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Thymosin β4 promotes autophagy and repair via HIF-1α stabilization in chronic granulomatous disease.

Life Sci Alliance

Giorgia Renga, Vasilis Oikonomou, Silvia Moretti +12 more

Chronic granulomatous disease (CGD) is a genetic disorder of the NADPH oxidase characterized by increased susceptibility to infections and hyperinflammation associated with defective autophagy and increased inflammasome activation. Herein, we demonstrate that thymosin β4 (Tβ4), a g-actin sequestering peptide with multiple and diverse intracellular and extracellular activities affecting inflammation, wound healing, fibrosis, and tissue regeneration, promoted in human and murine cells noncanonical autophagy, a form of autophagy associated with phagocytosis and limited inflammation via the death-associated protein kinase 1. We further show that the hypoxia inducible factor-1 (HIF-1)α was underexpressed in CGD but normalized by Tβ4 to promote autophagy and up-regulate genes involved in mucosal barrier protection. Accordingly, inflammation and granuloma formation were impaired and survival increased in CGD mice with colitis or aspergillosis upon Tβ4 treatment or HIF-1α stabilization. Thus, the promotion of endogenous pathways of inflammation resolution through HIF-1α stabilization is druggable in CGD by Tβ4.

High circulating elafin levels are associated with Crohn's disease-associated intestinal strictures.

PLoS One

Jiani Wang, Christina Ortiz, Lindsey Fontenot +5 more

Antimicrobial peptide expression is associated with disease activity in inflammatory bowel disease (IBD) patients. IBD patients have abnormal expression of elafin, a human elastase-specific protease inhibitor and antimicrobial peptide. We determined elafin expression in blood, intestine, and mesenteric fat of IBD and non-IBD patients.

Signaling mechanisms of growth hormone-releasing hormone receptor in LPS-induced acute ocular inflammation.

Proc Natl Acad Sci U S A

Wei Cheng Liang, Jia Lin Ren, Qiu Xiao Yu +8 more

Ocular inflammation is a major cause of visual impairment attributed to dysregulation of the immune system. Previously, we have shown that the receptor for growth-hormone-releasing hormone (GHRH-R) affects multiple inflammatory processes. To clarify the pathological roles of GHRH-R in acute ocular inflammation, we investigated the inflammatory cascades mediated by this receptor. In human ciliary epithelial cells, the NF-κB subunit p65 was phosphorylated in response to stimulation with lipopolysaccharide (LPS), resulting in transcriptional up-regulation of GHRH-R. Bioinformatics analysis and coimmunoprecipitation showed that GHRH-R had a direct interaction with JAK2. JAK2, but not JAK1, JAK3, and TYK2, was elevated in ciliary body and iris after treatment with LPS in a rat model of endotoxin-induced uveitis. This elevation augmented the phosphorylation of STAT3 and production of proinflammatory factors, including IL-6, IL-17A, COX2, and iNOS. In explants of iris and ciliary body, the GHRH-R antagonist, MIA-602, suppressed phosphorylation of STAT3 and attenuated expression of downstream proinflammatory factors after LPS treatment. A similar suppression of STAT3 phosphorylation was observed in human ciliary epithelial cells. In vivo studies showed that blocking of the GHRH-R/JAK2/STAT3 axis with the JAK inhibitor Ruxolitinib alleviated partially the LPS-induced acute ocular inflammation by reducing inflammatory cells and protein leakage in the aqueous humor and by repressing expression of STAT3 target genes in rat ciliary body and iris and in human ciliary epithelial cells. Our findings indicate a functional role of the GHRH-R/JAK2/STAT3-signaling axis in acute anterior uveitis and suggest a therapeutic strategy based on treatment with antagonists targeting this signaling pathway.

ACE inhibitor-mediated angioedema.

