https://pubs.rsc.org/en/content/articlepdf/2019/NP/C8NP00092A

Marine natural products.

■ Abstract Apoptosis is a genetically programmed, morphologically distinct form of cell death that can be triggered by a variety of physiological and pathological stimuli. Studies performed over the past 10 years have demonstrated that proteases play critical roles in initiation and execution of this process. The caspases, a family of cysteine-dependent aspartate-directed proteases, are prominent among the death proteases. Caspases are synthesized as relatively inactive zymogens that become activated by scaffold-mediated transactivation or by cleavage via upstream proteases in an intracellular cascade. Regulation of caspase activation and activity occurs at several different levels: ( a) Zymogen gene transcription is regulated; ( b) antiapoptotic members of the Bcl-2 family and other cellular polypeptides block proximity-induced activation of certain procaspases; and ( c) certain cellular inhibitor of apoptosis proteins (cIAPs) can bind to and inhibit active caspases. Once activated, caspases cleave a variety of intracellular polypeptides, including major structural elements of the cytoplasm and nucleus, components of the DNA repair machinery, and a number of protein kinases. Collectively, these scissions disrupt survival pathways and disassemble important architectural components of the cell, contributing to the stereotypic morphological and biochemical changes that characterize apoptotic cell death.

Mammalian caspases: structure ,a ctivation ,s ubstrates, and functions during apoptosis

ContextGuidelines advise that all adults undergo coronary heart disease (CHD)
risk assessment to guide preventive treatment intensity. Although the Framingham
Risk Score (FRS) is often recommended for this, it has been suggested that
risk assessment may be improved by additional tests such as coronary artery
calcium scoring (CACS).ObjectivesTo determine whether CACS assessment combined with FRS in asymptomatic
adults provides prognostic information superior to either method alone and
whether the combined approach can more accurately guide primary preventive
strategies in patients with CHD risk factors.Design, Setting, and ParticipantsProspective observational population-based study, of 1461 asymptomatic
adults with coronary risk factors. Participants with at least 1 coronary risk
factor (>45 years) underwent computed tomography (CT) examination, were screened
between 1990-1992, were contacted yearly for up to 8.5 years after CT scan,
and were assessed for CHD. This analysis included 1312 participants with CACS
results; excluded were 269 participants with diabetes and 14 participants
with either missing data or had a coronary event before CACS was performed.Main Outcome MeasureNonfatal myocardial infarction (MI) or CHD death.ResultsDuring a median of 7.0 years of follow-up, 84 patients experienced MI
or CHD death; 70 patients died of any cause. There were 291 (28%) participants
with an FRS of more than 20% and 221 (21%) with a CACS of more than 300. Compared
with an FRS of less than 10%, an FRS of more than 20% predicted the risk of
MI or CHD death (hazard ratio [HR], 14.3; 95% confidence interval [CI]; 2.0-104; P = .009). Compared with a CACS of zero, a CACS of more
than 300 was predictive (HR, 3.9; 95% CI, 2.1-7.3; P<.001).
Across categories of FRS, CACS was predictive of risk among patients with
an FRS higher than 10% (P<.001) but not with an
FRS less than 10%.ConclusionThese data support the hypothesis that high CACS can modify predicted
risk obtained from FRS alone, especially among patients in the intermediate-risk
category in whom clinical decision making is most uncertain.

http://www.canadadiagnostic.com/wp-content/uploads/2015/02/11_CACS-Framingham.pdf

Coronary artery calcium score combined with Framingham score for risk prediction in asymptomatic individuals

The protein kinase B/Akt signalling pathway in human malignancy.

Calcium ions are ubiquitous and versatile signaling molecules, capable of decoding a variety of extracellular stimuli (hormones, neurotransmitters, growth factors, etc.) into markedly different int...

https://www.physiology.org/doi/pdf/10.1152/physrev.00004.2005

Microdomains of intracellular Ca2+: molecular determinants and functional consequences.

The immediate early gene NUR77 (also called NGFI-B) is required for T cell antigen receptor-mediated cell death and is induced to very high levels in immature thymocytes and T cell hybridomas undergoing apoptosis. The Akt (PKB) kinase is a key player in transduction of anti-apoptotic and proliferative signals in T cells. Because Nur77 has a putative Akt phosphorylation site at Ser-350, and phosphorylation of this residue is critical for the transactivation activity of Nur77, we investigated whether Akt regulates Nur77. Coimmunoprecipitation experiments showed the detection of Nur77 in Akt immune complexes, suggesting that Nur77 and Akt physically interact. We further show that Akt specifically phosphorylates Ser-350 of the Nur77 protein within its DNA-binding domain in vitro and in vivo in 293 and NIH 3T3 cells. Because phosphorylation of Ser-350 of Nur77 is critical for its function as a transcription factor, we examined the effect of Akt on this function. By using luciferase assay experiments, we showed that phosphorylation of Nur77 by Akt decreased the transcriptional activity of Nur77 by 50--85%. Thus, we show that Akt interacts with Nur77 and inactivates Nur77 by phosphorylation at Ser-350 in a phosphatidylinositol 3-kinase-dependent manner, connecting the phosphatidylinositol 3-kinase-dependent Akt pathway and a nuclear receptor pathway.

https://www.pnas.org/content/pnas/98/7/3690.full.pdf

Akt phosphorylates and regulates the orphan nuclear receptor Nur77

Structures of aplysin and aplysinol, naturally occurring bromo-compounds

The phosphorylation and DNA binding of the DNA-binding domain of the orphan nuclear receptor NGFI-B.

Manganese-induced apoptosis in PC12 cells.

N-Propargyl-1 (R)-aminoindan, rasagiline, increases glial cell line-derived neurotrophic factor (GDNF) in neuroblastoma SH-SY5Y cells through activation of NF-κB transcription factor

Yoko Hirata

Papers

Akt phosphorylates and regulates the orphan nuclear receptor Nur77

Structures of aplysin and aplysinol, naturally occurring bromo-compounds

The phosphorylation and DNA binding of the DNA-binding domain of the orphan nuclear receptor NGFI-B.

Manganese-induced apoptosis in PC12 cells.

N-Propargyl-1 (R)-aminoindan, rasagiline, increases glial cell line-derived neurotrophic factor (GDNF) in neuroblastoma SH-SY5Y cells through activation of NF-κB transcription factor