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Introduction: Somatostatin (SST) is a peptide hormone primarily synthesized in the digestive and nervous systems. While its impact on the endocrine system is well-established, accumulating evidence suggests a crucial role for SST and its analogues inmodulating immune responses. Despite this, the precisemechanism through which SST regulates T cells has remained largely unknown. Methods: To elucidate the impact of SST on human T cells, we conducted a series of experiments involving cell culture assays, molecular analyses, and metabolic profiling. Human T cells were treated with SST, and various parameters including proliferation, cytokine production, and metabolic activities were assessed. Additionally, we employed pharmacological inhibitors and genetic manipulations to dissect the signaling pathways mediating SST's effects on T cells. Results: We showed that SST diminishes T-cell proliferation by influencing IL-2 production and T-cell mitochondrial respiration, while having no discernible impact on TCR-induced glycolysis. Our findings also identified that the regulatory influence of SST on T-cell responses and metabolism is contingent on its receptor, SSTR3. Moreover, we demonstrated that SST governs T-cell responses and metabolism by acting through the T-cell metabolic checkpoint GSK3. Discussion: Our study provides novel insights into the immunoregulatory function of SST in human T cells, highlighting the complex interplay between hormonal signaling and immune regulation. Understanding the molecular mechanisms underlying SST's effects on T cells may offer therapeutic opportunities for manipulating immune responses in various pathological conditions. [ABSTRACT FROM AUTHOR]

Inhibitory γ-aminobutyric acid (GABA)-ergic interneurons mediate inhibition in neuronal circuitry and support normal brain function. Consequently, dysregulation of inhibition is implicated in various brain disorders. Parvalbumin (PV) and somatostatin (SST) interneurons, the two major types of GABAergic inhibitory interneurons in the hippocampus, exhibit distinct morpho-physiological properties and coordinate information processing and memory formation. However, the molecular mechanisms underlying the specialized properties of PV and SST interneurons remain unclear. This study aimed to compare the transcriptomic differences between these two classes of interneurons in the hippocampus using the ribosome tagging approach. The results revealed distinct expressions of genes such as voltage-gated ion channels and GABAA receptor subunits between PV and SST interneurons. Gabrd and Gabra6 were identified as contributors to the contrasting tonic GABAergic inhibition observed in PV and SST interneurons. Moreover, some of the differentially expressed genes were associated with schizophrenia and epilepsy. In conclusion, our results provide molecular insights into the distinct roles of PV and SST interneurons in health and disease. [ABSTRACT FROM AUTHOR]

Inhibitory γ-aminobutyric acid (GABA)-ergic interneurons mediate inhibition in neuronal circuitry and support normal brain function. Consequently, dysregulation of inhibition is implicated in various brain disorders. Parvalbumin (PV) and somatostatin (SST) interneurons, the two major types of GABAergic inhibitory interneurons in the hippocampus, exhibit distinct morpho-physiological properties and coordinate information processing and memory formation. However, the molecular mechanisms underlying the specialized properties of PV and SST interneurons remain unclear. This study aimed to compare the transcriptomic differences between these two classes of interneurons in the hippocampus using the ribosome tagging approach. The results revealed distinct expressions of genes such as voltage-gated ion channels and GABAA receptor subunits between PV and SST interneurons. Gabrd and Gabra6 were identified as contributors to the contrasting tonic GABAergic inhibition observed in PV and SST interneurons. Moreover, some of the differentially expressed genes were associated with schizophrenia and epilepsy. In conclusion, our results provide molecular insights into the distinct roles of PV and SST interneurons in health and disease.