Int Immunopharmacol

Vincenzo Montinaro, Marco Cicardi

Angioedema (AE) occurring during ACE inhibitor therapy (ACEi-AE) is a rare complication involving between 0.1 and 0.7% of treated patients. AE can also complicate other therapeutic regimens that block the renin-angiotensin aldosterone system. Other drugs, such as immune suppressors, some type of antidiabetics or calcium antagonists, can increase the likelihood of ACEi-AE when associated to ACEi. There is a clear ethnic predisposition, since African-Americans or Hispanics show a higher prevalence of this condition compared to Caucasians. At least in African-Americans the genetic predisposition accounts for a general higher prevalence of AE, independently from the cause. People that experience ACEi-AE may have some recurrence when they are switched to an angiotensin-receptor blocker (ARB); however, epidemiological studies on large cohorts have shown that angiotensin receptor blockers (ARB) do not increase the likelihood of AE compared to other antihypertensives. Clinical manifestations consist of edema of face, lips, tongue, uvula and upper airways, requiring intubation or tracheotomy in severe cases. Attacks last for 48-72 h and require hospital admission in most cases. Intestinal involvement with sub-occlusive symptoms has also been reported. The pathogenesis of ACEi-AE depends mainly on a reduced catabolism and accumulation of bradykinin, which is normally metabolized by ACE. Genetic studies have shown that some single nucleotide polymorphisms at genes encoding relevant molecules for bradykinin metabolism and action may be involved in ACEi-AE, giving a basis for the ethnic predisposition. Treatment of ACEi-AE is still a matter of debate. Corticosteroids and antihistamines do not show efficacy. Some therapeutic attempts have shown some efficacy for fresh frozen plasma or C1 inhibitor concentrate infusion. Interventional studies with the specific bradykinin receptor antagonist icatibant have shown conflicting results; there might be a different ethnic predisposition to icatibant efficacy which has been proven in caucasian but not in black patients.

Diphenylbutylpiperidine Antipsychotic Drugs Inhibit Prolactin Receptor Signaling to Reduce Growth of Pancreatic Ductal Adenocarcinoma in Mice.

Gastroenterology

Prasad Dandawate, Gaurav Kaushik, Chandrayee Ghosh +24 more

Prolactin (PRL) signaling is up-regulated in hormone-responsive cancers. The PRL receptor (PRLR) is a class I cytokine receptor that signals via the Janus kinase (JAK)-signal transducer and activator of transcription and mitogen-activated protein kinase pathways to regulate cell proliferation, migration, stem cell features, and apoptosis. Patients with pancreatic ductal adenocarcinoma (PDAC) have high plasma levels of PRL. We investigated whether PRLR signaling contributes to the growth of pancreatic tumors in mice.

Splice variant of growth hormone-releasing hormone receptor drives esophageal squamous cell carcinoma conferring a therapeutic target.

Proc Natl Acad Sci U S A

Xiao Xiong, Xiurong Ke, Lu Wang +7 more

The extrahypothalamic growth hormone-releasing hormone (GHRH) and its cognate receptors (GHRH-Rs) and splice variants are expressed in a variety of cancers. It has been shown that the pituitary type of GHRH-R (pGHRH-R) mediates the inhibition of tumor growth induced by GHRH-R antagonists. However, GHRH-R antagonists can also suppress some cancers that do not express pGHRH-R, yet the underlying mechanisms have not been determined. Here, using human esophageal squamous cell carcinoma (ESCC) as a model, we were able to reveal that SV1, a known splice variant of GHRH-R, is responsible for the inhibition induced by GHRH-R antagonist MIA-602. We demonstrated that GHRH-R splice variant 1 (SV1) is a hypoxia-driven promoter of tumor progression. Hypoxia-elevated SV1 activates a key glycolytic enzyme, muscle-type phosphofructokinase (PFKM), through the nuclear factor kappa B (NF-κB) pathway, which enhances glycolytic metabolism and promotes progression of ESCC. The malignant actions induced by the SV1-NF-κB-PFKM pathway could be reversed by MIA-602. Altogether, our studies demonstrate a mechanism by which GHRH-R antagonists target SV1. Our findings suggest that SV1 is a hypoxia-induced oncogenic promoter which can be an alternative target of GHRH-R antagonists.

Cell-type-specific role of lamin-B1 in thymus development and its inflammation-driven reduction in thymus aging.

