. In addition, our results may also shed light on the mechanisms behind pathological endplate changes in human patients as a possible target for therapy.

Plasma adiponectin as an indicator of the effectiveness of CHD therapy in patients with metabolic syndrome

Background and Aims : Adiponectin has a potential effect on atherogenesis. In this regard, adiponectin can be considered as a possible target of therapy. The objective is to check whether the initial concentration of adiponectin or its change during therapy is related to the effectiveness of treatment of coronary heart disease (CHD) in patients with metabolic syndrome (MS).

Ceramide and Sphingosine-1-Phosphate in Neurodegenerative Disorders and Their Potential Involvement in Therapy.

Neurodegenerative disorders (ND) are progressive diseases of the nervous system, often without resolutive therapy. They are characterized by a progressive impairment and loss of specific brain regions and neuronal populations. Cellular and animal model studies have identified several molecular mechanisms that play an important role in the pathogenesis of ND. Among them are alterations of lipids, in particular sphingolipids, that play a crucial role in neurodegeneration. Overall, during ND, ceramide-dependent pro-apoptotic signalling is promoted, whereas levels of the neuroprotective spingosine-1-phosphate are reduced. Moreover, ND are characterized by alterations of the metabolism of complex sphingolipids. The finding that altered sphingolipid metabolism has a role in ND suggests that its modulation might provide a useful strategy to identify targets for possible therapies. In this review, based on the current literature, we will discuss how bioactive sphingolipids (spingosine-1-phosphate and ceramide) are involved in some ND (Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis) and their possible involvement in therapies.

Interleukin-35 in autoimmune dermatoses: Current concepts.

Interleukin-35 (IL-35) is a lately observed cytokine and is part of the IL-12 cytokine family. IL-35 includes two subunits, p35 and Epstein-Barr virus-induced gene 3, and activates subsequent signaling pathways by binding to receptors to mediate signal transduction, thereby modulating the immunoregulatory functions of T cells, B cells, macrophages, and other immune cell types. Although there is currently limited research on the roles of IL-35 in human autoimmunity, many studies have demonstrated that IL-35 may mediate immunosuppression. Therefore, it plays an essential role in some autoimmune dermatoses, including systemic lupus erythematosus, psoriasis, systemic sclerosis, and dermatomyositis. We will introduce the structure and biological characteristics of IL-35 and summarize its effects on the occurrence and development of autoimmune dermatoses in this article. It is suggested that IL-35 is a possible target for therapy in the aforementioned diseases.