GEP-NETs are heterogeneous tumors originating from the pancreas (panNET) or the intestinal tract. Only a few patients with NETs are amenable to curative tumor resection, and for most patients, only palliative treatments to successfully control the disease or manage symptoms remain, such as with synthetic somatostatin (SST) analogs (SSAs), such as octreotide (OCT) or lanreotide (LAN). However, even cells expressing low levels of SST receptors (SSTRs) may exhibit significant responses to OCT, which suggests the possibility that SSAs signal through alternative mechanisms, e.g., transforming growth factor (TGF)-β. This signaling mode has been demonstrated in the established panNET line BON but not yet in other permanent (i.e., QGP) or primary (i.e., NT-3) panNET-derived cells. Here, we performed qPCR, immunoblot analyses, and cell counting assays to assess the effects of SST, OCT, LAN, and TGF-β1 on neuroendocrine marker expression and cell proliferation in NT-3, QGP, and BON cells. SST and SSAs were found to regulate a set of neuroendocrine genes in all three cell lines, with the effects of SST, mainly LAN, often differing from those of OCT. However, unlike NT-3 cells, BON cells failed to respond to OCT with growth arrest but paradoxically exhibited a growth-stimulatory effect after treatment with LAN. As previously shown for BON, NT-3 cells responded to TGF-β1 treatment with induction of expression of SST and SSTR2/5. Of note, the ability of NT-3 cells to respond to TGF-β1 with upregulation of the established TGF-β target gene SERPINE1 depended on cellular adherence to a collagen-coated matrix. Moreover, when applied to NT-3 cells for an extended period, i.e., 14 days, TGF-β1 induced growth suppression as shown earlier for BON cells. Finally, next-generation sequencing-based identification of microRNAs (miRNAs) in BON and NT-3 revealed that SST and OCT impact positively or negatively on the regulation of specific miRNAs. Our results suggest that primary panNET cells, such as NT-3, respond similarly as BON cells to SST, SSA, and TGF-β treatment and thus provide circumstantial evidence that crosstalk of SST and TGF-β signaling is not confined to BON cells but is a general feature of panNETs. [ABSTRACT FROM AUTHOR]

The hippocampus has become a significant target of stress research in recent years because of its role in cognitive functioning, neuropathology, and regulation of the hypothalamic–pituitary–adrenal (HPA) axis. Despite the pervasive impact of stress on psychiatric and neurological disease, many of the circuit‐ and cell‐dependent mechanisms giving rise to the limbic regulation of the stress response remain unknown. Hippocampal excitatory neurons generally express high levels of glucocorticoid receptors (GRs) and are therefore positioned to respond directly to serum glucocorticoids. These neurons are, in turn, regulated by neighboring interneurons, subtypes of which have been shown to respond to stress exposure. However, GR expression among hippocampal interneurons is not well characterized. To determine whether key interneuron populations are direct targets for glucocorticoid action, we used two transgenic mouse lines to label parvalbumin‐positive (PV+) and somatostatin‐positive (SST+) interneurons. GR immunostaining of labeled interneurons was characterized within the dorsal and ventral dentate hilus, dentate cell body layer, and CA1 and CA3 stratum oriens and stratum pyramidale. While nearly all hippocampal SST+ interneurons expressed GR across all regions, GR labeling of PV+ interneurons showed considerable subregion variability. The percentage of PV+, GR+ cells was highest in the CA3 stratum pyramidale and lowest in the CA1 stratum oriens, with other regions showing intermediate levels of expression. Together, these findings indicate that, under baseline conditions, hippocampal SST+ interneurons are a ubiquitous glucocorticoid target, while only distinct populations of PV+ interneurons are direct targets. This anatomical diversity suggests functional differences in the regulation of stress‐dependent hippocampal responses. [ABSTRACT FROM AUTHOR]

The pontine nuclei comprising the locus coeruleus (LC) and Barrington’s nucleus (BRN) amongst others form the neural circuitry(s) that coordinates arousal and voiding behaviors. However, little is known about the synaptic connectivity of neurons within or across these nuclei. These include corticotropin-releasing factor (CRF+) expressing neurons in the BRN that control bladder contraction and somatostatin expressing (SST+) neurons whose role in this region has not been discerned. To determine the synaptic connectivity of these neurons, we employed optogenetic stimulation with recordings from BRN and LC neurons in brain stem slices of channelrhodopsin-2 expressing SST or CRF neurons. Optogenetic stimulation of CRF+ BRN neurons of CrfCre;chr2-yfp mice had little effect on either CRF+ BRN neurons, CRF– BRN neurons, or LC neurons. In contrast, in SstCre;chr2-yfp mice light-activated inhibitory postsynaptic currents (IPSCs) were reliably observed in a majority of LC but not BRN neurons. The GABAA receptor antagonist, bicuculline, completely abolished the light-induced IPSCs. To ascertain if these neurons were part of the neural circuitry that controls the bladder, the trans-synaptic tracer, pseudorabies virus (PRV) was injected into the bladder wall of CrfCre;tdTomato or SstCre;tdTomato mice. At 68–72 h post-viral infection, PRV labeled neurons were present only in the BRN, being preponderant in CRF+ neurons with few SST+ BRN neurons labeled from the bladder. At 76 and 96 h post-virus injection, increased labeling was observed in both BRN and LC neurons. Our results suggest SST+ neurons rather than CRF+ neurons in BRN can regulate the activity of LC neurons.