Aging Cell

Sibiao Yue, Xiaobin Zheng, Yixian Zheng

Cellular architectural proteins often participate in organ development and maintenance. Although functional decay of some of these proteins during aging is known, the cell-type-specific developmental role and the cause and consequence of their subsequent decay remain to be established especially in mammals. By studying lamins, the nuclear structural proteins, we demonstrate that lamin-B1 functions specifically in the thymic epithelial cells (TECs) for proper thymus organogenesis. An up-regulation of proinflammatory cytokines in the intra-thymic myeloid immune cells during aging accompanies a gradual reduction of lamin-B1 in adult TECs. We show that these cytokines can cause senescence and lamin-B1 reduction of the young adult TECs. Lamin-B1 supports the expression of TEC genes that can help maintain the adult TEC subtypes we identified by single-cell RNA-sequencing, thymic architecture, and function. Thus, structural proteins involved in organ building and maintenance can undergo inflammation-driven decay which can in turn contribute to age-associated organ degeneration.

Transcription factor networks in aged naïve CD4 T cells bias lineage differentiation.

Aging Cell

Bin Hu, Guangjin Li, Zhongde Ye +4 more

With reduced thymic activity, the population of naïve T cells in humans is maintained by homeostatic proliferation throughout adult life. In young adults, naïve CD4 T cells have enormous proliferative potential and plasticity to differentiate into different lineages. Here, we explored whether naïve CD4 T-cell aging is associated with a partial loss of this unbiased multipotency. We find that naïve CD4 T cells from older individuals have developed a propensity to develop into TH9 cells. Two major mechanisms contribute to this predisposition. First, responsiveness to transforming growth factor β (TGFβ) stimulation is enhanced with age due to an upregulation of the TGFβR3 receptor that results in increased expression of the transcription factor PU.1. Secondly, aged naïve CD4 T cells display altered transcription factor profiles in response to T-cell receptor stimulation, including enhanced expression of BATF and IRF4 and reduced expression of ID3 and BCL6. These transcription factors are involved in TH9 differentiation as well as IL9 transcription suggesting that the aging-associated changes in the transcription factor profile favor TH9 commitment.

In-depth serum proteomics reveals biomarkers of psoriasis severity and response to traditional Chinese medicine.

Theranostics

Meng Xu, Jingwen Deng, Kaikun Xu +24 more

Serum and plasma contain abundant biological information that reflect the body's physiological and pathological conditions and are therefore a valuable sample type for disease biomarkers. However, comprehensive profiling of the serological proteome is challenging due to the wide range of protein concentrations in serum. Methods: To address this challenge, we developed a novel in-depth serum proteomics platform capable of analyzing the serum proteome across ~10 orders or magnitude by combining data obtained from Data Independent Acquisition Mass Spectrometry (DIA-MS) and customizable antibody microarrays. Results: Using psoriasis as a proof-of-concept disease model, we screened 50 serum proteomes from healthy controls and psoriasis patients before and after treatment with traditional Chinese medicine (YinXieLing) on our in-depth serum proteomics platform. We identified 106 differentially-expressed proteins in psoriasis patients involved in psoriasis-relevant biological processes, such as blood coagulation, inflammation, apoptosis and angiogenesis signaling pathways. In addition, unbiased clustering and principle component analysis revealed 58 proteins discriminating healthy volunteers from psoriasis patients and 12 proteins distinguishing responders from non-responders to YinXieLing. To further demonstrate the clinical utility of our platform, we performed correlation analyses between serum proteomes and psoriasis activity and found a positive association between the psoriasis area and severity index (PASI) score with three serum proteins (PI3, CCL22, IL-12B). Conclusion: Taken together, these results demonstrate the clinical utility of our in-depth serum proteomics platform to identify specific diagnostic and predictive biomarkers of psoriasis and other immune-mediated diseases.

Serum Myostatin and IGF-1 as Gender-Specific Biomarkers of Frailty and Low Muscle Mass in Community-Dwelling Older Adults.

J Nutr Health Aging

J Chew, L Tay, J P Lim +5 more

(i) To investigate serum myostatin (absolute and normalized for total body lean mass (TBLM)) and IGF-1 as biomarkers of frailty and low relative appendicular skeletal muscle mass (RASM) in older adults, and; (ii) to examine gender differences in the association of serum myostatin and IGF-1 levels with frailty and low RASM.

