Breast cancer is the most commonly diagnosed cancer and a leading cause of cancer-related death among women worldwide. Somatostatin (SST) and Cannabinoids have an anti-proliferative and pro-apoptotic ...effect, but the mechanisms of their actions remain elusive. In the present study, we have evaluated the effects of SST, Cannabidiol (CBD) alone or in combination on receptor expression, cell proliferation and apoptosis and related downstream signalling pathways in MDA-MB-231 and MCF-7 breast cancer cells. The results presented here demonstrate the cell type and agonist-dependent changes in receptor expression at the cell membrane, inhibition of cell proliferation and increased apoptosis following treatment with SST and CBD alone and in combination. In comparison to MDA-MB-231 cells, MCF-7 cells treated with SST alone and in combination with CBD exhibited inhibition of phosphorylated Protein Kinase B (pAKT) and phosphorylated-Phosphoinositide 3-Kinase (pPI3K) expression. Importantly, inhibition of PI3K/AKT activation was accompanied by enhanced PTEN expression in MCF-7 cells. These results highlight the possible interaction between SSTR and CBR subtypes with the implication in the modulation of receptor expression, cell viability and signal transduction pathways in a breast cancer cell type-dependent manner.
•Breast cancer is the leading cause of cancer-related death among women worldwide.•Somatostatin and Cannabinoids displayed an anti-proliferative and pro-apoptotic effect in the cancer cell lines.•SST with or without CBD exhibited inhibition of signalling pathways associated with cell proliferation.•Our results indicate the possibility of SSTRs and CBRs crosstalk as novel therapeutic target in breast cancer treatment.
Somatostatin (SST) is a growth hormone inhibitory peptide involved in regulation of several physiological responses of cells including neurotransmission, cell migration, maturation, and neurite ...formation. In the present study, we examined the role of SST in
all-trans
retinoic acid (RA)–induced progression of neurite outgrowth in SH-SY5Y cells. We also determined the morphological and developmental changes in prominent intracellular markers of neurite growth including microtubule-associated protein 2 (MAP2), neuron-specific III β-tubulin (TUJ1), and Tau. Here, we present evidence that SST is a molecular determinant in regulating the transition of SH-SY5Y cells from non-neuronal entity to neuronal phenotype in response to RA. The results from present study reveal that SST changes the distributional pattern of MAP2/Tau and TUJ1, and activates extracellular signal–regulated kinase (ERK1/2) signaling pathway through SST receptors (SSTRs). The expression of MAP2 and Tau remains elevated upon treatment with RA and SST alone or in combination. Importantly, we identified that the cells displaying strong co-expression of SST and TUJ1 are more likely to bear elongated neurite formation than cells devoid of such expression. These findings show that the site-specific expression of MAP2 and TUJ1 is an essential determinant of neurite outgrowth in SH-SY5Y cells in RA-mediated differentiation. Taken together, results presented here further substantiates the role of SST in the promotion of neurite formation and elongation in SH-SY5Y cells in combination with RA. Investigating how SST can improve neurite formation in neurodegenerative disease may help to develop new therapeutic approach in improving cognitive function and memory loss.
Glaucoma is characterized by progressive damage of the retinal ganglion cells (RGCs), resulting in irreversible vision loss. Cannabinoids (CBs) ameliorate several factors that contribute to the ...progression of glaucoma, including increased intraocular pressure (IOP), degeneration of RGC and optical nerve (ON) damage. However, a direct correlation of specific CBs with the molecular events pertaining to glaucoma pathology is not well established. Therefore, this study aims to evaluate the role of cannabinol (CBN) on RGC protection, modulation of IOP, and its effects on the level of extracellular matrix (ECM) proteins using both in vitro and in vivo models of glaucoma.
When exposed to elevated hydrostatic pressure, CBN, in a dose-dependent manner, protected differentiated mouse 661W retinal ganglion precursor-like cells from pressure-induced toxicity. In human trabecular meshwork cells (hTM), CBN attenuated changes in the ECM proteins, including fibronectin and α-smooth muscle actin (α-SMA), as well as mitogen-activated protein kinases (phospho-ERK1/2) in the presence or absence of transforming growth factor-beta 2 (TGF-β2) induced stress. Ocular pharmacokinetic parameters were evaluated post-intravitreal (IVT) CBN delivery in vivo. Furthermore, we demonstrated that IVT-administered CBN improved pattern electroretinogram (pERG) amplitudes and reduced IOP in a rat episcleral vein laser photocoagulation model of glaucoma.
CBN promotes neuroprotection, abrogates changes in ECM protein, and normalizes the IOP levels in the eye. Therefore, our observations in the present study indicate a therapeutic potential for CBN in the treatment of glaucoma.
•The role of CBN in glaucoma pathology was evaluated using in vitro and in vivo experimental models.•CBN promotes 661W cell survival and abrogates changes in ECM protein expression in hTM cells.•CBN lowers IOP and normalizes pERG in rat episcleral vein laser photocoagulation glaucoma model.•These results suggest CBN as a potential therapeutic intervention for patients with glaucoma.
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.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Highlights • SSTR5 and CB1R exist as constitutive heterodimers in rat brain regions and cotransfected HEK-293 cells. • Concurrent receptor activation leads to preferential disruption of SSTR5/CB1R ...heterodimer and formation of SSTR5 homodimer. • SSTR5 plays the major role in the regulation of cAMP/PKA/ERK1/2 signaling pathways in cotransfected cells. • Time course of PI3K phosphorylation is altered upon concurrent receptor activation.
