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The existence of a shared genetic basis for mental disorders has long been documented, yet research on whether acquired epigenetic modifications exhibit common alterations across diseases is limited. Previous studies have found that abnormal methylation of cg14631053 at the SSTR4 promoter region mediates the onset of alcohol use disorder. However, whether aberrant methylation of the SSTR4 gene promoter is involved in other mental health disorders remains unclear. In this study, leveraging publicly available data, we identified that changes in methylation of cg14631053 from the SSTR4 promoter region are involved in the development of bipolar disorder and schizophrenia. Furthermore, the direction of methylation changes in the SSTR4 promoter region is disease-specific: hypomethylation is associated with the onset of bipolar disorder and schizophrenia, rather than major depressive disorder. Methylation levels of cg14631053 correlate with chronological age, a correlation that can be disrupted in patients with mental health disorders including schizophrenia and bipolar disorder. In conclusion, SSTR4 promoter methylation may serve as a marker for identifying bipolar disorder and schizophrenia, providing insights into a transdiagnostic mechanism for precision medicine in the future.

The existence of a shared genetic basis for mental disorders has long been documented, yet research on whether acquired epigenetic modifications exhibit common alterations across diseases is limited. Previous studies have found that abnormal methylation of cg14631053 at the SSTR4 promoter region mediates the onset of alcohol use disorder. However, whether aberrant methylation of the SSTR4 gene promoter is involved in other mental health disorders remains unclear. In this study, leveraging publicly available data, we identified that changes in methylation of cg14631053 from the SSTR4 promoter region are involved in the development of bipolar disorder and schizophrenia. Furthermore, the direction of methylation changes in the SSTR4 promoter region is disease-specific: hypomethylation is associated with the onset of bipolar disorder and schizophrenia, rather than major depressive disorder. Methylation levels of cg14631053 correlate with chronological age, a correlation that can be disrupted in patients with mental health disorders including schizophrenia and bipolar disorder. In conclusion, SSTR4 promoter methylation may serve as a marker for identifying bipolar disorder and schizophrenia, providing insights into a transdiagnostic mechanism for precision medicine in the future., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Zhao, Shi, Wang, Zheng and Xu.)

Alcohol dependence (AD), a disease can be affected by environmental factors with epigenetic modification like DNA methylation changes, is one of the most serious and complex public health problems in China and worldwide. Previous findings from our laboratory using the Illumina Infinium Human Methylation450 BeadChip suggested that methylation at the promoter of SSTR4 was one of the major form of DNA modification in alcohol-dependent populations. To investigate whether DNA methylation levels of the SSTR4 promoter influence alcohol-dependent behaviors, genomic DNA was extracted from the peripheral blood sample of 63 subjects with AD and 65 healthy controls, and pyrosequencing was used to verify the results of BeadChip array. Linear regression was used to analyze the correlation between the methylation levels of SSTR4 promoter and the scores of alcohol dependence scales. Gene expression of SSTR4 in brain tissue was obtained from the Genotype-Tissue Expression (GTEx) project and Human Brain Transcriptome database (HBT). We found the methylation levels of SSTR4 in AD group were significantly lower than healthy controls (two-tailed t-test, t = 14.723, p < 0.001). In addition, only weak to moderate correlations between the methylation levels of the SSTR4 promoter region and scale scores of Alcohol Use Disorders Identification Test (AUDIT), Life Events Scale (LES) and Wheatley Stress Profile (WSS) based on linear regression analyses (AUDIT: R2= 0.35, p < 0.001; LES: R2 = 0.27, p < 0.001; WSS: R2 = 0.49, p < 0.001). The hypomethylated status of SSTR4 may involve in the development of AD and increase the risk of AD persistence in Han Chinese males.

