Tissue Cells Research Articles

Experimental type 2 diabetes increases the number of insulin-positive cells in rat spleen

Type 2 diabetes (T2D) is a chronic metabolic disease, being one of the leading causes of death and disability worldwide. Immune system disorders play an important role in the T2D pathogenesis, and immune system is exposed to increased stress resulting both of changes in immunometabolic regulation and disruption of tissue homeostasis caused by oxidative stress and chronic inflammation. Opportunities for adaptation of immune organs in T2D are of interest, especially, potential ectopic expression of insulin. Under hyperglycemic conditions, insulin-containing cells were detected in various organs, including the spleen. The aim of the present work was to estimate the number of insulin-positive cells (IPCs) in the spleen of rats with experimental T2D. The disorder was induced in mature male Wistar rats by intraperitoneal administration of 110 mg/kg nicotinamide followed by 65 mg/kg streptozotocin. 30 days later, blood samples and spleens were obtained. The level of glycemia, insulin contents, activity of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) in blood were assessed as well as markers of oxidative stress in the spleen. Biochemical studies revealed an increase in ALT activity in blood, along with increase in malondialdehyde (MDA) levels and decreased levels of reduced glutathione (GSH) in the spleen tissue of rats with experimental T2D. Meanwhile the activity of superoxide dismutase (SOD) and catalase in the spleen did not change. An increase in MDA level associated with unchanged activity of antioxidant enzymes and decreased GSH content suggests the development of oxidative stress in the tissue. Microscopy of spleen tissues was examined by immunohistochemistry using antibodies to proinsulin and insulin, showing an increased number of insulin-positive cells (IPCs) in the spleen tissue of rats with experimental T2D compared with diabetes-free animals. Optical density of the IPC cytoplasm was found to be increased in diabetic rats, thus suggesting increased functional activity of IPCs. Increase of numbers and functional activities of IPCs in the spleen in experimental model of T2D may indicate an adaptive role of extra-pancreatic insulin expression under the conditions of oxidative stress and cytolysis, including those in immunopoietic organs.

TFAP2E is implicated in central nervous system, orofacial and maxillofacial anomalies

BackgroundPrevious studies in mouse, Xenopus and zebrafish embryos show strong tfap2e expression in progenitor cells of neuronal and neural crest tissues suggesting its involvement in neural crest specification. However, the...

Proinflammatory cytokines, chemokine CXCL17 and heat shock proteins in osteoarthritis of the knee joint

Osteoarthritis (OA), a common multifactorial disease of musculoskeletal system, is one of the leading causes of disability in the population. One of the most important pathogenetic factors of OA is a shift of cytokine profile towards pro-inflammatory state. Their increased levels lead to dysfunction of cartilage tissue cells with its damage. Purpose of the present study was to evaluate diagnostic significance of the most important cytokine and chemokine levels involved in pathogenesis of OA. The study involved 50 patients undergoing inpatient treatment at the “Hospital for War Veterans” (Vladivostok) with an established OA of the knee joints. The following mediators involved in the development of inflammation have been determined: interleukins IL-1â, IL-6, chemokine CXCL17, tumor necrosis factor TNFá and heat shock proteins HSP27, HSP70 in blood serum of patients being analyzed by ELISA test systems. It has been shown that the levels of interleukins IL-1â and IL-6, TNFá and CXCL17 in patients with OA exceeded those for healthy individuals. The levels of cytokines IL- 1â, IL-6, chemokine CXCL17 and TNFá in blood serum of OA patients were 7.4 (6.4-8.9), 33.7 (26.5-68.4); 33.8 (29.8- 61.0) and 6.5 (4.94-8.59) pg/ml, respectively, thus significantly exceeding the values for healthy person s (1.3 (1.2-1.4), 5.8 (4.2-6.3), 24.9 (19, 1-29.9) and 2.7 (2.1-3.1) pg/ml, p 0.05). In OA patients, the concentration of TNFá had a direct relationship with the chemokine CXCL17 (r = 0.83, p 0.05). The concentrations of heat shock proteins HSP27, HSP70 and their ratio were significantly lower in patients with OA compared to the control group (respectively: z = -3.06, p = 0.002; z = -4.41, p = 0.00001; z = -2.05, p = 0.04), thus allowing us to suggest the tolerance of chondrocytes to the influence of cytokines. At the same time, the concentration of HSP70 decreased as the disease progressed, while the level of HSP27 did not change significantly. Thus, determining the level of systemic intercellular mediators enables usage of these indexes as potential biochemical markers for predicting severity of the disease and assessing their fundamental role in pathogenesis of knee OA.