"First-generation" somatostatin receptor agonists (SSTRAs) octreotide and lanreotide are the most commonly used first-line pharmacological therapy for patients with acromegaly. A subset of patients respond only partially or not at all to the first-generation SSTRA, necessitating the use of additional pharmacological agents or other modes of therapy. Pasireotide is a "second-generation" SSTRA that has multi-receptor activity. Prospective studies have shown promise in the use of pasireotide in patients with poor response to first-generation SSTRA. Here we elucidate the molecular pathways of resistance to first-generation SSTRA, the mechanism of action, pre-clinical and clinical evidence of the use of pasireotide in patients having incomplete / lack of response to first-generation SSTRA. We also discuss the clinical, pathological, and radiological markers predicting response to pasireotide, and the difference in side-effect profiles of pasireotide, compared to first-generation SSTRA. [ABSTRACT FROM AUTHOR]

Introduction: Somatostatin (SST) is a peptide hormone primarily synthesized in the digestive and nervous systems. While its impact on the endocrine system is well-established, accumulating evidence suggests a crucial role for SST and its analogues in modulating immune responses. Despite this, the precise mechanism through which SST regulates T cells has remained largely unknown., Methods: To elucidate the impact of SST on human T cells, we conducted a series of experiments involving cell culture assays, molecular analyses, and metabolic profiling. Human T cells were treated with SST, and various parameters including proliferation, cytokine production, and metabolic activities were assessed. Additionally, we employed pharmacological inhibitors and genetic manipulations to dissect the signaling pathways mediating SST's effects on T cells., Results: We showed that SST diminishes T-cell proliferation by influencing IL-2 production and T-cell mitochondrial respiration, while having no discernible impact on TCR-induced glycolysis. Our findings also identified that the regulatory influence of SST on T-cell responses and metabolism is contingent on its receptor, SSTR3. Moreover, we demonstrated that SST governs T-cell responses and metabolism by acting through the T-cell metabolic checkpoint GSK3., Discussion: Our study provides novel insights into the immunoregulatory function of SST in human T cells, highlighting the complex interplay between hormonal signaling and immune regulation. Understanding the molecular mechanisms underlying SST's effects on T cells may offer therapeutic opportunities for manipulating immune responses in various pathological conditions., 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. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Zhang, Feng, Lin and Li.)

Highlights • SST gene transfer prevents kindling-induced seizures in some fully-kindled rats. • Kindling increases Type-1 NSC division and microglial activation in rat hippocampi. • SST gene transfer normalizes Type-1 NSC division in treatment responders. • SST treatment does not affect microglial activation in the hippocampi of kindled rats. • SST gene transfer may mediate effects on kindled seizures through neurogenesis. Abstract Neurogenesis persists throughout life in the hippocampi of all mammals, including humans. In the healthy hippocampus, relatively quiescent Type-1 neural stem cells (NSCs) can give rise to more proliferative Type-2a neural progenitor cells (NPCs), which generate neuronal-committed Type-2b NPCs that mature into Type-3 neuroblasts. Many Type-3 neuroblasts survive and mature into functionally integrated granule neurons over several weeks. In kindling models of epilepsy, neurogenesis is drastically upregulated and many new neurons form aberrant connections that could support epileptogenesis and/or seizures. We have shown that sustained vector-mediated hippocampal somatostatin (SST) expression can both block epileptogenesis and reverse seizure susceptibility in fully kindled rats. Here we test whether adeno-associated virus (AAV) vector-mediated sustained SST expression modulates hippocampal neurogenesis and microglial activation in fully kindled rats. We found significantly more dividing Type-1 NSCs and a corresponding increased number of surviving new neurons in the hippocampi of kindled versus sham-kindled rats. Increased numbers of activated microglia were found in the granule cell layer and hilus of kindled rats at both time points. After intrahippocampal injection with either eGFP or SST-eGFP vector, we found similar numbers of dividing Type-1 NSCs and -2 NPCs and surviving BrdU+ neurons and glia in the hippocampi of kindled rats. Upon observed variability in responses to SST-eGFP (2/4 rats exhibited Grade 0 seizures in the test session), we conducted an additional experiment. We found significantly fewer dividing Type-1 NSCs in the hippocampi of SST-eGFP vector-treated responder rats (5/13 rats) relative to SST-eGFP vector-treated non-responders and eGFP vector-treated controls that exhibited high-grade seizures on the test session. The number of activated microglia was upregulated in the GCL and hilus of kindled rats, regardless of vector treatment. These data support the hypothesis that sustained SST expression exerts antiepileptic effects potentially through normalization of neurogenesis and suggests that abnormally high proliferating Type-1 NSC numbers may be a cellular mechanism of epilepsy. [ABSTRACT FROM AUTHOR]