Guohu Weng,1 Bo Zhou,2 Tao Liu,3 Zhengxin Huang,2 Shixiong Huang3 1Department of Encephalopathy, Hainan Provincial Hospital of Traditional Chinese Medicine, Haikou, 570203, Hainan, People’s Republic of China; 2Department of Cardiology, Hainan Provincial Hospital of Traditional Chinese Medicine, Haikou, 570203, Hainan, People’s Republic of China; 3Department of Neurology, Hainan General Hospital, Hainan Affiliated Hospital of Hainan Medical University, Haikou, 570311, Hainan, People’s Republic of ChinaCorrespondence: Shixiong HuangDepartment of Neurology, Hainan General Hospital, Hainan Affiliated Hospital of Hainan Medical University, No. 19 Xiuhua Road, Xiuying District, Haikou, 570311, Hainan, People’s Republic of ChinaTel/Fax +86-0898-68642129Email huangsx0813@163.comPurpose: Many researches have investigated the functions of tetramethylpyrazine (TMP) in Alzheimer’s disease (AD). This study aimed to discuss the underlying mechanism of TMP in AD mice.Methods: TMP (200 mg/kg) was administered to 6-month-old APP/PS1 transgenic mice, and behavioral changes and hippocampal nerve injury in AD mice were detected. Apoptosis and autophagy-related protein levels were detected. Changes in gene expression before and after TMP treatment were compared using transcriptome sequencing. The effects of Cullin 4B (CUL4B) overexpression and somatostatin receptor 4 (SSTR4) silencing on AD symptoms and SSTR4 ubiquitination in APP/PS1 mice were observed. SH-SY5Y and PC12 cells were treated with 25 μmol/L Aβ25– 35 and TMP to observe cell viability, apoptosis, and autophagy. Cell viability and apoptosis were measured again after treatment with proteasome inhibitor MG132 or lysosomal inhibitor 3-mA.Results: TMP treatment improved the behavioral cognition of APP/PS1 mice and improved the neuronal apoptosis and damage in brain tissue. CUL4B was significantly upregulated in APP/PS1 mouse brain tissue, and SSRT4 protein was downregulated, and the levels of CUL4B and SSRT4 were negatively correlated. TMP treatment downregulated CUL4B, inhibited SSRT4 ubiquitination and upregulated SSRT4 protein level in APP/PS1 mouse brain tissue, while CUL4B overexpression or SSRT4 silencing reversed the effect of TMP. TMP and MG132 improved the decreased activity, increased apoptosis and increased SSRT4 protein in SH-SY5Y and PC12 cells treated with Aβ25– 35, but not 3-mA. CUL4B overexpression promoted the ubiquitination of SSTR4 in cells, which partially reversed the effect of TMP.Conclusion: TMP could improve the cognitive ability of AD mice by inhibiting CUL4B expression and the ubiquitination degradation of SSTR, and alleviating neuronal apoptosis and injury. This study may offer a new therapeutic option for AD treatment.Keywords: Alzheimer disease, tetramethylpyrazine, somatostatin receptor 4, ubiquitination, Cullin 4B

Chronic stress has been implicated in mental illnesses and depressive behaviors. Somatostatin 4 receptor (SSTR4) has been shown to mediate anxiolytic and depression-like effects. Here, we aimed to explore the potential of SSTR4 as a diagnostic marker for chronic stress in mice. The mice were divided into single stress, chronic restraint stress, and control groups, and Sstr4 mRNA expression in the pituitary, lungs, and thymus, its protein expression in the thymus, were analyzed. Compared to controls, Sstr4 mRNA expression decreased significantly in the pituitary gland of the chronic and single-stress groups (P = 0.0181 and 0.0022, respectively) and lungs of the single-stress group (P = 0.0124), whereas it significantly increased in the thymus of the chronic-stress group (P = 0.0313). Thymic SSTR4 expression did not decrease significantly in stress groups compared to that in the control group (P = 0.0963). These results suggest that SSTR4 expression fluctuates in response to stress. Furthermore, Sstr4 mRNA expression dynamics in each organ differed based on single or chronic restraint stress-loading periods. In conclusion, this study suggests that investigating SSTR4 expression in each organ could allow for its use as a stress marker to estimate the stress-loading period and aid in diagnosing chronic stress. [ABSTRACT FROM AUTHOR]

