Recombinant human thrombopoietin therapy for primary immune thrombocytopenia in pregnancy: a retrospective comparative cohort study.

BACKGROUND: Treatment options for pregnant women with immune thrombocytopenia (ITP) who do not respond to first-line treatment are limited. Few studies have reported the use of recombinant human thrombopoietin (rhTPO) for this subset of patients. AIMS: To investigate the efficacy and safety of rhTPO in ITP during pregnancy and determine obstetric outcomes and predictors of treatment response. METHODS: From July 2013 to October 2022, the data of 81 pregnant women with ITP and a platelet count < 30 × 109/L who did not respond to steroids and/or intravenous immunoglobulin were retrospectively analysed. Of these patients, 33 received rhTPO treatment (rhTPO group) while 48 did not (control group). Baseline characteristics, haematological disease outcomes before delivery, obstetric outcomes, and adverse events were compared between groups. In the rhTPO group, a generalised estimating equation (GEE) was used to investigate the factors influencing the response to rhTPO treatment. RESULTS: The baseline characteristics were comparable between both groups (P > 0.05, both). Compared with controls, rhTPO patients had higher platelet counts (median [interquartile range]: 42 [21.5-67.5] vs. 25 [19-29] × 109/L, P = 0.002), lower bleeding rate (6.1% vs. 25%, P = 0.027), and lower platelet transfusion rate before delivery (57.6% vs. 97.9%, P < 0.001). Gestational weeks of delivery (37.6 [37-38.4] vs 37.1 [37-37.2] weeks, P = 0.001) were longer in the rhTPO group than in the control group. The rates of caesarean section, postpartum haemorrhage, foetal or neonatal complications, and complication types in both groups were similar (all P > 0.05). No liver or renal function impairment or thrombosis cases were observed in the rhTPO group. GEE analysis revealed that the baseline mean platelet volume (MPV) (odds ratio [OR]: 0.522, P = 0.002) and platelet-to-lymphocyte ratio (PLR) (OR: 1.214, P = 0.025) were predictors of response to rhTPO treatment. CONCLUSION: rhTPO may be an effective and safe treatment option for pregnancies with ITP that do not respond to first-line treatment; it may have slightly prolonged the gestational age of delivery. Patients with a low baseline MPV and high baseline PLR may be more responsive to rhTPO treatment. The present study serves as a foundation for future research.

Prevalence of and risk factors for chlamydia in female outpatients with genital tract infections: a nationwide multi-center, cross-sectional study in China.

Introduction: Chlamydia trachomatis is the etiological agent of the commonest sexually transmitted bacterial infection. This study aimed to examine the prevalence of genital chlamydia and associated risk factors in Chinese female outpatients with genital tract infections. Methods: A prospective, multicenter epidemiological study of genital chlamydia prevalence in 3008 patients with genital tract infections in 13 hospitals in 12 provinces of China was performed between May 2017 and November 2018. Vaginal secretion specimens were collected for the clinical diagnosis of vaginitis, whereas cervical secretion specimens were tested for Chlamydia trachomatis and Neisseria gonorrhoeae. All patients participated in a one-on-one cross-sectional questionnaire interview. Results: Totally 2,908 participants were included. The prevalence rates of chlamydia and gonococcal infections in women with genital tract infections were 6.33% (184/2908) and 0.01% (20/2908), respectively. Multivariate analysis showed high risk factors for chlamydia were premarital sex behavior, first sexual intercourse before the age of 20 and bacterial vaginosis. Discussion: Given that most chlamydia cases are asymptomatic and no vaccine is currently available, chlamydia prevention strategies should include behavioral interventions as well as early screening programs to identify and treat individuals with genital tract infections, especially those with the above identified risk factors.

Tumor-associated myeloid cells in cancer immunotherapy.

Tumor-associated myeloid cells (TAMCs) are among the most important immune cell populations in the tumor microenvironment, and play a significant role on the efficacy of immune checkpoint blockade. Understanding the origin of TAMCs was found to be the essential to determining their functional heterogeneity and, developing cancer immunotherapy strategies. While myeloid-biased differentiation in the bone marrow has been traditionally considered as the primary source of TAMCs, the abnormal differentiation of splenic hematopoietic stem and progenitor cells, erythroid progenitor cells, and B precursor cells in the spleen, as well as embryo-derived TAMCs, have been depicted as important origins of TAMCs. This review article provides an overview of the literature with a focus on the recent research progress evaluating the heterogeneity of TAMCs origins. Moreover, this review summarizes the major therapeutic strategies targeting TAMCs with heterogeneous sources, shedding light on their implications for cancer antitumor immunotherapies.