Switching on the furnace: Regulation of heat production in brown adipose tissue.

Mol Aspects Med

Li Li, Baoguo Li, Min Li +1 more

Endothermy requires a source of endogenous heat production. In birds, this is derived primarily from shivering, but in mammals it is mostly non-shivering thermogenesis (NST). Brown adipose tissue (BAT) is a specialized tissue found in Eutherian mammals that is the source of most NST. Heat production in BAT depends primarily on the activity of uncoupling protein 1 (UCP1), which decouples transport of protons across the inner mitochondrial membrane from synthesis of ATP. UCP1 and hence heat production of BAT is regulated by many factors. In this paper we discuss the main factors activating UCP1 and increasing heat production. Probably the most well-known activator is the catecholamine norepinephrine (NE) which is released from sympathetic nerve endings and binds to adrenergic receptors that are abundantly expressed on BAT. NE stimulates release of free-fatty acids. It was previously thought that such FFAs were essential for activation of UCP1. However recent work has suggested intracellular lipolysis is not essential and FFAs can be derived from extracellular sources. Thyroid hormones also exert impacts on metabolic rate via effects on brown adipocytes which express type 2 deiodinase. Knocking out DIO2 makes mice cold intolerant. Parathyroid hormone appears to also be a potent regulator of BAT activity and may be an important mediator of elevated expenditure during cancer cachexia, although this is disputed by observations that cachexia wasting is not blunted in UCP1 KO mice. Cardiac natriuretic peptides have also been implicated in regulating BAT thermogenesis and the interconversion of beige adipocytes from their white to brown form. Activation of BAT thermogenesis may be an important component of the post-ingestion rise in heat production. Recent work suggests the gut derived hormone secretin may play a key role in this effect, directly linking BAT activation to the alimentary tract. Not only gut hormones but also metabolites derived from gut microbiota such as butyrate may be an important activator of BAT during cold exposure. Additional regulatory factors include bone morphogenic proteins, fibroblast growth factor 21, Vascular endothelial growth factors and transient receptor potential vanilloid receptors which are important components of thermal sensing and hence how brown adipose tissue responds to the cold. In the future the main challenge is to understand how these regulatory factors combine with each other and with inhibitory factors to control heat production from BAT, and what their relative importance is in differing circumstances. Knocking out UCP1 has revealed other sources of heat production in BAT including creatine-dependent cycles and a futile cycle of Ca2+ shuttling into and out of the endoplasmic reticulum via the SERCA and ryanodine receptors.

ZNF479 downregulates metallothionein-1 expression by regulating ASH2L and DNMT1 in hepatocellular carcinoma.

Cell Death Dis

Yi-Ju Wu, Bor-Sheng Ko, Shu-Man Liang +6 more

Decreased expression of metallothionein-1 (MT-1) is associated with a poor prognosis in hepatocellular carcinoma (HCC). Here, we found that MT-1 expression was suppressed by 14-3-3ε, and MT-1 overexpression abolished 14-3-3ε-induced cell proliferation and tumor growth. We identified that 14-3-3ε induced expression of ZNF479, a novel potential transcriptional regulator by gene expression profiling and ZNF479 contributed to 14-3-3ε-suppressed MT-1 expression. ZNF479 induced the expression of DNMT1, UHRF1, and mixed-lineage leukemia (MLL) complex proteins (ASH2L and Menin), and increased tri-methylated histone H3 (H3K4me3) levels, but suppressed H3K4 (H3K4me2) di-methylation. ZNF479-suppressed MT-1 expression was restored by silencing of ASH2L and DNMT1. Furthermore, ZNF479 expression was higher in HCC tissues than that in the non-cancerous tissues. Expression analyses revealed a positive correlation between the expression of ZNF479 and DNMT1, UHRF1, ASH2L, and Menin, and an inverse correlation with that of ZNF479, ASH2L, Menin, and MT-1 isoforms. Moreover, correlations between the expression of ZNF479 and its downstream factors were more pronounced in HCC patients with hepatitis B. Here, we found that ZNF479 regulates MT-1 expression by modulating ASH2L in HCC. Approaches that target ZNF479/MLL complex/MT-1 or related epigenetic regulatory factors are potential therapeutic strategies for HCC.