The Dual Role of Survival Genes in Neurons and Cancer Cells: a Strategic Clinical Application of DX2 in Neurodegenerative Diseases and Cancer.

In cancer cells, survival genes contribute to uncontrolled growth and the survival of malignant cells, leading to tumor progression. Neurons are post-mitotic cells, fully differentiated and non-dividing after neurogenesis and survival genes are essential for cellular longevity and proper functioning of the nervous system. This review explores recent research findings regarding the role of survival genes, particularly DX2, in degenerative neuronal tissue cells and cancer cells. Survival gene DX2, an exon 2-deleted splice variant of AIMP2 (aminoacyl-tRNA synthetase-interacting multi-functional protein 2), was found to be overexpressed in various cancer types. The potential of DX2 inhibitors as an anti-cancer drug arises from its unique ability to interact with various oncoproteins, such as KRAS and HSP70. Meanwhile, AIMP2 has been reported as a multifunctional cell death-inducing gene, and survival gene DX2 directly and indirectly inhibits AIMP2-induced cell death. DX2 plays multifaceted survival roles in degenerating neurons via various signaling pathways, including PARP 1, TRAF2, and p53 pathways. It is noteworthy that genes that were previously classified as oncogenes, such as AKT and XBP1, are now being considered as curative transgenes for targeting neurodegenerative diseases. A strategic direction for clinical application of survival genes in neurogenerative disease and in cancer is justified.

RNA Sequencing Revealed a Weak Response of Gingival Fibroblasts Exposed to Hyaluronic Acid.

Hyaluronic acid was proposed to support soft tissue recession surgery and guided tissue regeneration. The molecular mechanisms through which hyaluronic acid modulates the response of connective tissue cells remain elusive. To elucidate the impact of hyaluronic acid on the connective tissue cells, we used bulk RNA sequencing to determine the changes in the genetic signature of gingival fibroblasts exposed to 1.6% cross-linked hyaluronic acid and 0.2% natural hyaluronic acid. Transcriptome-wide changes were modest. Even when implementing a minimum of 1.5 log2 fold-change and a significance threshold of 1.0 -log10, only a dozenth of genes were differentially expressed. Upregulated genes were PLK3, SLC16A6, IL6, HBEGF, DGKE, DUSP4, PTGS2, FOXC2, ATAD2B, NFATC2, and downregulated genes were MMP24 and PLXNA2. RT-PCR analysis supported the impact of hyaluronic acid on increasing the expression of a selected gene panel. The findings from bulk RNA sequencing suggest that gingival fibroblasts experience weak changes in their transcriptome when exposed to hyaluronic acid.

Physicochemical characterization and antitumor activity in vitro of a polysaccharide from Christia vespertilionis.

CVP-2 is a homogeneous polysaccharide extracted from the whole plant of Christia vespertilionis, with an average molecular weight of approximately 92,920 Da. Its main chain consists of repeating units of [3,5)-α-L-Araf-(1]2 → [5)-α-L-Araf-(1]2→, with branches at the C-3 position: branch 1 is α-L-Araf-(1→, and branch 2 is α-L-Araf-(1 → 4)-. Additionally, the structure includes β-D-Gclp-(1 → [4)-β-D-Glap-(1]2 → 5)-α-L-Araf-(1→. In vitro experiments conducted on cancer and normal cell lines demonstrated that the purified polysaccharide exhibited a significant pro-apoptotic effect on lung and liver cancer cells, while having no impact on the growth of normal tissue cells at dosage concentrations ranging from 125 to 1000 μg/mL. The inhibition of cell viability at 1000 μg/mL CVP-2 was 49.63 % for A549, 2.6 % for 16HBE, 28.56 % for HepG2, and 12.64 % for LX-2. Compared to the drug-free group, the death rates of A549, 16HBE, HepG2, and LX-2 cells increased by 37.13 %, 4.15 %, 26.00 %, and 4.41 %, respectively. CVP-2 was found to inhibit the G1/S phase of the cell cycle. The potential anticancer mechanism of CVP-2 involves a reduction in the Bcl-2/Bax protein in cancer cells, with no significant effect on the growth of normal cells. Therefore, CVP-2 holds great promise as a broad-spectrum antitumor agent and dietary supplement.

