Apoptosis - the regulated destruction of a cell - is a complicated process. The decision to die cannot be taken lightly, and the activity of many genes influence a cell's likelihood of activating its self-destruction programme. Once the decision is taken, proper execution of the apoptotic programme requires the coordinated activation and execution of multiple subprogrammes. Here I review the basic components of the death machinery, describe how they interact to regulate apoptosis in a coordinated manner, and discuss the main pathways that are used to activate cell death.

The biochemistry of apoptosis

The programmed cell death that occurs as part of normal mammalian development was first observed nearly a century ago (Collin 1906). It has since been established that approximately half of all neurons in the neuroaxis and >99.9% of the total number of cells generated during the course of a human lifetime go on to die through a process of apoptosis (for review, see Datta and Greenberg 1998; Vaux and Korsmeyer 1999). The induction of developmental cell death is a highly regulated process and can be suppressed by a variety of extracellular stimuli. The purification in the 1950s of the nerve growth factor (NGF), which promotes the survival of sympathetic neurons, set the stage for the discovery that peptide trophic factors promote the survival of a wide variety of cell types in vitro and in vivo (Levi-Montalcini 1987). The profound biological consequences of growth factor (GF) suppression of apoptosis are exemplified by the critical role of target-derived neurotrophins in the survival of neurons and the maintenance of functional neuronal circuits. (Pettmann and Henderson 1998). Recently, the ability of trophic factors to promote survival have been attributed, at least in part, to the phosphatidylinositide 38-OH kinase (PI3K)/c-Akt kinase cascade. Several targets of the PI3K/c-Akt signaling pathway have been recently identified that may underlie the ability of this regulatory cascade to promote survival. These substrates include two components of the intrinsic cell death machinery, BAD and caspase 9, transcription factors of the forkhead family, and a kinase, IKK, that regulates the NF-kB transcription factor. This article reviews the mechanisms by which survival factors regulate the PI3K/c-Akt cascade, the evidence that activation of the PI3K/c-Akt pathway promotes cell survival, and the current spectrum of c-Akt targets and their roles in mediating c-Akt-dependent cell survival.

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Cellular survival: a play in three Akts

In many instances, permeabilization of mitochondrial membranes is a rate-limiting step of apoptotic or necrotic cell demise. This has important consequences for the pathophysiology of cell death, as well as for its pharmacological control.

Mitochondrial control of cell death

Apoptosis is a physiological cell suicide program that is critical for the development and maintenance of healthy tissues. Dysregulation of cell death pathways occur in cancer, autoimmune and immunodeficiency diseases, reperfusion injury after ischemic episodes, and in neurodegenerative disorders. Thus, proteins involved in apoptosis regulation are of intense biological interest and many are attractive therapeutic targets. This review discusses the Inhibitor of Apoptosis (IAP) family of proteins. First discovered in baculoviruses, IAPs were shown to be involved in suppressing the host cell death response to viral infection. Interestingly, ectopic expression of some baculoviral IAPs blocks apoptosis in mammalian cells, suggesting conservation of the cell death program among diverse species and commonalities in the mechanism used by the IAPs to inhibit apoptosis. Although the mechanism used by the IAPs to suppress cell death remains debated, several studies have provided insights into the biochemical functions of these intriguing proteins. Moreover, a variety of reports have suggested an important role for the IAPs in some human diseases.

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IAP family proteins—suppressors of apoptosis

Neuronal death underlies the symptoms of many human neurological disorders, including Alzheimer's, Parkinson's and Huntington's diseases, stroke, and amyotrophic lateral sclerosis. The identification of specific genetic and environmental factors responsible for these diseases has bolstered evidence for a shared pathway of neuronal death--apoptosis--involving oxidative stress, perturbed calcium homeostasis, mitochondrial dysfunction and activation of cysteine proteases called caspases. These death cascades are counteracted by survival signals, which suppress oxyradicals and stabilize calcium homeostasis and mitochondrial function. With the identification of mechanisms that either promote or prevent neuronal apoptosis come new approaches for preventing and treating neurodegenerative disorders.