In Alzheimer’s disease (AD), the impaired clearance of β-amyloid peptide (Aβ) due to disrupted tight junction and transporter proteins is the prominent cause of disease progression. Somatostatin ...(SST) blocks the aggregation of Aβ and inflammation whereas reduction of SST levels in the CSF and brain tissue is associated with impaired cognitive function and memory loss. However, the role of SST in preservation of blood-brain barrier (BBB) integrity and functionality in Aβ-induced toxicity is not known. In the present study using human CMEC/D3 cells, we demonstrate that SST prevents Aβ-induced BBB permeability by regulating LRP1 and RAGE expression and improving the disrupted tight junction proteins. Furthermore, SST abrogates Aβ-induced JNK phosphorylation and expression of MMP2. Taken together, results presented here suggest that SST might serve as a therapeutic intervention in AD via targeting multiple pathways responsible for neurotoxicity, impaired BBB function, and disease progression.
A chemically diverse family of small-molecule signals, the ascarosides, control developmental diapause (dauer), olfactory learning, and social behaviors of the nematode model organism, Caenorhabditis ...elegans . The ascarosides act upstream of conserved signaling pathways, including the insulin, TGF-β, serotonin, and guanylyl cyclase pathways; however, the sensory processes underlying ascaroside function are poorly understood. Because ascarosides often are multifunctional and show strongly synergistic effects, characterization of their receptors will be essential for understanding ascaroside biology and may provide insight into molecular mechanisms that produce synergistic outcomes in small-molecule sensing. Based on DAF-8 immunoprecipitation, we here identify two G-protein–coupled receptors, DAF-37 and DAF-38, which cooperatively mediate ascaroside perception. daf-37 mutants are defective in all responses to ascr#2, one of the most potent dauer-inducing ascarosides, although this mutant responds normally to other ascarosides. In contrast, daf-38 mutants are partially defective in responses to several different ascarosides. Through cell-specific overexpression, we show that DAF-37 regulates dauer when expressed in ASI neurons and adult behavior when expressed in ASK neurons. Using a photoaffinity-labeled ascr#2 probe and amplified luminescence assays (AlphaScreen), we demonstrate that ascr#2 binds to DAF-37. Photobleaching fluorescent energy transfer assays revealed that DAF-37 and DAF-38 form heterodimers, and we show that heterodimerization strongly increases cAMP inhibition in response to ascr#2. These results suggest that that the ascarosides' intricate signaling properties result in part from the interaction of highly structure-specific G-protein–coupled receptors such as DAF-37 with more promiscuous G-protein–coupled receptors such as DAF-38.
•GABAC ρ3 expression decreases in the cortex, striatum and hippocampus of HD tg mouse brain.•Loss of GABAc ρ3 receptor immunoreactivity may account for diminished inhibitory input and ...neurodegeneration in HD.•Activation of GABARs and inhibition of glutamatergic pathway might protect neuronal loss in HD.
In the present study, we describe the distribution of GABAC ρ3 receptor immunoreactivity in the cortex, striatum and hippocampus of wild type (wt) and 11 weeks old HD transgenic (tg) R6/2 mouse brain. In the brain of wt mice, GABAC ρ3 immunoreactivity is well expressed in neuronal cells, nerve fibers and axonal processes. In comparison to wt, GABAC ρ3 receptor like immunoreactivity decreases significantly in all three brain regions of R6/2 mice. The altered distributional pattern and significant changes in GABAC ρ3 receptor immunoreactivity as seen in the R6/2 mouse brain might be a plausible molecular mechanism for excitotoxicity in HD pathogenesis due to the loss of inhibitory input.
Molecular iodine has been used as an efficient catalyst for an improved and rapid one-pot synthesis of 2,4,5-trisubstituted and 1,2,4,5-tetrasubstituted imidazoles in excellent yields. The ...significant features of the iodine-catalyzed condensation are operational simplicity, inexpensive reagents, high yield of products and the use of non-toxic reagents.
▪
Molecular iodine has been used an efficient catalyst for an improved and rapid one-pot synthesis of 2,4,5-trisubstituted and 1,2,4,5-tetra substituted imidazoles in excellent yields. The significant features of the iodine-catalyzed condensation are operational simplicity, inexpensive reagents, high yield of products and the use of non-toxic reagents.
Purpose
Propylthiouracil (PTU)-induced hypothyroidism is a well-established model for assessing hormonal and morphological changes in thyroid as well as other central and peripheral tissues. ...Somatostatin (SST) is known to regulate hormonal secretion and synthesis in endocrine tissues; however, nothing is currently known about the distribution of SST and its receptor in hypothyroidism.
Method
In the present study, the comparative immunohistochemical distribution of SST and somatostatin receptors (SSTRs) were analyzed in PTU-induced hypothyroid rats. Rats were treated with PTU for 15 days followed by a co-administration of levothyroxine (LVT) for 15 days. After PTU and LVT treatments (day 30), rats were further administered LVT alone for 15 more days (day 45). The subcellular distribution of SST and SSTR subtypes was determined by peroxidase immunohistochemistry in the thyroid gland collected from control and treated rats.
Results
SST and SSTR subtypes were found to be moderately expressed in control thyroid tissues. SST and SSTR subtypes like immunoreactivity increased significantly in follicular and parafollicular epithelial cells in the thyroid of PTU-treated rats. The PTU-induced changes in the expression of SST and SSTR subtypes were suppressed by the administration of the LVT. In addition to thyroid tissues, SST and SSTRs expression was also changed in non-follicular tissues including blood vessels, smooth muscle cells, and connective tissue following treatments.
Conclusion
The present study revealed a distinct subcellular distribution of SST and SSTR subtypes in the thyroid and provides a new insight for the role of SST and SSTR subtypes in hypothyroidism in addition to its well-established role in negative regulation of hormonal secretion.
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