Multiple members of the mitogen-activated protein kinase family are necessary for PED/PEA-15 anti-apoptotic function.

293 kidney embryonic cells feature very low levels of the anti-apoptotic protein PED. In these cells, expression of PED to levels comparable with those occurring in normal adult cells inhibits apoptosis induced by growth factor deprivation and by exposure to H(2)O(2) or anisomycin. In PED-expressing 293 cells (293(PED)), inhibition of apoptosis upon growth factor deprivation was paralleled by decreased phosphorylation of JNK1/2. In 293(PED) cells, decreased apoptosis induced by anisomycin and H(2)O(2) was also accompanied by block of JNK1/2 and p38 phosphorylations, respectively. Impaired activity of these stress kinases by PED correlated with inhibition of stress-induced Cdc-42, MKK4, and MKK6 activation. At variance with JNK1/2 and p38, PED expression increased basal and growth factor-stimulated Ras-Raf-1 co-precipitation and MAPK phosphorylation and activity. Treatment of 293(PED) cells with the MEK inhibitor PD98059 blocked ERK1/2 phosphorylations with no effect on inhibition of JNK1/2 and p38 activities. Complete rescue of JNK and p38 functions in 293(PED) cells by overexpressing JNK1 or p38, respectively, enabled only partial recovery of apoptotic response to growth factor deprivation and anisomycin. However, simultaneous rescue of JNK and p38 activities accompanied by block of ERK1/2 fully restored these responses. Thus, PED controls activity of the ERK, JNK, and p38 subfamilies of MAPKs. PED anti-apoptotic function in the 293 cells requires PED simultaneous activation of ERK1/2 and inhibition of the JNK/p38 signaling systems by PED

Clinical Features, Cardiovascular Risk Profile, and Therapeutic Trajectories of Patients with Type 2 Diabetes Candidate for Oral Semaglutide Therapy in the Italian Specialist Care

Introduction: This study aimed to address therapeutic inertia in the management of type 2 diabetes (T2D) by investigating the potential of early treatment with oral semaglutide. Methods: A cross-sectional survey was conducted between October 2021 and April 2022 among specialists treating individuals with T2D. A scientific committee designed a data collection form covering demographics, cardiovascular risk, glucose control metrics, ongoing therapies, and physician judgments on treatment appropriateness. Participants completed anonymous patient questionnaires reflecting routine clinical encounters. The preferred therapeutic regimen for each patient was also identified. Results: The analysis was conducted on 4449 patients initiating oral semaglutide. The population had a relatively short disease duration (42%  60% of patients, and more often than sitagliptin or empagliflozin. Conclusion: The study supports the potential of early implementation of oral semaglutide as a strategy to overcome therapeutic inertia and enhance T2D management

Lung Fibrosis in Carcinoid Syndrome

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Treatment of a pituitary metastasis from a neuroendocrine tumour: Case report and literature review

Herein we report a rare case of a pituitary metastasis from a neuroendocrine tumour mimicking an adenoma. Moreover, starting from this unusual case, the relevant literature concerning the diagnosis and management of patients with metastasis at pituitary level is reviewed. A 69-year-old woman was admitted to our Unit for severe headache, diplopia, and critical visual field impairment. MRI showed a large pituitary mass compressing the optic chiasm and infiltrating the cavernous sinus. Trans-sphenoidal biopsy revealed a pituitary metastasis from a neuroendocrine tumour, in line with the multiple liver lesions that were already considered metastases from an ileal primary neuroendocrine tumour. In vitro receptor characterisation of both pituitary and liver tissues by immunohistochemistry showed a heterogeneous somatostatin receptor subtype pattern, with a predominant expression of sst2 within the pituitary lesion. However, the liver metastasis receptor profile was completely different from the pituitary. Octreotide LAR was administered first, followed by receptor radiometabolic therapy with radiolabelled somatostatin analogues (90Y-DOTATOC and 177Lu-DOTATATE). After 16 months, MRI showed a significant shrinkage of the sellar mass. Moreover, disappearance of diplopia and visual defects, together with a considerable improvement in quality of life were gradually recorded. To our knowledge, this is the first case of combined treatment using 'cold' and radiolabelled octreotide in a pituitary metastasis from a neuroendocrine tumour. © Springer Science+Business Media, LLC 2007

Treatment of a pituitary metastasis from a neuroendocrine tumour: Case report and literature review