Gut Microbiota Regulates the Homeostasis of Dendritic Epidermal T Cells.

Dendritic epidermal T cells (DETCs) are a γδ T cell subset residing in the skin epidermis. Although they have been known for decades, the fate of DETCs has largely remained enigmatic. Recent studies have highlighted the relationship between the gut microbiome and γδ T cells in various epithelial and non-epithelial tissues, such as the small intestine, lung, liver, gingiva, and testis. While the skin microbiota has been shown to impact skin γδ T cells, a direct relationship between the gut microbiota and DETCs remains unexplored. In this study, we investigated whether DETCs are regulated by the gut microbiota in the steady-state skin epidermis. We examined the occurrence of DETCs in Balb/c mice, which have a skin epidermis barely populated with DETCs, compared to C57BL/6 mice, under different housing conditions. Our findings reveal that local skin inflammation markedly increases DETC numbers in the ear epidermis of Balb/c mice and that DETCs are activated by environmental factors. Furthermore, an investigation of the gut microbiota under different housing conditions revealed distinct microbial compositions and functional profiles. Taken together, these results suggest a strong connection between DETCs and gut microbiota.

A CONCISE REVIEW FOR EXPLORING DEEP LEARNING'S POTENTIAL IN CERVICAL CANCER PREDICTION FROM MEDICAL IMAGES

: Cervical cancer originates in the cervix situated between the vagina and the bottom end of the uterus. It evolves gradually which begins with the appearance of aberrant cells in the cervical tissue. These aberrant cells might develop into cancer cells and migrate more into the cervix and adjacent tissues if they are not treated. Therefore, a patient's survival depends on rapid identification of cervical cancer. Various imaging modalities are widely used to identify cervical nodules as pre-cancer or cancer cells. But limited results were determined and takes more time and needs many skilled radiologists. To solve this problem, many Deep Learning (DL) frameworks have emerged in these decades for automatic cervical cancer detection and categorization. These algorithms can detect suspicious nodules early, improving patient outcomes and aiding physicians in decision-making, thereby reducing fatality risk. This study provides an in-depth analysis of many DL frameworks developed to recognize and categorize cervical cancer from various imaging modalities. Initially, different cervical cancer categorization systems designed by many researchers based on DL algorithms are briefly examined. Comparison research is carried out to comprehend the shortcomings of those algorithms and recommend an alternative method for accurately classifying cervical cancer in order to regulate worldwide morality rates.

Cadmium sulfide (CdS) nanoparticles and Cd2+ accumulated by Portulaca oleracea L. using a hydroponic system: Constructed wetland perspective.

To identify cadmium sulfide nanoparticles (CdS NPs) and Cd hyperaccumulators for Cd-contaminated waters. A potential species of constructed wetland plants (P. oleracea) was examined for their CdS NPs and Cd ions tolerance and accumulation. This study evaluated the P. oleracea life traits response, Cd accumulation, bioaccumulation factor (BCF), and translocation factor (TF) to assess their abilities to absorb and accumulate Cd. P. oleracea demonstrates high tolerance to both CdS NPs and Cd stress, with no significant effects observed on biomass, leaf color, plant height, or root length. High accumulation of Cd was noted in plant tissues, with higher Cd in the roots than in the stems and leaves. The Cd levels in plants subjected to CdS NPs were higher than those in the Cd treatment group. CdS NPs aggregates were identified within the plant cells in root and shoot tissues using transmission electron microscopy (TEM). The BCF values ranged from 6.96 to 548.10 for the Cd treatment and 12.91-499.66 for CdS NPs, indicating the ability of P. oleracea to accumulate Cd and NPs. Additionally, TF values for Cd at 0.05 and 0.1 mg/L were above 1, showing effective translocation capability. The findings suggest that P. oleracea demonstrates significant potential as a Cd-hyperaccumulator, exhibiting a robust ability to extract Cd and CdS NPs from contaminated waters. It is a feasible plant in a constructed wetland for Cd removal.