Clinical nutrition service capacity of 445 secondary or above hospitals in Sichuan, China: the 2021 annual survey.

BACKGROUND AND OBJECTIVES: To investigate the capacity of clinical nutrition services in secondary and tertiary hospitals in the Sichuan Province, China. METHODS AND STUDY DESIGN: Convenience sampling was used. E-questionnaires were distributed to all eligible medical institutions in Sichuan through the official network of provincial and municipal clinical nutrition quality control centers. The data obtained were sorted in Microsoft Excel and analyzed by SPSS. RESULTS: A total of 519 questionnaires were returned, of which 455 were valid. Only 228 hospitals were accessible to clinical nutrition services, of which 127 hospitals had independently set up clinical nutrition departments (CNDs). The ratio of clinical nutritionists to beds was 1:214. During the last decade, the rate of constructing new CNDs was maintained at approximately 5 units/year. A total of 72.4% of hospitals managed their clinical nutrition units as part of their medical technology departments. The specialist number ratio of senior, associate, intermediate and junior is approximately 1:4:8:10. There were 5 common charges for clinical nutrition. CONCLUSIONS: The sample representation was limited, and the capacity of clinical nutrition services may have been overestimated. Secondary and tertiary hospitals in Sichuan are currently in the second high tide of department establishment, with a positive trend of departmental affiliation standardization and a basic formation of a talent echelon.

MicroRNA-423-5p Mediates Cocaine-Induced Smooth Muscle Cell Contraction by Targeting Cacna2d2.

Cocaine abuse increases the risk of atherosclerotic cardiovascular disease (CVD) and causes acute coronary syndromes (ACS) and hypertension (HTN). Significant research has explored the role of the sympathetic nervous system mediating the cocaine effects on the cardiovascular (CV) system. However, the response of the sympathetic nervous system alone is insufficient to completely account for the CV consequences seen in cocaine users. In this study, we examined the role of microRNAs (miRNAs) in mediating the effect of cocaine on the CV system. MiRNAs regulate many important biological processes and have been associated with both response to cocaine and CV disease development. Multiple miRNAs have altered expression in the CV system (CVS) upon cocaine exposure. To understand the molecular mechanisms underlying the cocaine response in the CV system, we studied the role of miRNA-423-5p and its target Cacna2d2 in the regulation of intracellular calcium concentration and SMC contractility, a critical factor in the modulation of blood pressure (BP). We used in vivo models to evaluate BP and aortic stiffness. In vitro, cocaine treatment decreased miR-423-5p expression and increased Cacna2d2 expression, which led to elevated intracellular calcium concentrations and increased SMC contractility. Overexpression of miR-423-5p, silencing of its target Cacna2d2, and treatment with a calcium channel blocker reversed the elevated SMC contractility caused by cocaine. In contrast, suppression of miR-423-5p increased the intracellular calcium concentration and SMC contractibility. In vivo, smooth muscle-specific overexpression of miR-423-5p ameliorated the increase in BP and aortic stiffness associated with cocaine use. Thus, miR-423-5p regulates SMC contraction by modulating Cacna2d2 expression increasing intracellular calcium concentrations. Modulation of the miR-423-5p-Cacna2d2-Calcium transport pathway may represent a novel therapeutic strategy to improve cocaine-induced HTN and aortic stiffness.

Role and mechanism of the p-JAK2/p-STAT3 signaling pathway in follicular development in PCOS rats.