Inhibitory γ-aminobutyric acid (GABA)-ergic interneurons mediate inhibition in neuronal circuitry and support normal brain function. Consequently, dysregulation of inhibition is implicated in various brain disorders. Parvalbumin (PV) and somatostatin (SST) interneurons, the two major types of GABAergic inhibitory interneurons in the hippocampus, exhibit distinct morpho-physiological properties and coordinate information processing and memory formation. However, the molecular mechanisms underlying the specialized properties of PV and SST interneurons remain unclear. This study aimed to compare the transcriptomic differences between these two classes of interneurons in the hippocampus using the ribosome tagging approach. The results revealed distinct expressions of genes such as voltage-gated ion channels and GABA A receptor subunits between PV and SST interneurons. Gabrd and Gabra6 were identified as contributors to the contrasting tonic GABAergic inhibition observed in PV and SST interneurons. Moreover, some of the differentially expressed genes were associated with schizophrenia and epilepsy. In conclusion, our results provide molecular insights into the distinct roles of PV and SST interneurons in health and disease., 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 © 2023 Huang, Lin, Hsiao, Wang, Ajibola, Abdulmajeed, Lin, Li, Chen, Lien, Chiu and Cheng.)

Abstract: Somatostatin has a wide biological profile resulting from its actions on the five receptor subtypes (sst1–5). Recently somatostatin was shown to exert analgesic effects via activation of the sst4 receptor. Although the analgesia in pain models is established, the precise molecular mechanism has yet to be fully elucidated. This research aimed to identify possible anti-nociceptive mechanisms, showing functional links of the sst4 receptor to G-protein coupled inward rectifying potassium (GIRK) channels and reduction of voltage stimulated calcium influx within the pain processing pathway. Whole cell voltage clamp experiments and calcium imaging experiments were conducted on DRG neurons prepared from adult rats. Application of an sst4 receptor selective agonist, J-2156, on DRG neurons induced a GIRK modulated potassium current, and inhibited voltage sensitive calcium current. Both mechanisms are thought to contribute to the analgesic properties of sst4 receptor agonists. [Copyright &y& Elsevier]

Highlights: [•] Oral anti-IL-6 mAb, tocilizumab (TCZ)(Actemra®), was examined in EAE. [•] Oral TCZ inhibited disease and inflammation in actively fed mice. [•] Transferred cells from TCZ fed donors protected recipients from disease. [•] Oral TCZ inhibited IL-6/IL-12 and increased IL-10. [ABSTRACT FROM AUTHOR]

Highlights: [•] Influence of a SSTR4 agonist, J-2156, on TRPV1 activity in DRG neurons was assessed. [•] J-2145 concentrationally inhibited capsaicin induced calcium influx. [•] J-2156 concentrationally inhibited capsaicin induced sodium influx. [•] J-2145 inhibition of capsaicin induced calcium influx is augmented after CFA treatment. [•] This inhibition identifies a contributing mechanism to the analgesic effects of J-2156. [Copyright &y& Elsevier]

An analog of somatostatin with hormonal and antitumor activity was synthesized. An optimum synthesis method was developed, yielding standard pharmaceutical somatostatin analog substance for preclinical and clinical studies. A quality control method was developed for inclusion in the draft manufacturer's pharmacopeia monograph for pharmacological somatostatin analog substance. [ABSTRACT FROM AUTHOR]

Highlights: [•] Coupling between the bilateral pre-Bötzinger complex (preBötC) regions was analyzed. [•] PreBötC neurons directly project to the hypoglossal premotor and motor areas. [•] Inter-preBötC glutamatergic action potential propagation was visually demonstrated. [•] Population recruitment in a single inspiratory cycle in the preBötC is chaotic. [•] Pathways from the preBötC to other medullary regions are well functioning at birth. [ABSTRACT FROM AUTHOR]

Highlights: [•] Somatostatin system plays a significant role in the progression of human prostate cancer. [•] Activation of SS1R and SS2R/SS5R leads to relevant antiproliferative effect. [•] SS1R, SS2R and SS5R are differently distributed among lysosomes and microsomes. [•] SS1R and the SS2R/SS5R dimer represent potential novel targets for the treatment of late-stage prostate cancer. [ABSTRACT FROM AUTHOR]

Highlights: [•] β1- and β2-adrenoceptors (ARs) are expressed in different interneurons in the mPFC. [•] These interneurons include PV-, CR-, CB-, SST- and Reelin-immunoreactive cells. [•] CR-ir cells are less likely to express β1/2-ARs than the other types of cells. [•] SST-ir cells are more likely to express β2-AR than the other types of interneurons. [Copyright &y& Elsevier]