Drug treatment for spinal muscular atrophy types II and III.

Cochrane Database Syst Rev

Renske I Wadman, W Ludo van der Pol, Wendy Mj Bosboom +4 more

Spinal muscular atrophy (SMA) is caused by a homozygous deletion of the survival motor neuron 1 (SMN1) gene on chromosome 5, or a heterozygous deletion in combination with a (point) mutation in the second SMN1 allele. This results in degeneration of anterior horn cells, which leads to progressive muscle weakness. Children with SMA type II do not develop the ability to walk without support and have a shortened life expectancy, whereas children with SMA type III develop the ability to walk and have a normal life expectancy. This is an update of a review first published in 2009 and previously updated in 2011.

Post-weaning social isolation exacerbates aggression in both sexes and affects the vasopressin and oxytocin system in a sex-specific manner.

Neuropharmacology

Vinícius Elias de Moura Oliveira, Inga D Neumann, Trynke R de Jong

Post-weaning social isolation (PWSI) is known to induce exaggerated and abnormal aggression in male rats. Here we aimed to assess the effects of PWSI on aggressiveness and social behavior in both male and female rats. Furthermore, we evaluated how PWSI affects the central oxytocin (OXT) and vasopressin (AVP) systems in both sexes. Wistar rats were isolated (IS) or group housed (GH) in same-sex groups immediately after weaning. After seven weeks, rats underwent an intruder test to assess aggression. In one group, brains were immediately dissected afterwards for in situ hybridization and receptor autoradiography. The other group underwent additional anxiety-like and social behavior tests. PWSI induced increased (abnormal) aggression and impaired social memory in both sexes. Especially IS females exhibited abnormal aggression towards juveniles. Furthermore, PWSI increased OXT mRNA expression in the paraventricular nucleus of the hypothalamus (PVN) and decreased OXTR binding in the anterior portion of the nucleus accumbens (NAcc), independent of the sex. V1a receptor binding was decreased in the lateral hypothalamus (LH) and dentate gyrus (DG) in IS rats, regardless of sex. However, V1a receptor binding in the anterior portion of the bed nucleus of stria terminalis (BNSTa) was decreased in IS females but increased in IS males. Taken together, our data support PWSI as a reliable model to exacerbate aggression not only in male but also in female rats. In addition, OXT receptors in the NAcca and V1a receptors in the LH, DG, and BNSTa may play a role in the link between PWSI and aggression. This article is part of the Special Issue entitled 'Current status of the neurobiology of aggression and impulsivity'.

Effects of tesamorelin on non-alcoholic fatty liver disease in HIV: a randomised, double-blind, multicentre trial.

Lancet HIV

Takara L Stanley, Lindsay T Fourman, Meghan N Feldpausch +16 more

Non-alcoholic fatty liver disease (NAFLD) is a substantial cause of comorbidity in people with HIV and there are no proven pharmacological treatments for the disease in this population. We assessed the effects of tesamorelin on liver fat and histology in people with HIV and NAFLD.

Immunomodulatory effect of thymopentin on lymphocytes from supramammary lymph nodes of dairy cows.

Immunol Lett

Ran Guan, Wei Xu, Lijia Yuan +3 more

Previous study showed that injection of thymopentin (TP 5) in the area of supramammary lymph nodes (SMLN) had therapeutic effect on the intramammary infection (IMI) in cows. This study was to explore the underlying mechanisms by investigating the immunomodulatory effect of TP 5 on SMLN lymphocytes. Lymphocyte proliferation, cell cycle distribution and cytokine mRNA expression were determined by MTT, FCM and RT-qPCR, respectively. Laser scanning confocal microscope (LSCM) was used to observe the binding between TP 5 and SMLN lymphocytes. Moreover, RNA-sequencing (RNA-seq) was performed to observe the difference between the lymphocytes with and without TP 5 treatment. The results showed that TP 5 significantly promoted lymphocyte proliferation, accelerated cell cycle progression, and enhanced mRNA expression of IL-17A and IL-17F. Laser scanning confocal microscopic analysis revealed the binding of TP 5 to the surface of SMLN lymphocytes. A total of 1094 genes were identified as differentially expressed genes (DEGs) using RNA-seq with 692 up- and 402 down-regulated genes. 48 significantly enriched GO terms were identified by RNA-seq. In KEGG analysis, 1/3 of DEGs were enriched in the immune system pathway, including IL-17 signaling pathway, cytokine-cytokine receptor interaction, Th1 and Th2 cell differentiation, T cell receptor signaling pathway, Th17 cell differentiation. Among them, IL-17 signaling pathway was the most prominent. This study suggested that the therapeutic benefit of TP 5 in the treatment of bovine mastitis might be attributed to its immunomodulatory activity in SMLN lymphocytes.