Alcohol dependence (AD), a disease can be affected by environmental factors with epigenetic modification like DNA methylation changes, is one of the most serious and complex public health problems in China and worldwide. Previous findings from our laboratory using the Illumina Infinium Human Methylation450 BeadChip suggested that methylation at the promoter of SSTR4 was one of the major form of DNA modification in alcohol-dependent populations. To investigate whether DNA methylation levels of the SSTR4 promoter influence alcohol-dependent behaviors, genomic DNA was extracted from the peripheral blood sample of 63 subjects with AD and 65 healthy controls, and pyrosequencing was used to verify the results of BeadChip array. Linear regression was used to analyze the correlation between the methylation levels of SSTR4 promoter and the scores of alcohol dependence scales. Gene expression of SSTR4 in brain tissue was obtained from the Genotype-Tissue Expression (GTEx) project and Human Brain Transcriptome database (HBT). We found the methylation levels of SSTR4 in AD group were significantly lower than healthy controls (two-tailed t -test, t = 14.723, p < 0.001). In addition, only weak to moderate correlations between the methylation levels of the SSTR4 promoter region and scale scores of Alcohol Use Disorders Identification Test (AUDIT), Life Events Scale (LES) and Wheatley Stress Profile (WSS) based on linear regression analyses (AUDIT: R 2 = 0.35, p < 0.001; LES: R 2 = 0.27, p < 0.001; WSS: R 2 = 0.49, p < 0.001). The hypomethylated status of SSTR4 may involve in the development of AD and increase the risk of AD persistence in Han Chinese males. [ABSTRACT FROM AUTHOR]

Patients with alcohol dependence (AD) are known to develop poor social skills, to report a higher number of adverse childhood experiences (ACEs) and to attempt suicide more frequently than the general population. The background for the association between ACEs and a higher risk of suicide still remains understudied. SSTR4 rs2567608 is a functional polymorphism of the gene for somatostatin receptor subtype 4, predominantly found in the CA1 hippocampus area and involved in memory formation. We hypothesize that the functional polymorphism SSTR4 rs2567608, general self-efficacy, and adverse childhood experiences influence the risk of suicide attempt in patients with AD.

The recently suggested pivotal role of somatostatin (SOM) receptor 4 (SSTR4) in inflammation and nociception in several non-intestinal organs and in gastrointestinal (GI) physiology, necessitates exploration of the role of SSTR4 in GI pathophysiology. Therefore, the role of SSTR4 in GI activity was explored by investigating the effects of SSTR4 deficiency on intestinal motility, smooth muscle contractility and on the expression of SSTRs and neuropeptides in the healthy and Schistosoma mansoni-infected murine small intestine. Functional experiments revealed no differences in intestinal motility or smooth muscle cell contractility between wild-type and SSTR4 knockout ( SSTR4–/–) mice in physiological conditions. As revealed by multiple immunofluorescent labellings, RT-PCR and quantitative real time RT-PCR (qPCR), genetic deficiency of SSTR4 considerably altered the expression of SOM and SSTRs in non-inflamed and inflamed conditions, affecting both extrinsic and intrinsic components of the intestinal innervation, along with SSTR expression in several non-neuronal cell types. Moreover, substance P and calcitonin gene-related peptide expression were significantly elevated in SSTR4–/– mice, confirming the modulatory role of SSTR4 on intestinal pro-inflammatory neuropeptide expression. These data suggest that SSTR4 plays a previously unexpected modulatory role in the regulation of intestinal SSTR expression. Moreover, in addition to the recently described inhibitory effects of SSTR4 on the neuronal release of pro-inflammatory peptides, SSTR4 appears also to be involved in the neuronal expression of both pro- and anti-inflammatory peptides in the murine small intestine. [ABSTRACT FROM AUTHOR]

Background: Habitat transitions have considerable consequences in organism homeostasis, as they require the adjustment of several concurrent physiological compartments to maintain stability and adapt to a changing environment. Within the range of molecules with a crucial role in the regulation of different physiological processes, neuropeptides are key agents. Here, we examined the coding status of several neuropeptides and their receptors with pleiotropic activity in Cetacea. Results: Analysis of 202 mammalian genomes, including 41 species of Cetacea, exposed an intricate mutational landscape compatible with gene sequence modification and loss. Specifically for Cetacea, in the 12 genes analysed we have determined patterns of loss ranging from species-specific disruptive mutations (e.g. neuropeptide FF-amide peptide precursor; NPFF) to complete erosion of the gene across the cetacean stem lineage (e.g. somatostatin receptor 4; SSTR4). Conclusions: Impairment of some of these neuromodulators may have contributed to the unique energetic metabolism, circadian rhythmicity and diving response displayed by this group of iconic mammals. [ABSTRACT FROM AUTHOR]