Highlights: [•] Hyperpolarization-activated cyclic nucleotide-gated (HCN) cation channels are involved in multiple physiological processes. [•] HCN channels are excellent targets of various cellular signals to finely regulate neuronal responses to external stimuli. [•] Dysregulation of HCN channels is involved in a variety of neurological disorders. [ABSTRACT FROM AUTHOR]

Highlight: [•] Somatostatin (SST) facilitate excitability of tooth-pulp evoked C1 neurons. [•] SST2a receptor(R) immunoreactive C1 dorsal horn neurons co-expressed GAD67. [•] SST2AR expressed GABAergic interneurons contributes to trigeminal nociception [ABSTRACT FROM AUTHOR]

Abstract: Generation of surrogate β-cells is the need of the day to compensate the short supply of islets for transplantation to diabetic patients requiring daily shots of insulin. Over the years several sources of stem cells have been claimed to cater to the need of insulin producing cells. These include human embryonic stem cells, induced pluripotent stem cells, human perinatal tissues such as amnion, placenta, umbilical cord and postnatal tissues involving adipose tissue, bone marrow, blood monocytes, cord blood, dental pulp, endometrium, liver, labia minora dermis-derived fibroblasts and pancreas. Despite the availability of such heterogonous sources, there is no substantial breakthrough in selecting and implementing an ideal source for generating large number of stable insulin producing cells. Although the progress in derivation of β-cell like cells from embryonic stem cells has taken a greater leap, their application is limited due to controversy surrounding the destruction of human embryo and immune rejection. Since multipotent mesenchymal stromal cells are free of ethical and immunological complications, they could provide unprecedented opportunity as starting material to derive insulin secreting cells. The main focus of this review is to discuss the merits and demerits of MSCs obtained from human peri- and post-natal tissue sources to yield abundant glucose responsive insulin producing cells as ideal candidates for prospective stem cell therapy to treat diabetes. [Copyright &y& Elsevier]

Highlights: [•] Several peptides are expressed in the PVN-RVLM neurons. [•] The large majority of PVN-RVLM neurons expressed OT and Dyn. [•] The PVN-RVLM neurons predominantly co-expressed multiple peptides. [•] Peptides were differentially distributed between subdivisions of PVN-RVLM neurons. [Copyright &y& Elsevier]

Highlights: [•] Cortical GABA neuron abnormalities in schizophrenia may have a prenatal origin. [•] Transcription regulators and other developmental factors govern GABA neuron ontogeny. [•] Deficits in ontogenetic transcription factors have been reported in schizophrenia. [•] Maternal immune activation may be involved in GABA neuron deficits in schizophrenia. [ABSTRACT FROM AUTHOR]

Abstract: All-trans retinoic acid (RA) signals via binding to retinoic acid receptors (RARs α, β, and γ). RA directly influences expression of Pdx1, a transcription factor essential for pancreatic development and beta-cell (β-cell) maturation. In this study we follow the differentiation of cultured wild-type (WT) vs. RARβ knockout (KO) embryonic stem (ES) cells into pancreatic islet cells. We found that RARβ KO ES cells show greatly reduced expression of some important endocrine markers of differentiated islet cells, such as glucagon, islet amyloid polypeptide (Iapp), and insulin 1 (Ins1) relative to WT. We conclude that RARβ activity is essential for proper differentiation of ES cells to pancreatic endocrine cells. [Copyright &y& Elsevier]

Abstract: Objective: Human growth hormone (hGH), as well as the other members of the same polypeptide hormone family, have a four-helix bundle structure linked by two disulfide bridges, C53–C165 and C182–C189 in hGH. The C-terminal disulfide bridge of growth hormone is evolutionally conserved but its role is unknown. Our aim was to determine its importance for GH structure and/or function. Design: We disrupted the highly conserved C-terminal disulfide bridge of hGH by substituting one or both of its cysteines by alanines. Mutant and wild type hGH genes were expressed in human embryonic kidney (HEK)-293 cells and the hGH analogs were characterized in vitro regarding biological activity, stability and binding to GH receptor (GHR) as well as GH binding protein (GHBP). Results: Disrupting the hGH C-terminal disulfide bridge significantly reduces binding affinity to GHR and GHBP. If one of the cysteines is removed, the stability of the molecule is reduced but this feature is reversed when both cysteines are absent. However, despite decreased binding affinity and stability, biological activity is only modestly decreased when the disulfide bridge is removed. Conclusions: Our study reveals the importance of the C-terminal disulfide bridge of GH for receptor binding and the detrimental effect of its unpaired cysteines on stability as well as, to a lesser extent, biological activity. This improved knowledge of structure–function relationships helps better understand the biology of GH and related molecules. This could have an impact on diagnosis and treatment of patients with growth disorders. [Copyright &y& Elsevier]