OBJECTIVE: To identify the association between the phosphorylated Janus kinase 2/phosphorylated signal transducer and activator of transcription (p-JAK2/p-STAT3) signaling pathway and follicular development in polycystic ovary syndrome (PCOS) rats, and explore the underlying mechanism. To evaluate the role of exogenous JAK2 inhibitor AG490 in the model and the associations among luteinizing hormone/choriogonadotropin receptor (LHCGR), follicle-stimulating hormone receptor (FSHR), cytochrome P450 17α (CYP17a), cytochrome P450 19 (CYP19), and PCOS. RESULTS: Rat models of PCOS was established. PCOS rats were intraperitoneally treated with double-distilled water (ddH2O)/DMSO/AG490. The rate of ovarian morphological recovery in the AG490 group was significantly higher compared with the DMSO group (83.3 % vs 9.1 %, X2 = 12.68, P < 0.001). Moreover, the short in the time the estrous cycle was resumed in the AG490 group (hazard ratio = 16.32, P < 0.001) compared with the DMSO group. Compared with the controls, p-JAK2, p-STAT3, LHCGR, and CYP17a expression levels were increased whereas that of FSHR and CYP19 were decreased in the ovaries of PCOS rats. However, an opposite trend was observed after treatment with AG490. Software prediction revealed that the p-STAT3 bound to the promoter regions of LHCGR, FSHR, CYP17a, and CYP19 genes. This finding was confirmed by results of correlation analysis (R = 0.834, -0.836, 0.875 and -0.712, respectively, all P < 0.001). CONCLUSION: This study demonstrated that the p-JAK2/p-STAT3 signaling pathway was involved in follicular development in PCOS rats by upregulating LHCGR and CYP17a expression, and downregulating that of FSHR and CYP19. AG490 treatment exerted beneficial effects. LHCGR, FSHR, CYP17a, and CYP19 are candidate genes associated with follicular development in PCOS rats.

Curcumin Alleviates Hyperandrogenism and Promotes Follicular Proliferation in Polycystic Ovary Syndrome Rats: Insights on IRS1/PI3K/GLUT4 and PTEN Modulations.

OBJECTIVE: To explore the effect of curcumin on the insulin receptor substrate 1 (IRS1)/phosphatidylinositol-3-kinase (PI3K)/endometrial expression of glucose 4 (GLUT4) signalling pathway and its regulator, phosphatase and tensin homolog (PTEN), in a rat model of polycystic ovarian syndrome (PCOS). METHODS: PCOS model was induced by letrozole intragastric administration. Sprague-Dawley rats were randomized into 4 groups according to a random number table: (1) control group; (2) PCOS group, which was subjected to PCOS and received vehicle; (3) curcumin group, which was subjected to PCOS and treated with curcumin (200 mg/kg for 2 weeks); and (4) curcumin+LY294002 group, which was subjected to PCOS, and treated with curcumin and LY294002 (a specific PI3K inhibitor). Serum hormone levels (17 ß-estradiol, follicle stimulating hormone, luteinizing hormone, progesterone, and testosterone) were measured by enzyme linked immunosorbent assay, and insulin resistance (IR) was assessed using the homeostasis model assessment of IR. Ovarian tissues were stained with haematoxylin and eosin for pathological and apoptosis examination. Expression levels of key transcriptional regulators and downstream targets, including IRS1, PI3K, protein kinase B (AKT), GLUT4, and PTEN, were measured via reverse transcription polymerase chain reaction and Western blot, respectively. RESULTS: The PCOS group showed impaired ovarian morphology and function. Compared with the PCOS group, curcumin treatment exerted ovarioprotective effects, down-regulated serum testosterone, restored IR, inhibited inflammatory cell infiltration in ovarian tissues, decreased IRS1, PI3K, and AKT expressions, and up-regulated GLUT4 and PTEN expressions in PCOS rats (P<0.05 or P<0.01). In contrast, IRS1, PI3K, AKT, and PTEN expression levels were not significantly different between PCOS and curcumin+LY294002 groups (P>0.05). CONCLUSION: The beneficial effects of curcumin on PCOS rats included the alteration of serum hormone levels and recovery of morphological ovarian lesions, in which, PTEN, a new target, may play a role in regulating the IRS1/PI3K/GLUT4 pathway.

Disruption of Aokap6 near the kojic acid gene cluster affects the growth and kojic acid production in Aspergillus oryzae.

The kojic acid gene cluster of Aspergillus oryzae plays a key role in kojic acid synthesis. Although the kojic acid gene cluster has been found in 2010, there is little information on the function of the genes located near the kojic acid gene cluster of A. oryzae and whether these genes affect the kojic acid gene cluster containing kojA, kojR and kojT. Here, Aokap6 near the kojic acid gene cluster of A. oryzae was identified and characterized. The Aokap6 disrupted mutants were constructed by the CRISPR/Cas9 system, which exhibited increased mycelium growth and conidial formation. Disruption of Aokap6 enhanced the tolerance to cell wall, oxidative and heat stress but not osmotic stress. Deletion of Aokap6 repressed kojic acid production, together with the reduced expression of kojA, kojR and kojT. Meanwhile, knockout of kojA, kojR and kojT led to the declined expression of Aokap6, indicating that Aokap6 is required for kojic acid production in coordination with kojA, kojR and kojT. Furthermore, overexpression of kojA, kojR and kojT had no effects on the transcript level of Aokap6, and overexpression of kojA in Aokap6 deletion strain could rescue the reduced yield of kojic acid, suggesting that Aokap6 is involved in kojic acid synthesis acting upstream of kojA. These findings provide new insight for the further understanding of kojic acid gene cluster and kojic acid production in A. oryzae.