α-Synuclein in Parkinson's Disease: From Bench to Bedside.

α-Synuclein (α-syn), a pathological hallmark of PD, is emerging as a bridging element at the crossroads between neuro/immune-inflammatory responses and neurodegeneration in PD. Several evidence show that pathological α-syn accumulates in neuronal and non-neuronal cells (i.e., neurons, microglia, macrophages, skin cells, and intestinal cells) in central and peripheral tissues since the prodromal phase of the disease, contributing to brain pathology. Indeed, pathological α-syn deposition can promote neurogenic/immune-inflammatory responses that contribute to systemic and central neuroinflammation associated with PD. After providing an overview of the structure and functions of physiological α-syn as well as its pathological forms, we review current studies about the role of neuronal and non-neuronal α-syn at the crossroads between neuroinflammation and neurodegeneration in PD. In addition, we provide an overview of the correlation between the accumulation of α-syn in central and peripheral tissues and PD, related symptoms, and neuroinflammation. Special attention was paid to discussing whether targeting α-syn can represent a suitable therapeutical approach for PD.

Single-cell transcriptomic and cell‑type‑specific regulatory networks in Polima temperature-sensitive cytoplasmic male sterility of Brassica napus L.

BackgroundThermosensitive male sterility (TMS) is a heritable agronomic trait influenced by the interaction between genotype and environment. The anthers of plants are composed of various specialized cells, each of which plays different roles in plant reproduction. In rapeseed (Brassica napus L.), Polima (pol) temperature-sensitive cytoplasmic male sterility (TCMS) is widely used in two-line breeding because its fertility can be partially restored at certain temperatures. The pol-TCMS line exhibits abnormal anther development and pollen abortion at high (restrictive) temperatures (HT, 25 °C) compared to at low (permissive) temperatures (LT, 16 °C). However, the response of different anther cell types to HT and the dynamic regulation of genes under such conditions remain largely unknown.ResultsWe present the first single-cell transcriptomic atlas of Brassica napus early developing flower bud tissues in response to HT. We identified 8 cell types and 17 transcriptionally distinct cell clusters via known marker genes under LT and HT treatment conditions. Under HT conditions, changes in the gene expression patterns of different cell clusters were observed, with the number of down-regulated genes in various cell types exceeding that of up-regulated genes. Pseudotime trajectory analysis revealed that HT strongly affected the development of early stamen/anther tissue cells. In combination with the snRNA-seq, WGCNA, and bulk RNA-seq results, we found that many transcription factors play crucial roles in the response to HT, especially heat response family genes.ConclusionsOur study revealed the transcriptional regulatory network of floral bud tissue in the pol-TCMS line under HT/LT conditions and increased our understanding of high-temperature-induced anther developmental abnormalities, which may help researchers utilize TCMS in the two-line breeding of Brassica plants.

Effect of age and sex differences on the abundances of neuronal, glial, and endothelial cells in non-diseased brain tissue.

Neuroinflammatory and neurodegenerative diseases are influenced by the complex interplay of different cell types within the brain, and understanding the proportions and dynamics of neuronal, glial, and endothelial cells is crucial for deciphering the mechanisms of these diseases. Certain risk factors, such as age and sex differences, are thought to play a significant role in the susceptibility, progression, and response to neurological disease. Therefore, investigation of age- and sex-related differences in cell type proportions is needed to elucidate the biological basis of these diseases. Advances in sequencing technology have enabled large-scale transcriptomic studies, such as the Genotype-Tissue Expression (GTEx) project, providing valuable resources for investigating the cellular landscape of the human brain. In this analysis, we used brain sample data from the GTEx project, comprising 1646 samples with an age range of 20-70 years. The relative abundance of excitatory and inhibitory neurons, astrocytes, oligodendrocytes, microglia, and endothelial cells was estimated from the RNA sequencing data using a deconvolution-based analysis. Spearman correlation analysis between the individuals' calendar ages and cell type proportions revealed a statistically significant decrease in the proportion of neurons with increasing age. In contrast, the proportions of astrocytes and endothelial cells showed a significant increase. Furthermore, endothelial cells exhibited the strongest correlation coefficient, positively associating with age. In addition, the findings indicate sex-based differences in age-related changes to cell type proportions. An age-associated decrease in neuronal proportions was only observed in male donors, while no significant change was found in females. Additionally, an age-associated increase in astrocyte proportions was exclusively seen in males, whereas only females exhibited a significant increase in microglia proportions. Furthermore, we identified sex-based differences in baseline cell type proportions. Male originating samples exhibited higher proportions of excitatory neurons, while female samples showed higher proportions of microglia and endothelial cells. Our results show that both age and sex affect the proportions of cell types in non-diseased brain tissue samples. These findings contribute to our understanding of the effects of age and sex differences on the cellular composition of the brain and shed light on the potential roles of age and sex in neurological diseases.