Several observations have pointed to a major pathogenic role of somatostatin depletion with respect to amyloid accumulation, which is often thought to be the crucial event in a cascade leading to Alzheimer's disease (AD). As methylation of CpG islands plays an important role in gene silencing, we studied the methylation status of the CpG islands in the promoters of somatostatin (SST) and in that of its receptor subtype in the cerebral cortex, SSTR4, in tissue samples from the middle temporal (Brodmann area 22) and superior frontal gyrus (Brodmann area 9) of 5 severely affected AD patients aged 72-94 years (Braak stages V-C or VI-C) and 5 non-demented controls aged 50-92 years. Bisulfite sequencing of DNA from cortical gray and infracortical white matter showed that the DNA methylation status at the promoters of SST and SSTR4 did not significantly differ between AD and control samples in any of the regions analyzed. We confirmed these results using deep bisulfite sequencing of PCR products from the SST promoter amplified from DNA from the cortical gray of the superior frontal gyrus of all AD patients and non-demented controls. We observed a trend toward increased DNA methylation with increasing age. In conclusion, deregulated somatostatin signaling in the AD cortices studied cannot be explained by hypermethylation of the SST or SSTR4 promoter CpG islands., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Somatostatin (also named as growth hormone-inhibiting hormone or somatotropin release-inhibiting factor) is a regulatory peptide important for the proper functioning of the endocrine system, local inflammatory reactions, mood and motor coordination, and behavioral responses to stress. Somatostatin exerts its effects via binding to G-protein-coupled somatostatin receptors of which the fourth subtype (SSTR4) is a particularly important receptor mediating analgesic, anti-inflammatory, and anti-depressant effects without endocrine actions. Thus, SSTR4 agonists are promising drug candidates. Although the knowledge of the atomic resolution-binding modes of SST would be essential for drug development, experimental elucidation of the structures of SSTR4 and its complexes is still awaiting. In the present study, structures of the somatostatin–SSTR4 complex were produced using an unbiased, blind docking approach. Beyond the static structures, the binding mechanism of SST was also elucidated in the explicit water molecular dynamics (MD) calculations, and key binding modes (external, intermediate, and internal) were distinguished. The most important residues on both receptor and SST sides were identified. An energetic comparison of SST binding to SSTR4 and 2 offered a residue-level explanation of receptor subtype selectivity. The calculated structures show good agreement with available experimental results and indicate that somatostatin binding is realized via prerequisite binding modes and an induced fit mechanism. The identified binding modes and the corresponding key residues provide useful information for future drug design targeting SSTR4. [ABSTRACT FROM AUTHOR]

Pain relief is the principal action of opioids. Somatostatin (SST), a growth hormone inhibitory peptide is also known to alleviate pain even in cases when opioids fail. Recent studies have shown that mice are prone to sustained pain and devoid of analgesic effect in the absence of somatostatin receptor 4 (SSTR4). In the present study, using brain slices, cultured neurons and HEK-293 cells, we showed that SSTR4 and δ-Opioid receptor (δOR) exist in a heteromeric complex and function in synergistic manner. SSTR4 and δOR co-expressed in cortical/striatal brain regions and spinal cord. Using cultured neuronal cells, we describe the heterogeneous complex formation of SSTR4 and δOR at neuronal cell body and processes. Cotransfected cells display inhibition of cAMP/PKA and co-activation of SSTR4 and δOR oppose receptor trafficking induced by individual receptor activation. Furthermore, downstream signaling pathways either associated with withdrawal or pain relief are modulated synergistically with a predominant role of SSTR4. Inhibition of cAMP/PKA and activation of ERK1/2 are the possible cellular adaptations to prevent withdrawal induced by chronic morphine use. Our results reveal direct intra-membrane interaction between SSTR4 and δOR and provide insights for the molecular mechanism for the anti-nociceptive property of SST in combination with opioids as a potential therapeutic approach to avoid undesirable withdrawal symptoms. [ABSTRACT FROM AUTHOR]

Distribution of somatostatin receptors (SSTR1-5) was determined in the rat eye. Reverse transcriptase-polymerase chain reaction (RT-PCR) analyses revealed that SSTR4 and SSTR2 are major subtypes expressed predominantly in the iris/ciliary body and retina, respectively, and that SSTR1, SSTR3 and SSTR5 are minor subtypes expressed preferentially in the posterior eye segments including the retina. In situ hybridization showed predominant SSTR4 expression in the posterior iris epithelium and ciliary body, suggesting functional roles of somatostatin in the autonomic nervous system in the anterior segments of the eye. The differential expression of SSTR1-5 may be related to distinct roles of somatostatin in the physiology of different ocular tissues.