Evaluation of Immunoreactivity and Protection Efficacy of Seneca Valley Virus Inactivated Vaccine in Finishing Pigs Based on Screening of Inactivated Agents and Adjuvants.

Seneca Valley virus (SVV), also known as Senecavirus A (SVA), is a non-enveloped and single-strand positive-sense RNA virus, which belongs to the genus of Senecavirus within the family Picornaviridae. Porcine idiopathic vesicular disease (PIVD) caused by SVV has frequently been prevalent in America and Southeast Asia (especially in China) since the end of 2014, and has caused continuing issues. In this study, an SVV strain isolated in China, named SVV LNSY01-2017 (MH064435), was used as the stock virus for the preparation of an SVV-inactivated vaccine. The SVV culture was directly inactivated using binary ethyleneimine (BEI) and ß-propiolactone (BPL). BPL showed a better effect as an SVV inactivator, according to the results of pH variation, inactivation kinetics, and the detection of VP1 content during inactivation. Then, SVV inactivated by BPL was subsequently emulsified using different adjuvants, including MONTANIDETM ISA 201 VG (ISA 201) and MONTANIDETM IMG 1313 VG N (IMS 1313). The immunoreactivity and protection efficacy of the inactivated vaccines were then evaluated in finishing pigs. SVV-BPL-1313 showed a better humoral response post-immunization and further challenge tests post-immunization showed that both the SVV-BPL-201 and SVV-BPL-1313 combinations could resist challenge from a virulent SVV strain. The SVV LNSY01-2017-inactivated vaccine candidate developed here represents a promising alternative to prevent and control SVV infection in swine.

Associations Between Poor Oral Hygiene and Risk of Pancreatic Cancer: A Meta-analysis of Observational Studies.

OBJECTIVES: Epidemiological studies have reported the association of poor oral hygiene, especially periodontal disease, and tooth loss with the risk of pancreatic cancer (PC). However, these studies have yielded inconsistent results. Therefore, this systematic review and meta-analysis aimed to investigate the relationship between oral disease and PC. METHODS: We systematically searched the PubMed, Embase, and Cochrane Library databases for English literature since inception through May 2021. We used relative risks, hazard ratios, or odds ratios to measure the association between oral disease and PC. A fixed- or random-effects model was applied to evaluate pooled risk estimates, and sensitivity and subgroup analyses were performed to identify sources of heterogeneity and pooled estimation. RESULTS: We identified 17 relevant observational studies involving 1,352,256 participants. Notably, oral disease correlated significantly with PC (hazard ratio [HR], 1.32; 95% confidence interval [CI], 1.13-1.54). In subgroup analyses, subjects with periodontal disease (HR, 1.38; 95% CI, 1.12-1.71) had a higher risk of developing PC than those with tooth loss (HR, 1.19; 95% CI, 0.97-1.46). CONCLUSIONS: The results suggest that subjects with oral disease may face a significant and independent risk of PC. However, the mechanisms linking oral disease and PC are uncertain, and additional investigations of this correlation are warranted.

Relevance of small right-to-left shunt in contrast-enhanced transcranial Doppler in young and middle-aged patients with cryptogenic stroke: a report of two cases and literature review.