Gut virome dysbiosis impairs antitumor immunity and reduces 5-fluorouracil treatment efficacy for colorectal cancer.

Despite the established influence of gut bacteria, the role of the gut virome in modulating colorectal cancer (CRC) patient chemotherapy response remains poorly understood. In this study, we investigated the impact of antiviral (AV) drug-induced gut virome dysbiosis on the efficacy of 5-FU in CRC treatment. Using a subcutaneous CRC mouse model, we assessed tumor growth and immune responses following AV treatment, fecal microbiota transplantation (FMT), and 5-FU administration. AV therapy reduced the abundance of gut DNA and RNA viruses, leading to accelerated tumor growth, shortened survival, and diminished chemotherapy efficacy. FMT restored the gut virome, improving tumor suppression and extending the survival of 5-FU-treated mice. Metagenomic sequencing revealed significant changes in virome composition, AV treatment expanded Kahnovirus, Petivirales, and Enterogokushovirus, whereas FMT enriched Peduovirus STYP1, Mahlunavirus rarus, and Jouyvirus ev207. AV treatment reduced the number of dendritic cells and CD8+ T cells in peripheral blood and tumor tissues, impairing antitumor immunity, FMT reversed these deficiencies. To further investigate the underlying mechanisms, we examined the TLR3-IRF3-IFN-β pathway, essential for recognizing viral RNA and triggering immune responses. AV treatment downregulated this pathway, impairing immune cell recruitment and reducing chemotherapy efficacy, while activation of TLR3 with Poly(I:C) restored pathway function and enhanced the effectiveness of 5-FU. These findings suggest the importance of maintaining gut virome integrity or activating TLR3 as adjunct strategies to enhance chemotherapy outcomes in CRC patients.

Dynamics of aquaporin content in the aero-hematic barrier during the latent phase of toxic pulmonary edema

The study evaluates the dynamics of aquaporin (aquaporin-1, aquaporin-5, and epithelial sodium channel) content in the aero-hematic barrier during the latent phase of rat intoxication with carbonyl chloride (phosgene), thermal decomposition products of fluoroplast containing perfluoroisobutylene, and nitrogen dioxide. Rat intoxication was modeled using average lethal concentrations of these toxic substances. At 30 and 60 minutes post-exposure, pulmonary coefficient was measured and histological and immunohistochemical studies were performed. Western blot analysis was used to determine the aquaporin-5 content in rat lung tissues exposed to the thermal decomposition products of fluoroplast. It was found that rat intoxication with phosgene and thermal decomposition products of fluoroplast containing perfluoroisobutylene led to an increase in the relative content of aquaporin-5 and epithelial sodium channel-positive cells in lung tissues as early as 30 minutes post-exposure. At 60 minutes post-exposure, there were signs of the interstitial phase of toxic pulmonary edema and an increase in the pulmonary coefficient. Exposure to nitrogen dioxide resulted in an increase in the pulmonary coefficient and the relative content of aquaporin-5-positive cells, as well as pronounced signs of the interstitial phase of edema 30 minutes post-exposure. Western blot analysis using anti-aquaporin-5 antibodies revealed an increase in the staining intensity of complexes with molecular weights of 25 and 50 kDa, suggesting the formation of aquaporin-5 tetramers and their likely translocation from the intracellular compartment to the plasma membrane of alveolar cells. These findings indicate that aquaporin-5 plays an important role in the pathogenesis of toxic pulmonary edema induced by the studied pneumotoxicants. Targeting these molecules may be a promising approach for pathogenetic therapy of poisoning.

Bmal1-mediated circadian MELK expression potentiates MELK inhibitor chronotherapy for esophageal cancer.