Apoptosis in neurodegenerative disorders

Mitochondria and apoptosis

Autophagy-Sirtuin1(SIRT1) Alleviated the Coronary Atherosclerosis (AS) in Mice through Regulating the Proliferation and Migration of Endothelial Progenitor Cells (EPCs) via wnt/β-catenin/GSK3β Signaling Pathway

Scope: Antioxidants, including vitamin E (VE) and grape seed extract, as anti-aging supplementation have been widely used to improve human health. However, the role of gut microbiota in dietary antioxidant supplementation is debatable. This study aimed to assess the longitudinal impact of dietary supplementation with antioxidant compounds on body health and the gut microbiota. Methods and results: One hundred and twenty healthy individuals were randomly divided into a placebo group (amylodextrin) and three experimental groups ingesting different supplement (VE, grape seed extract, or mixed berry juice). Blood and fecal samples were collected during three intervention phases. We found that VE and mixed berry juice ameliorated blood cholesterol levels by reducing the levels of low-density lipoprotein cholesterol (LDL-C) in healthy volunteers. After the intervention, there was an increase in the relative abundance of short-chain fatty acid (SCFA)-producing bacteria and bile acid metabolizers. Specifically, the abundances of Lachnospira sp. and Faecalibacterium spp. increased in the VE and berry juice groups. Interestingly, the gut microbiota of poor responders harbored a greater proportion of disease-associated bacterial species. Conclusion: Juice and VE could promote health by lowering LDL-C, partly and indirectly by affecting gut bacteria with the ability to produce SCFAs or metabolize bile acids.

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Supplementation with Berry Juice and Vitamin E Ameliorates Blood Cholesterol Level and Alters Gut Microbiota Composition

Objective: To evaluate the interventional effects of music therapy on pain and anxiety of burn patients in wound dressing change. Methods: The meta-analysis method was adopted. Databases including China National Knowledge Internet, Wanfang Database, and VIP database were retrieved with the search terms in Chinese version of ", , /, /", and PubMed, Embase, and Cochrane Library were retrieved with the search terms in English version of "music, burn, dressing change/wound dressing, pain/ache/sore" to obtain the publicly published randomized controlled trials on the application of music therapy for wound dressing change in burn patients from the establishment of each database to May 2021. The outcome indexes included pain score/percentage and anxiety score after dressing change. Rev Man 5.4 and Stata 14.0 statistical software were used to conduct a meta-analysis of eligible studies. Results: A total of 520 burn patients from 7 studies were included, including 260 patients in music therapy group who received music therapy and 260 patients in routine dressing change group who received routine dressing change. The bias risk of all the 7 included studies was uncertain. Compared with those in routine dressing change group, the pain percentages (relative risk=0.06, 95% confidence interval=0.01-0.41, P<0.01) and pain scores after dressing change (standardized mean difference (SMD)=-0.91, 95% confidence interval=-1.61--0.22, P<0.05) of patients in music therapy group were significantly lower. Subgroup analysis showed that music type and timing of intervention might be the source of heterogeneity in pain scores after dressing change. The anxiety scores of patients in music therapy group were significantly lower than those in routine dressing change group (SMD=-0.64, 95% confidence interval=-1.09--0.19, P<0.01). There was no publication bias in pain or anxiety scores after dressing change. Conclusions: Music therapy can relieve the pain and anxiety of burn patients during dressing change.

Z Li

Papers

Mitochondria and apoptosis

Autophagy-Sirtuin1(SIRT1) Alleviated the Coronary Atherosclerosis (AS) in Mice through Regulating the Proliferation and Migration of Endothelial Progenitor Cells (EPCs) via wnt/β-catenin/GSK3β Signaling Pathway

Supplementation with Berry Juice and Vitamin E Ameliorates Blood Cholesterol Level and Alters Gut Microbiota Composition

[Meta-analysis of the interventional effects of music therapy on pain and anxiety of burn patients in wound dressing change].

Healthcare Utilization in Childhood Interstitial Lung Disease: A Report From a Major Tertiary Care Center