AIM: The clinical relevance of small right-to-left shunt (RLS) in young patients with cryptogenic stroke is unknown. We aimed to analyze and understand the relationship between cryptogenic stroke and small RLS by studying specific cases. MATERIALS AND METHODS: Clinical data from two cases of small RLS-related cryptogenic stroke in young patients were collected prospectively and analyzed. We followed up the patients for >1 year after discharge. RESULTS: Case 1. A 50-year-old man was admitted for slurred speech and right hemiplegia and was diagnosed with acute cerebral infarction. Contrast-enhanced transcranial Doppler (c-TCD) and contrast-enhanced transthoracic echocardiography (c-TTE) revealed a microbubble and 20-30 microbubbles per section, respectively, in the resting state. Three months later, he was readmitted for stroke recurrence. Transesophageal echocardiography (TEE) confirmed a patent foramen ovale (PFO), and he underwent transcatheter closure of the PFO. Case 2. A 48-year-old man was admitted for right hemiplegia with slurred speech. Brain magnetic resonance imaging showed acute cerebral infarction. c-TCD and contrast-enhanced TEE (c-TEE) revealed <10 microbubbles and approximately 20 microbubbles per section, respectively. These findings suggested a PFO. Two months later, he was readmitted for stroke recurrence. He underwent transcatheter closure of the PFO. Follow-up of cases 1 and 2 at >1 and >1.5 years after discharge, respectively, showed no stroke recurrence. CONCLUSION: We suspected that a small RLS may cause cryptogenic stroke. A small RLS in c-TCD in stroke patients may not be actually small, and c-TEE/c-TTE may be valuable in finding larger RLSs.

The state-dependent impulsive control for a general predator-prey model.

In this paper, a general predator-prey model with state-dependent impulse is considered. Based on the geometric analysis and Poincaré map or successor function, we construct three typical types of Bendixson domains to obtain some sufficient conditions for the existence of order-1 periodic solutions. At the same time, the existing domains are discussed with respect to the system parameters. Moreover, the Analogue of Poincaré Criterion is used to obtain the asymptotic stability of the periodic solutions. Finally, to illustrate the results, an example is presented and some numerical simulations are carried out.

The E3 ubiquitin ligase component, Cereblon, is an evolutionarily conserved regulator of Wnt signaling.

Immunomodulatory drugs (IMiDs) are important for the treatment of multiple myeloma and myelodysplastic syndrome. Binding of IMiDs to Cereblon (CRBN), the substrate receptor of the CRL4CRBN E3 ubiquitin ligase, induces cancer cell death by targeting key neo-substrates for degradation. Despite this clinical significance, the physiological regulation of CRBN remains largely unknown. Herein we demonstrate that Wnt, the extracellular ligand of an essential signal transduction pathway, promotes the CRBN-dependent degradation of a subset of proteins. These substrates include Casein kinase 1α (CK1α), a negative regulator of Wnt signaling that functions as a key component of the ß-Catenin destruction complex. Wnt stimulation induces the interaction of CRBN with CK1α and its resultant ubiquitination, and in contrast with previous reports does so in the absence of an IMiD. Mechanistically, the destruction complex is critical in maintaining CK1α stability in the absence of Wnt, and in recruiting CRBN to target CK1α for degradation in response to Wnt. CRBN is required for physiological Wnt signaling, as modulation of CRBN in zebrafish and Drosophila yields Wnt-driven phenotypes. These studies demonstrate an IMiD-independent, Wnt-driven mechanism of CRBN regulation and provide a means of controlling Wnt pathway activity by CRBN, with relevance for development and disease.

Pharmaceutical targeting of succinate dehydrogenase in fibroblasts controls bleomycin-induced lung fibrosis.

Idiopathic pulmonary fibrosis (IPF) is characterized by excessive deposition of extracellular matrix in the lung with fibroblast-to-myofibroblast transition, leading to chronically compromising lung function and death. However, very little is known about the metabolic alterations of fibroblasts in IPF, and there is still a lack of pharmaceutical agents to target the metabolic dysregulation. Here we show a glycolysis upregulation and fatty acid oxidation (FAO) downregulation in fibroblasts from fibrotic lung, and perturbation of glycolysis and FAO affects fibroblasts transdifferentiation. In addition, there is a significant accumulation of succinate both in fibrotic lung tissues and myofibroblasts, where succinate dehydrogenase (SDH) operates in reverse by reducing fumarate to succinate. Then succinate contributes to glycolysis upregulation and FAO downregulation by stabilizing HIF-1α, which promotes the development of lung fibrosis. In addition, we identify a near-infrared small molecule dye, IR-780, as a targeting agent which stimulates mild inhibition of succinate dehydrogenase subunit A (SDHA) in fibroblasts, and which inhibits TGF-ß1 induced SDH and succinate elevation, then to prevent fibrosis formation and respiratory dysfunction. Further, enhanced cell retention of IR-780 is shown to promote severe inhibition of SDHA in myofibroblasts, which may contribute to excessive ROS generation and selectively induces myofibroblasts to apoptosis, and then therapeutically improves established lung fibrosis in vivo. These findings indicate that targeting metabolic dysregulation has significant implications for therapies aimed at lung fibrosis and succinate dehydrogenase is an exciting new therapeutic target to treat IPF.