Esophageal squamous cell carcinoma (ESCC) remains a global health challenge. Circadian clock and Maternal embryonic leucine zipper kinase (MELK) play a key role in tumorigenesis. However, a link between circadian clock dysregulation and MELK function in the occurrence and development of ESCC remains elusive. Here, In the in vivo and in vitro systems, we found for the first time that MELK exhibits pronounced circadian rhythms expression in mice esophageal tissue, xenograft model and human ESCC cells. The diurnal differences expression between peak (ZT0) and trough (ZT12) points in normal esophageal tissue is nearly 10-fold. Circadian expression of MELK in ESCC cells was regulated by Bmal1 through binding to the MELK promoter. Supporting this, the levels of MELK were increased significantly in ESCC patients, and was accompanied with altered expression of core clock genes, especially, Bmal1 is prominently upregulated. Most importantly, Bmal1-deleted eliminated the rhythmic expression of MELK, while knockdown of other core genes had no effect on MELK expression. Furthermore, in nude mice with transplanted tumor, the anticancer effect of OTS167 at ZT0 administration is twice that of ZT12. Implications: Our findings suggest that MELK represents a therapeutic target, and can as a regulator of circadian control ESCC growth, with these findings advance our understanding of the clinical potential of chronotherapy and the importance of time-based MELK inhibition in cancer treatment.

Stratified Medicine Paediatrics: Cell free DNA and serial tumour sequencing identifies subtype specific cancer evolution and epigenetic states.

We profiled a large heterogenous cohort of matched diagnostic-relapse tumour tissue and paired plasma-derived cell free DNA (cfDNA) from patients with relapsed and progressive solid tumours of childhood. Tissue and cfDNA sequencing results were concordant, with a wider spectrum of mutant alleles and higher degree of intra-tumour heterogeneity captured by the latter, if sufficient circulating tumour-derived DNA (ctDNA) was present. Serial tumour sequencing identified putative drivers of relapse, with alterations in epigenetic drivers being a common feature. In keeping with epigenetic alterations being a common driver of many childhood cancers, fragmentomics analysis of cfDNA identified tumour-specific epigenetic states and transcription factor binding sites accessible in chromatin. This study leverages a large and well-annotated genomic dataset of aggressive childhood malignancies, identifies genomic and epigenetic drivers of childhood cancer relapse, and highlights the power and practicality of cfDNA analysis to capture both intra-tumoural heterogeneity and the epigenetic state of cancer cells.

Exploring the effects of lactulose on lung-intestinal tissue-associated factors and the TLR4/NF-κB signaling pathway in COPD rats based on lung-gut axis theory.

Chronic obstructive pulmonary disease (COPD) is a systemic inflammatory disease impacting both the respiratory and gastrointestinal systems, with its pathogenesis closely linked to the lung-gut axis theory. In this study, we established a rat model of COPD using a fumigation method combined with intra-airway administration of lipopolysaccharide (LPS) to investigate the effects of lactulose on lung and intestinal tissues, focusing on related inflammatory markers and the TLR4/NF-κB signaling pathway. We further explored the therapeutic effects and mechanisms of lactulose on the lung-intestinal tissues in COPD rats, aiming to expand its potential application in chronic respiratory diseases. Subsequently, damage to lung and colon tissue was assessed using hematoxylin and eosin (HE) staining techniques, and ultrastructural changes in lung tissue cells were observed using transmission electron microscopy. Additionally, the study detected the expression of TNF-α, IL-1β, MUC5AC, TLR4, and NF-κB in lung tissue, along with the expression of MUC2, TLR4, and NF-κB in colon tissue, to evaluate the degree of tissue damage. The research findings indicated that the integrity of the airway and colon mucosal barrier in COPD rats was compromised. Intervention with lactulose significantly reduced pathological damage to lung and intestinal tissue and improved the microstructure of lung tissue. In addition, lactulose downregulated the expression of TNF-α, IL-1β, and MUC5AC in lung tissue, upregulated the expression of MUC2 in colon tissue, and inhibited the activity of the TLR4/NF-κB signaling pathway in lung and colon tissue, effectively mitigating inflammatory damage. Our findings demonstrated that lactulose effectively alleviates COPD-associated inflammation by inhibiting the TLR4/NF-κB signaling pathway within the lung-gut axis, underscoring its promise for treating multi-organ inflammation. This study provides a novel diagnostic and therapeutic perspective for the systemic management of COPD.