Metabolomic profile of diet-induced obesity mice in response to humanin and small humanin-like peptide 2 treatment.

Metabolomics

Hemal H Mehta, Jialin Xiao, Ricardo Ramirez +4 more

The mitochondrial-derived peptides (MDPs) are a novel group of natural occurring peptides that have important signaling functions and biological activity. Both humanin and small-humanin-like peptide 2 (SHLP2) have been reported to act as insulin sensitizers and modulate metabolism.

Tesamorelin, liver fat, and NAFLD in the setting of HIV.

Lancet HIV

Jennifer Audsley, Joe Sasadeusz, Sharon R Lewin

Synthesis and Pharmacological Evaluation of Hybrids Targeting Opioid and Neurokinin Receptors.

Molecules

Karol Wtorek, Anna Adamska-Bartłomiejczyk, Justyna Piekielna-Ciesielska +6 more

Morphine, which acts through opioid receptors, is one of the most efficient analgesics for the alleviation of severe pain. However, its usefulness is limited by serious side effects, including analgesic tolerance, constipation, and dependence liability. The growing awareness that multifunctional ligands which simultaneously activate two or more targets may produce a more desirable drug profile than selectively targeted compounds has created an opportunity for a new approach to developing more effective medications. Here, in order to better understand the role of the neurokinin system in opioid-induced antinociception, we report the synthesis, structure-activity relationship, and pharmacological characterization of a series of hybrids combining opioid pharmacophores with either substance P (SP) fragments or neurokinin receptor (NK1) antagonist fragments. On the bases of the in vitro biological activities of the hybrids, two analogs, opioid agonist/NK1 antagonist Tyr-[d-Lys-Phe-Phe-Asp]-Asn-d-Trp-Phe-d-Trp-Leu-Nle-NH2 (2) and opioid agonist/NK1 agonist Tyr-[d-Lys-Phe-Phe-Asp]-Gln-Phe-Phe-Gly-Leu-Met-NH2 (4), were selected for in vivo tests. In the writhing test, both hybrids showed significant an antinociceptive effect in mice, while neither of them triggered the development of tolerance, nor did they produce constipation. No statistically significant differences in in vivo activity profiles were observed between opioid/NK1 agonist and opioid/NK1 antagonist hybrids.

[ACE-inhibition and bradykinin-mediated angioedema].

Rev Med Liege

D Ndjekembo Shango, O Simonet, F Vallot +2 more

Angiotensin converting enzyme inhibitors (ACE-i) are the most common cause of bradykininin angioedema. These bradykinin-mediated angioedemas are sometimes confused with histamine-induced angioedema, which may cause a late diagnosis and hence poor initial management, deleterious to the patient. This report describes a patient with a bradykinin-mediated angioedema soon after the initiation of perindopril, with laryngeal involvement requiring orotracheal intubation in emergency. The diagnosis was confirmed later and the assay of the activity of the enzymes involved in the catabolism of kinins - aminopeptidase P (APP), carboxypeptidase N (CPN) and Angiotensin-Converting Enzyme (ACE) - demonstrated a decrease of activity of both APP and ACE. As the diagnosis was not made initially, the specific treatments - concentrate of C1 inhibitor or antagonist of the B2 receptor of bradykinin (Icatibant) - were not administered. Any angioedema occurring during a treatment with ACE-i should be considered as a bradykinin-mediated angioedema.