The expression of platelet-derived growth factor, epidermal growth factor, and insulin-like growth factor-II in patients with polycystic ovary syndrome and its correlation with pregnancy outcomes.

BACKGROUND: Polycystic ovary syndrome (PCOS) is a common endocrine and metabolic disorder with complex pathogenesis. This study aimed to analyze the expression of platelet-derived growth factor (PDGF), epidermal growth factor (EGF), and insulin-like growth factor-II (IGF-II) in patients with PCOS and its correlation with pregnancy outcomes. METHODS: A total of 104 PCOS patients admitted to the Cangzhou Central Hospital from January 2015 to February 2018 were selected as the PCOS group, and 92 healthy pregnant women who received health examinations in the hospital during the same period were selected as the control group. Levels of PDGF, EGF, and IGF-II in serum were detected. The expression of PDGF, EGF, and IGF-II in different populations were compared. Age at pregnancy, body mass index (BMI), waist-to-hip ratio before pregnancy, parity, family history of hypertension, family history of diabetes, and serological indicators of pregnant women in the PCOS group were collected, such as follicle stimulating hormone (FSH), luteinizing hormone (LH), estradiol (E2), fasting insulin (INS), and free testosterone index (FTI). Multivariate logistic regression was used to analyze the risk factors that affect the pregnancy outcomes of PCOS patients. RESULTS: The expression levels of PDGF, EGF, and IGF-II in the PCOS group were significantly higher than those in the control group (P<0.05). Among 76 pregnant PCOS patients, 34 cases had adverse pregnancy outcomes and 42 did not. Age at pregnancy, BMI before pregnancy, waist-to-hip ratio before pregnancy, LH, INS, FTI, PDGF, EGF, and IGF-II expression levels were positively correlated with the pregnancy outcome of PCOS patients (P<0.05). The BMI before pregnancy, waist-to-hip ratio before pregnancy, INS, FTI, and expression levels of PDGF, EGF, and IGF-II were revealed as independent risk factors that affect the pregnancy outcomes of PCOS patients (P<0.05). CONCLUSIONS: The expression levels of PDGF, EGF, and IGF-II are high in PCOS patients. The BMI, waist-to-hip ratio before pregnancy, INS, FTI, and the expression levels of PDGF, EGF, IGF-II are independent risk factors that affect the pregnancy outcomes of PCOS patients. Corresponding measures should be actively taken for PCOS patients with high-risk factors to improve both maternal and infant outcomes.

Downregulation of glial genes involved in synaptic function mitigates Huntington's disease pathogenesis.

Most research on neurodegenerative diseases has focused on neurons, yet glia help form and maintain the synapses whose loss is so prominent in these conditions. To investigate the contributions of glia to Huntington's disease (HD), we profiled the gene expression alterations of Drosophila expressing human mutant Huntingtin (mHTT) in either glia or neurons and compared these changes to what is observed in HD human and HD mice striata. A large portion of conserved genes are concordantly dysregulated across the three species; we tested these genes in a high-throughput behavioral assay and found that downregulation of genes involved in synapse assembly mitigated pathogenesis and behavioral deficits. To our surprise, reducing dNRXN3 function in glia was sufficient to improve the phenotype of flies expressing mHTT in neurons, suggesting that mHTT's toxic effects in glia ramify throughout the brain. This supports a model in which dampening synaptic function is protective because it attenuates the excitotoxicity that characterizes HD.