Herein we report a rare case of a pituitary metastasis from a neuroendocrine tumour mimicking an adenoma. Moreover, starting from this unusual case, the relevant literature concerning the diagnosis and management of patients with metastasis at pituitary level is reviewed. A 69-year-old woman was admitted to our Unit for severe headache, diplopia, and critical visual field impairment. MRI showed a large pituitary mass compressing the optic chiasm and infiltrating the cavernous sinus. Trans-sphenoidal biopsy revealed a pituitary metastasis from a neuroendocrine tumour, in line with the multiple liver lesions that were already considered metastases from an ileal primary neuroendocrine tumour. In vitro receptor characterisation of both pituitary and liver tissues by immunohistochemistry showed a heterogeneous somatostatin receptor subtype pattern, with a predominant expression of sst2 within the pituitary lesion. However, the liver metastasis receptor profile was completely different from the pituitary. Octreotide LAR was administered first, followed by receptor radiometabolic therapy with radiolabelled somatostatin analogues (90Y-DOTATOC and 177Lu-DOTATATE). After 16 months, MRI showed a significant shrinkage of the sellar mass. Moreover, disappearance of diplopia and visual defects, together with a considerable improvement in quality of life were gradually recorded. To our knowledge, this is the first case of combined treatment using 'cold' and radiolabelled octreotide in a pituitary metastasis from a neuroendocrine tumour. © Springer Science+Business Media, LLC 2007

Uncoupling Protein 3 (UCP3) Modulates the Activity of Sarco/Endoplasmic Reticulum Ca2+-ATPase (SERCA) by Decreasing Mitochondrial ATP Production*

The uncoupling proteins UCP2 and UCP3 have been postulated to catalyze Ca2+ entry across the inner membrane of mitochondria, but this proposal is disputed, and other, unrelated proteins have since been identified as the mitochondrial Ca2+ uniporter. To clarify the role of UCPs in mitochondrial Ca2+ handling, we down-regulated the expression of the only uncoupling protein of HeLa cells, UCP3, and measured Ca2+ and ATP levels in the cytosol and in organelles with genetically encoded probes. UCP3 silencing did not alter mitochondrial Ca2+ uptake in permeabilized cells. In intact cells, however, UCP3 depletion increased mitochondrial ATP production and strongly reduced the cytosolic and mitochondrial Ca2+ elevations evoked by histamine. The reduced Ca2+ elevations were due to inhibition of store-operated Ca2+ entry and reduced depletion of endoplasmic reticulum (ER) Ca2+ stores. UCP3 depletion accelerated the ER Ca2+ refilling kinetics, indicating that the activity of sarco/endoplasmic reticulum Ca2+ (SERCA) pumps was increased. Accordingly, SERCA inhibitors reversed the effects of UCP3 depletion on cytosolic, ER, and mitochondrial Ca2+ responses. Our results indicate that UCP3 is not a mitochondrial Ca2+ uniporter and that it instead negatively modulates the activity of SERCA by limiting mitochondrial ATP production. The effects of UCP3 on mitochondrial Ca2+ thus reflect metabolic alterations that impact on cellular Ca2+ homeostasis. The sensitivity of SERCA to mitochondrial ATP production suggests that mitochondria control the local ATP availability at ER Ca2+ uptake and release sites

Uncoupling Protein 3 (UCP3) Modulates the Activity of Sarco/Endoplasmic Reticulum Ca2+-ATPase (SERCA) by Decreasing Mitochondrial ATP Production*

The uncoupling proteins UCP2 and UCP3 have been postulated to catalyze Ca2+ entry across the inner membrane of mitochondria, but this proposal is disputed, and other, unrelated proteins have since been identified as the mitochondrial Ca2+ uniporter. To clarify the role of UCPs in mitochondrial Ca2+ handling, we down-regulated the expression of the only uncoupling protein of HeLa cells, UCP3, and measured Ca2+ and ATP levels in the cytosol and in organelles with genetically encoded probes. UCP3 silencing did not alter mitochondrial Ca2+ uptake in permeabilized cells. In intact cells, however, UCP3 depletion increased mitochondrial ATP production and strongly reduced the cytosolic and mitochondrial Ca2+ elevations evoked by histamine. The reduced Ca2+ elevations were due to inhibition of store-operated Ca2+ entry and reduced depletion of endoplasmic reticulum (ER) Ca2+ stores. UCP3 depletion accelerated the ER Ca2+ refilling kinetics, indicating that the activity of sarco/endoplasmic reticulum Ca2+ (SERCA) pumps was increased. Accordingly, SERCA inhibitors reversed the effects of UCP3 depletion on cytosolic, ER, and mitochondrial Ca2+ responses. Our results indicate that UCP3 is not a mitochondrial Ca2+ uniporter and that it instead negatively modulates the activity of SERCA by limiting mitochondrial ATP production. The effects of UCP3 on mitochondrial Ca2+ thus reflect metabolic alterations that impact on cellular Ca2+ homeostasis. The sensitivity of SERCA to mitochondrial ATP production suggests that mitochondria control the local ATP availability at ER Ca2+ uptake and release sites