Abstract: A large body of evidence shows that methamphetamine (METH) causes sustained damage to the brain in animal models and human METH users. In chronic users there are indications of cognitive and motor deficits. Striatal neuropeptides are in a position to modulate the neurochemical effects of METH and consequently striatal neural damage. Somatostatin (SST) is an intrinsic striatal neuropeptide that has been shown to inhibit glutamate transmission; glutamate is integral to METH toxicity and contributes to nitric oxide (NO) synthesis. We hypothesize that SST will protect from METH by inhibition of NO synthesis and thus reducing oxidative stress. To this end, the SST analogue octreotide (OCT) was microinjected into the striatum prior to a systemic injection of METH (30mg/kg). We then assessed 3-nitrotyrosine (3-NT), an indirect index of NO production, tyrosine hydroxylase (TH) protein levels (dopamine terminal marker) and Fluoro-Jade C positive cells (degenerating cells). The SST agonist OCT dose dependently attenuated the METH-induced accumulation of striatal 3-NT. Moreover, pretreatment with OCT effectively mitigated cell death but failed to protect dopamine terminals. Next we co-infused OCT and NMDA and measured 3-NT and Fluoro-Jade C staining. Treatment with OCT had no effect on these parameters. The data demonstrate that SST attenuates the METH-induced production of NO protecting the striatum from the METH-induced cell loss. However, SST failed to prevent the toxicity of the dopamine terminals suggesting that pre- and post-synaptic striatal damage occur via independent mechanisms. [Copyright &y& Elsevier]

Diabetic retinopathy (DR) has been considered to be a microcirculatory disease of the retina. However, there is emerging evidence to suggest that retinal neurodegeneration is an early event in the pathogenesis of DR, which may antedate, and also participates in, the microcirculatory abnormalities that occur in DR. Therefore, the study of the underlying mechanisms that lead to neurodegeneration will be essential for identifying new therapeutic targets in the early stages of DR. Elevated levels of glutamate, oxidative stress, the overexpression of the renin-angiotensin system and the upregulation of RAGE play an essential role in the retinal neurodegeneration induced by diabetes. Finally, the balance between the neurotoxic and neuroprotective factors is crucial in determining the survival of retinal neurons. In this review we will focus on neurotrophic factors already synthesized by the retina in physiological conditions as a new therapy strategy for neuroprotection. [ABSTRACT FROM AUTHOR]

Objective: Intestinal ischemia-reperfusion (IIR)-induced gut injury remains a challenge for critically ill patients despite the oxidative stress theory that has been elaborated. This study aimed to test whether Toll-like receptor 4 (TLR4) is involved in gut injury during IIR and whether somatostatin (SST) affects TLR4-nuclear factor-kappaB (NF-kappaB) cytokine pathway in the intestinal mucosa of macaques.Design: Fifteen macaques were randomized into control, IIR, and SST + IIR groups. Pieces of isolated ileal epithelium from each animal were incubated with lipopolysaccharide (LPS), interferon-gamma, or SST. Expression of TLR4 and NF-kappaBp65 was evaluated by immunohistochemical staining, Western blot analysis and reverse transcription polymerase chain reaction. Cytokine levels were measured by ELISA. Radioimmunoassay was used to determine of SST levels.Measurements and Main Results: Significant overexpression (IIR vs control) of ileal TLR4 (0.17 +/- 0.03 vs 0.05 +/- 0.02), NF-kappaBp65 (0.55 +/- 0.11 vs 0.15 +/- 0.05), and TNF-alpha (213.2 +/- 29.2 vs 56.0 +/- 10.04) after IIR was greatly decreased (p < 0.05) by prophylactic use of SST (TLR4: 0.06 +/- 0.02; NF-kappaBp65: 0.26 +/- 0.09; TNF-alpha: 97.1 +/- 32.3) in vivo. TLR4 expression in the ileal epithelium treated with LPS and SST (1,330 +/- 93) was significantly lower than that in the ileal epithelium treated with LPS alone (2,088 +/- 126) in vitro. SST levels in plasma (3.67 +/- 0.41 ng/ml) and ileal mucosa (1,402.3 +/- 160 ng/mg protein) of the IIR group were significantly lower than those (6.09 +/- 1.29 ng/ml, 2,234. 8 +/- 301.8 ng/mg protein) in the control group (p < 0.05).Conclusions: Endogenous SST is a crucial inhibitor of massive inflammatory injury in the intestinal mucosa via direct suppression of the TLR4-NF-kappaB cytokine pathway induced by LPS in ileal epithelium. IIR attacks caused shortages of endogenous SST in the plasma and intestinal mucosa of macaques in this study. Therefore, preventive supplements of SST may limit intestinal injury of macaques by IIR. [ABSTRACT FROM AUTHOR]