When a neuron dies, through injury or disease, the body loses all communication that passes through it. The brain compensates by rerouting the flow of information through other neurons in the network. Eventually, if the loss of neurons becomes too great, compensation becomes impossible. This process happens in Alzheimer's, Parkinson's, and Huntington's disease. In the case of Huntington's disease, the cause is mutation to a single gene known as huntingtin. The mutation is present in every cell in the body but causes particular damage to parts of the brain involved in mood, thinking and movement. Neurons and other cells respond to mutations in the huntingtin gene by turning the activities of other genes up or down, but it is not clear whether all of these changes contribute to the damage seen in Huntington's disease. In fact, it is possible that some of the changes are a result of the brain trying to protect itself. So far, most research on this subject has focused on neurons because the huntingtin gene plays a role in maintaining healthy neuronal connections. But, given that all cells carry the mutated gene, it is likely that other cells are also involved. The glia are a diverse group of cells that support the brain, providing care and sustenance to neurons. These cells have a known role in maintaining the connections between neurons and may also have play a role in either causing or correcting the damage seen in Huntington's disease. The aim of Onur et al. was to find out which genes are affected by having a mutant huntingtin gene in neurons or glia, and whether severity of Huntington's disease improved or worsened when the activity of these genes changed. First, Onur et al. identified genes affected by mutant huntingtin by comparing healthy human brains to the brains of people with Huntington's disease. Repeating the same comparison in mice and fruit flies identified genes affected in the same way across all three species, revealing that, in Huntington's disease, the brain dials down glial cell genes involved in maintaining neuronal connections. To find out how these changes in gene activity affect disease severity and progression, Onur et al. manipulated the activity of each of the genes they had identified in fruit flies that carried mutant versions of huntingtin either in neurons, in glial cells or in both cell types. They then filmed the flies to see the effects of the manipulation on movement behaviors, which are affected by Huntington's disease. This revealed that purposely lowering the activity of the glial genes involved in maintaining connections between neurons improved the symptoms of the disease, but only in flies who had mutant huntingtin in their glial cells. This indicates that the drop in activity of these genes observed in Huntington's disease is the brain trying to protect itself. This work suggests that it is important to include glial cells in studies of neurological disorders. It also highlights the fact that changes in gene expression as a result of a disease are not always bad. Many alterations are compensatory, and try to either make up for or protect cells affected by the disease. Therefore, it may be important to consider whether drugs designed to treat a condition by changing levels of gene activity might undo some of the body's natural protection. Working out which changes drive disease and which changes are protective will be essential for designing effective treatments.

Improvement of obesity-associated disorders by a small-molecule drug targeting mitochondria of adipose tissue macrophages.

Pro-inflammatory activation of adipose tissue macrophages (ATMs) is causally linked to obesity and obesity-associated disorders. A number of studies have demonstrated the crucial role of mitochondrial metabolism in macrophage activation. However, there is a lack of pharmaceutical agents to target the mitochondrial metabolism of ATMs for the treatment of obesity-related diseases. Here, we characterize a near-infrared fluorophore (IR-61) that preferentially accumulates in the mitochondria of ATMs and has a therapeutic effect on diet-induced obesity as well as obesity-associated insulin resistance and fatty liver. IR-61 inhibits the classical activation of ATMs by increasing mitochondrial complex levels and oxidative phosphorylation via the ROS/Akt/Acly pathway. Taken together, our findings indicate that specific enhancement of ATMs oxidative phosphorylation improves chronic inflammation and obesity-related disorders. IR-61 might be an anti-inflammatory agent useful for the treatment of obesity-related diseases by targeting the mitochondria of ATMs.

Rejuvenation of Senescent Endothelial Progenitor Cells by Extracellular Vesicles Derived From Mesenchymal Stromal Cells.

Mesenchymal stromal cell (MSC) transplantation is a form of the stem-cell therapy that has shown beneficial effects for many diseases. The use of stem-cell therapy, including MSC transplantation, however, has limitations such as the tumorigenic potential of stem cells and the lack of efficacy of aged autologous cells. An ideal therapeutic approach would keep the beneficial effects of MSC transplantation while circumventing the limitations associated with the use of intact stem cells. This study provides proof-of-concept evidence that MSC-derived extracellular vesicles represent a promising platform to develop an acellular therapeutic approach that would just do that. Extracellular vesicles are membranous vesicles secreted by MSCs and contain bioactive molecules to mediate communication between different cells. Extracellular vesicles can be taken up by recipient cells, and once inside the recipient cells, the bioactive molecules are released to exert the beneficial effects on the recipient cells. This study, for the first time to our knowledge, shows that extracellular vesicles secreted by MSCs recapitulate the beneficial effects of MSCs on vascular repair and promote blood vessel regeneration after ischemic events. Furthermore, MSCs from aged donors can be engineered to produce extracellular vesicles with improved regenerative potential, comparable to MSCs from young donors, thus eliminating the need for allogenic young donors for elderly patients.