In the present study, the putative promoter region of rSSTR4 gene has been cloned and characterized. Primer extension and RNAase protection analysis reveals the existence of multiple transcriptional initiation sites, the five major ones mapping between -126 and -18 relative to the ATG initiation codon. Sequence analysis reveals that the region lacks TATA and CCAAT promoter elements, possesses a high GC content and contains a number of potential SP1 binding sites. In addition, potential AP-2, GCF, and PuF binding sites and an octimer motif were also identified. Thus, the promoter of rSSTR4 shows similar features to promoters of highly regulated growth factor receptors and oncogenes. The potential role these transcriptional binding sites play in regulating rSSTR4 expression is currently being investigated.

Somatostatin has a modulatory role in regulating the membrane conductance in hippocampal neurons. To examine the signal transducing molecules involved in this process, we isolated the cDNA encoding the dominant rat hippocampal somatostatin receptor, SSTR4. Distribution of SSTR4 in the adult central nervous system was restricted to the hippocampus, cerebral cortex, striatum, hypothalamus, and thalamus, as determined by Northern blot analysis and in situ hybridization. In SSTR4-expressing Chinese hamster ovary cells, SSTR4 was functionally coupled not only to inhibition of adenylate cyclase, but also to activation of both arachidonate release and mitogen-activated protein (MAP) kinase cascade, with similar ED50 values. All of these pathways, including both MAP kinase kinase and MAP kinase activation, were completely blocked by pretreatment with pertussis toxin. On the other hand, neither inositol 1,4,5-trisphosphate synthesis nor intracellular Ca2+ mobilization was induced upon SSTR4 stimulation. These data indicate that the hippocampal functions of somatostatin might be mediated through diverse but selective second messenger systems activated via SSTR4 and reveal an unsuspected coupling of a neuronal SSTR subtype to a mitogenic signaling pathway. SSTR4, in addition, provides a useful system to study the Ca(2+)-independent, Gi-dependent (pertussis toxin-sensitive) pathway of MAP kinase activation.

Background:Malignant pleural mesothelioma (MPM) is an aggressive neoplasm arising from mesothelial lining of pleura. CD26 molecules preferentially expressed on epithelioid type of MPM. This study investigates the molecular mechanisms of CD26 regulating MPM cells in vitro and in vivo.Methods:Biochemical and cell biological approaches were used for identifying a novel molecular target of MPM. Its contribution to tumour expansion has been also assessed using animal models. The clinical samples of MPM were also assessed for its expression.Results:We identify that cytostatic effects in MPM are mediated by somatostatin (SST) receptor 4 (SSTR4), being inhibited by the interaction of CD26 molecules. We also indicates that SSTR4-mediated cytostatic effects are regulated by SHP-2 PTP, and that this inhibitory effect by SST agonist is enhanced via lipid raft clustering of associated molecules following crosslinking of anti-CD26 antibody. Finally, using an in vivo xenograft model, we demonstrate that the anti-tumour effect of anti-CD26 mAb is enhanced when combined with SSTR4 agonist treatment, and that SSTR4 is highly coexpressed with CD26 on epithelioid or biphasic types of MPM tissues obtained from patients' surgical specimens.Conclusions:Combination therapy with humanised anti-CD26 mAb and SSTR4 agonist may therefore potentiate anti-tumour effect on MPM. [ABSTRACT FROM AUTHOR]

Somatostatin receptor subtype 4 (SST4) has been shown to mediate analgesic, antidepressant and anti-inflammatory functions without endocrine actions; therefore, it is proposed to be a novel target for drug development. To overcome the species differences of SST4 receptor expression and function between humans and mice, we generated an SST4 humanized mouse line to serve as a translational animal model for preclinical research. A transposon vector containing the hSSTR4 and reporter gene construct driven by the hSSTR4 regulatory elements were created. The vector was randomly inserted in Sstr4-deficient mice. hSSTR4 expression was detected by bioluminescent in vivo imaging of the luciferase reporter predominantly in the brain. RT-qPCR confirmed the expression of the human gene in the brain and various peripheral tissues consistent with the in vivo imaging. RNAscope in situ hybridization revealed the presence of hSSTR4 transcripts in glutamatergic excitatory neurons in the CA1 and CA2 regions of the hippocampus; in the GABAergic interneurons in the granular layer of the olfactory bulb and in both types of neurons in the primary somatosensory cortex, piriform cortex, prelimbic cortex and amygdala. This novel SST4 humanized mouse line might enable us to investigate the differences of human and mouse SST4 receptor expression and function and assess the effects of SST4 receptor agonist drug candidates.