Somatostatin has antinociceptive effects by acting on somatostatin (sst) receptors in primary afferent neurons. Five sst receptor subtypes (sst1–5) have been identified. In the present study we assessed the expression and localization of the sst receptor subtypes in lumbar dorsal root ganglia of normal rats and of rats with unilateral antigen-induced arthritis (AIA) in the knee joint. We used polymerase chain reaction (PCR) of material from dorsal root ganglia and immunohistochemistry in dorsal root ganglion paraffin sections. PCR data show that sst1, sst2(a), sst2(b), sst3, and sst4 receptors are expressed in lumbar dorsal root ganglia of the rat. The sst5 receptor was expressed in a few samples. Available antibodies revealed sst2(a) and sst2(b) receptor-like immunoreactivity in the vast majority of neurons, and sst4 receptor-like immunoreactivity in about 40% of the dorsal root ganglion neurons and in some satellite cells. Real time PCR at 3, 10 and 21 days after induction of AIA did not reveal changes in receptor expression. Immunohistochemistry showed that a similar high proportion of neuronal profiles expressed sst2(b) receptor-like IR in control and AIA rats, but the proportion of neuronal profiles with sst2(a) receptor-like IR was significantly lower in acute and chronic AIA rats than in control rats. Although the proportion of neuronal profiles with sst4 receptor-like IR was significantly higher at 21 days than at 3 days values at 3 or at 21 days were not significantly different from control.These data show that the majority of dorsal root ganglion neurons exhibit somatostatin receptor-like IR thus suggesting a high potential for inhibition by somatostatin. The reduction in the proportion of neuronal profiles with sst2(a) immunoreactivity suggests that inhibition of neuronal activity by somatostatin is reduced during painful arthritis. [Copyright &y& Elsevier]

The actions of somatostatin (SST) in the nervous system are mediated by specific high affinity SST receptors (SSTR1-5). However, the role of this hormone and the distribution of its receptor subtypes have not yet been defined in neural structures of the human fetus. We have analyzed four neural tissues (CNS, hypothalamus, pituitary and spinal cord) from early to midgestation for the expression of five human SSTR mRNAs, using a reverse transcription–polymerase chain reaction and Southern blot approach. These fetal neural tissues all express mRNA for multiple SSTR subtypes from as early as 16 weeks of fetal life but the developmental patterns of expression vary considerably. Transcripts for SSTR1 and SSTR2A are the most widely distributed, being expressed in all four neural tissues. SSTR2A is often the earliest transcript to be detected (7.5 weeks in CNS). SSTR3 mRNA is confined to the pituitary, hypothalamus, and spinal cord. SSTR4 is expressed in fetal brain, hypothalamus and spinal cord but not pituitary. SSTR5 mRNA is detectable in the pituitary and spinal cord by 14–16 weeks of fetal life. This mapping of SSTR mRNA expression patterns in human fetal neural tissues is an important first step toward our goal of determining the role of SST in the nervous system during early stages in human development. [Copyright &y& Elsevier]

Recent advances in the development of potent and selective peptide and non-peptide ligands for peptidergic receptors are anticipated to help further unravel the roles of class I and II G-protein-coupled receptors in the pathogenesis of human diseases and to accelerate the clinical utility of small molecule peptidomimetics. Peptidomimetic drug discovery directed towards somatostatin agonists, urotensin II antagonists, gonadotropin-releasing hormone antagonists, neurotensin and complement C5a modulators, melanocortin-4 agonists and vasopressin V2 agonists has achieved success through integration of conformational-based drug design, site-directed mutagenesis, screening, combinatorial chemistry and classical medicinal chemistry. Acceptance that discreet ensembles of secondary structural motifs underpin the interactions of peptides with their cognate receptors has enabled the development of molecules which mimic or stabilize such pharmacophores. [Copyright &y& Elsevier]

G-protein-coupled receptors (GPCRs) are the largest class of cell-surface receptors and are encoded by over 1000 genes in the human genome. Their activation mechanism is investigated using live cells, cultured cortical neurons, and brain slices in combination with fluorescence resonance energy transfer (FRET) and fluorescence correlation spectroscopy (FCS) including auto and cross correlation. [Copyright &y& Elsevier]