Biomarkers of cellular senescence and major health outcomes in older adults.

The geroscience hypothesis proposes that underlying biological processes, such as the accumulation of senescent cells, have deleterious effects on multiple tissues and increase the risk of many chronic conditions with aging. Senescent cells produce heterogenous biomarkers, also called senescence-associated secretory phenotype (SASP). Circulating concentrations of senescence biomarkers may reflect an underlying burden of senescent cells in various tissues. Plasma levels of these proteins have been associated with increased mortality and poorer physical function. The associations of them with the incidence of major age-related conditions including heart failure, cardiovascular disease, stroke, and dementia, have not been studied. We measured 35 senescence biomarkers in baseline plasma samples from 1678 participants aged 70-79years old in the longitudinal Health ABC cohort study. Clinical outcomes were ascertained and validated over an average 11.5year follow-up. In models adjusted for age, sex, and race, higher levels of most of senescence biomarkers were associated with increased risk of all-cause mortality, mobility limitation, and heart failure. Several were also associated with an increased risk of coronary heart disease, stroke, and dementia. Very few were associated with the risk of cancer. Proteins that were selected by Lasso regression for each outcome that commonly included GDF15 and IL6, significantly improved the prediction of mortality, mobility limitation, and heart failure compared with age, sex, and race alone. These results indicate that levels of senescence biomarkers predict an increased risk of several age-related clinical outcomes and may identify individuals most likely to benefit from senotherapeutics.

Reception of damage and activation of growth of connective tissue: crucial regulatory milestones of regeneration in humans

Tissue damage activates programs aimed at the survivalof the body and restoration of its integrity, but fora long time the molecular and cellular mechanisms of theirimplementation remained undeciphered. In recent years, a number of importantinformation has been obtained about the regulation of regeneration processes,which significantly clarify a number of ideas about the regulationof the response to damage and deserve attention in termsof searching for new targets for controlling this process. Thisreview briefly summarizes the basic regulatory mechanisms associated with theearly stages of the human tissue response to injury. Italso provides current data on the mechanisms of damage receptionand the role of stromal cells in the formation ofprimary connective tissue as a structure that determines the outcome.

Linsitinib inhibits IGF-1-induced cell proliferation and hyaluronic acid secretion by suppressing PI3K/Akt and ERK pathway in orbital fibroblasts from patients with thyroid-associated ophthalmopathy.

Thyroid-associated ophthalmopathy (TAO), an autoimmune disorder of the retrobulbar tissue, is present in up to 50 percent of Graves's hyperthyroidism patients. Insulin-like growth factor 1 receptor (IGF-1R) has received attention as a target for the development of therapeutic agent for TAO. IGF-1R and TSHR (thyroid stimulating hormone receptor) interact with each other to form a physical or functional complex, further promoting the development of TAO. Linsitinib, OSI-906, is an inhibitor of IGF-1R and has been reported to inhibit cell proliferation of several tumor cells. Linsitinib has been receiving attention not only for its anticancer effect, but also for its anti-inflammatory effects. It has been reported that linsitinib reduces infiltration of inflammatory cells in orbital tissues, resulting in the reduction of muscle edema and adipose tissues in an experimental murine model for Graves' disease. In the current study, we investigated the issue of whether linsitinib inhibits the IGF-1-induced proliferation of orbital fibroblasts (OFs) via the suppression of phosphatidylinositol 3-kinase (PI3K) / Akt and extracellular signal-regulated kinase (ERK) pathway. Our results showed that pretreatment with linsitinib inhibited IGF-1-induced cell proliferation and hyaluronic acid secretion in the OFs of TAO patients. In addition, our results showed that pretreatment with linsitinib inhibited IGF-1-induced phosphorylation of IGF-1Rβ at Tyr1135, Akt at Ser473, and ERK in the OFs of patients with TAO. These results indicate that linsitinib inhibits IGF-1-induced cell proliferation and hyaluronic acid secretion in the OFs of TAO patients by suppressing the PI3K/Akt and ERK pathways, validating the use of linsitinib as a novel therapeutic agent for TAO.