The pontine nuclei comprising the locus coeruleus (LC) and Barrington's nucleus (BRN) amongst others form the neural circuitry(s) that coordinates arousal and voiding behaviors. However, little is known about the synaptic connectivity of neurons within or across these nuclei. These include corticotropin-releasing factor (CRF + ) expressing neurons in the BRN that control bladder contraction and somatostatin expressing (SST + ) neurons whose role in this region has not been discerned. To determine the synaptic connectivity of these neurons, we employed optogenetic stimulation with recordings from BRN and LC neurons in brain stem slices of channelrhodopsin-2 expressing SST or CRF neurons. Optogenetic stimulation of CRF + BRN neurons of Crf Cre ;chr2-yfp mice had little effect on either CRF + BRN neurons, CRF - BRN neurons, or LC neurons. In contrast, in Sst Cre ;chr2-yfp mice light-activated inhibitory postsynaptic currents (IPSCs) were reliably observed in a majority of LC but not BRN neurons. The GABA A receptor antagonist, bicuculline, completely abolished the light-induced IPSCs. To ascertain if these neurons were part of the neural circuitry that controls the bladder, the trans- synaptic tracer, pseudorabies virus (PRV) was injected into the bladder wall of Crf Cre ;tdTomato or Sst Cre ;tdTomato mice. At 68-72 h post-viral infection, PRV labeled neurons were present only in the BRN, being preponderant in CRF + neurons with few SST + BRN neurons labeled from the bladder. At 76 and 96 h post-virus injection, increased labeling was observed in both BRN and LC neurons. Our results suggest SST + neurons rather than CRF + neurons in BRN can regulate the activity of LC neurons., 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 © 2021 Garcia DuBar, Cosio, Korthas, Van Batavia, Zderic, Sahibzada, Valentino and Vicini.)

Background: Chylothorax is a rare disease, defined as an abnormal accumulation of chylous lymphatic effusion in thoracic cavity, with a high mortality rate in pediatric patients. At present, there are few studies on the treatment of pediatric chylothorax, and conservative treatments like somatostatin (SST) and pleurodesis are performed empirically. SST has been used for treating pediatric chylothorax over 20 years, and povidone-iodine chemical pleurodesis (PICP) is adopted in recent years with a high cure rate, but both the effect are still uncertain. The safety and efficacy of SST and PICP in treating pediatric chylothorax was compared in this study., Methods: From January 2009 to May 2020, 27 pediatric chylothorax patients who accepted life support, SST and PICP treatment were retrospectively reviewed in this study. Their medical history, clinical manifestations, pleural effusion examinations, treatment methods, effects, and complications were screened. PICP and SST was performed in 19 and 8 children, respectively. Each patient was followed up after discharge from the hospital., Results: After admission, chest X-ray and ultrasound diagnosed pleural effusion in 27 patients (18 males and 9 females), including 13 and 6 cases on the left and right side, and 8 cases on both sides. In the pleural effusion, the mean leukocyte count was (9,826±9,482)×10 6 /L, the mean lymphocyte ratio was (84.82±6.58)%, the mean triglyceride content was 7.11±6.63 mmol/L. In PICP and SST group, the mean length of stay was 38.42±19.42 and 35.13±12.72 d (P=0.664), the mean time of thoracic drainage was 24.58±16.34 and 19.63±8.88 d (P=0.440), the mean time of parenteral nutrition was 27.16±18.29 and 25.25±13.52 d (P=0.793), respectively. PICP was performed for 3.16±2.27 times, and SST was used for 14.75±9.08 d with the dosage of 0.5 to 10 µg/kg/hour. After the treatment, all patients in PICP group had mild chest pain and low-grade fever, and 12 cases were observed with transient decrease of oxygen saturation. Eight patients in SST group had nausea and vomit, and 1 child had diarrhea simultaneously. Both were cured by symptomatic treatment, thoracic drainage and discontinuing using SST. Three children were diagnosed with refractory chylothorax and cured by PICP after SST. Pleural effusion in 27 patients was finally absorbed. All of them achieved a clinical cure successfully, and there was no recurrence during discharge follow-up., Conclusions: PICP has a high success rate and few adverse reactions in treating spontaneous chylothorax in pediatric patients, expected to be a new treatment option for pediatric chylothorax after SST., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/tp-20-199). The authors have no conflicts of interest to declare., (2020 Translational Pediatrics. All rights reserved.)