bims-nadaut 2023-08-13 papers

bims-nadaut

Biomed News

on NAD and autophagy

Issue of 2023‒08‒13
six papers selected by
Niall Wilson
Newcastle University

Targeting SARM1 improves autophagic stress-induced axonal neuropathy.
Design, synthesis, and biological evaluation of a series of benzofuran[3,2-d]pyrimidine-4(3H)-one derivatives containing thiosemicarbazone analogs as novel PARP-1 inhibitors.
Salvianolic acid B ameliorates neuroinflammation and neuronal injury via blocking NLRP3 inflammasome and promoting SIRT1 in experimental subarachnoid hemorrhage.
Clock genes regulate skeletal muscle energy metabolism through NAMPT/NAD+/SIRT1 following heavy-load exercise.
Salidroside ameliorates acetaminophen-induced acute liver injury through the inhibition of endoplasmic reticulum stress-mediated ferroptosis by activating the AMPK/SIRT1 pathway.
Parkinson's disease neurons exhibit alterations in mitochondrial quality control proteins.

Autophagy. 2023 Aug 10.

Targeting SARM1 improves autophagic stress-induced axonal neuropathy.

Hye Ran Kim, Hye Jin Lee, Yewon Jeon, So Young Jang, Yoon Kyoung Shin, Jean Ho Yun, Hye Ji Park, Hyongjong Koh, Kyung Eun Lee, Jung Eun Shin, Hwan Tae Park.

  Macroautophagy/autophagy, a lysosome-dependent self-degradative process, is a critical mechanism for the clearance of misfolded proteins and dysfunctional organelles in neurons. In the peripheral nervous system, autophagic stress is associated with the development of peripheral neuropathy. However, the molecular mechanism of axonal neuropathy induced by autophagic stress due to dysfunction of autophagy in peripheral neurons in vivo is still unclear. We found that dorsal root ganglion (DRG) neuron-specific atg7 (autophagy related 7) knockout (atg7-cKO) mice employing two different Cre recombinase systems exhibited sensory neuropathy approximately 2 months after birth. In electron microscopy analysis, axon degeneration was clearly observed in the myelinated fibers of the sciatic nerve before the appearance of neuronal cell death. Dystrophic axons filled with abnormal vesicular accumulations and amorphous inclusions were specifically localized in the myelinated axons within the DRG in atg7-cKO mice, indicating the presence of autophagic stress in proximal axons. In line with the EM findings, the mutant mice showed preferential induction of axonal injury-associated genes, including ATF3 (activating transcription factor 3), in large-size DRG neurons that constitute myelinated fibers without axotomy. SARM1 (sterile alpha and HEAT/Armadillo motif containing 1), the central executioner of Wallerian degeneration, was activated in the sciatic nerves of atg7-cKO mice, and axonal degeneration and sensory neuropathy in atg7-cKO mice were prevented via expression of a dominant-negative Sarm1 transgene. Our findings demonstrate the importance of SARM1-dependent axon degeneration in the development of peripheral sensory neuropathy induced by impairment of autophagy.

Keywords:  Activating transcription factor 3; Wallerian degeneration; autophagy; dorsal root ganglion; dystrophic axon; peripheral neuropathy

DOI:  https://doi.org/10.1080/15548627.2023.2244861
Bioorg Chem. 2023 Oct;pii: S0045-2068(23)00420-0. [Epub ahead of print]139 106759

Design, synthesis, and biological evaluation of a series of benzofuran[3,2-d]pyrimidine-4(3H)-one derivatives containing thiosemicarbazone analogs as novel PARP-1 inhibitors.

Yuanjiang Wang, Kun Li, Wenqing Xu, Shaohua Gou.

  Poly ADP ribose polymerase-1 (PARP-1), one of the most important members of the PARP protein family, plays a crucial role in DNA damage repair, gene transcription, and apoptosis of cancer cells. In this work, benzofuran[3,2-d]pyrimidine-4(3H)-one was used as a framework to design and synthesize a series of novel PARP-1 inhibitors by introducing thiosemicarbazone or its derivatives into the scafford. Among all the target compounds, 19b and 19c were found to exhibit more potent inhibitory activity and higher selectivity against PARP-1 than Olaparib, especially the latter had an IC50 value of 0.026 μM against PARP-1 enzyme and a PARP-2/PARP-1 selectivity of 85.19-fold over Olapanib. Apart from strong cytotoxicity against the tested cancer cell lines, 19c was most sensitive to SK-OV-3 cells, with an IC50 value of 4.98 μM superior to Olaparib. Anti-cancer mechanism studies revealed that 19c could inhibit DNA single-strand breakage repair and aggravate DNA double-strand breakage by inhibiting PARP-1 activity, and promote the apoptosis of cancer cells through the mitochondrial apoptosis pathway.

Keywords:  Anti-tumor; PARP-1 inhibitor; Poly ADP-ribose polymerase; Thiosemicarbazone

DOI:  https://doi.org/10.1016/j.bioorg.2023.106759
Front Immunol. 2023 ;14 1159958

Salvianolic acid B ameliorates neuroinflammation and neuronal injury via blocking NLRP3 inflammasome and promoting SIRT1 in experimental subarachnoid hemorrhage.

Dayong Xia, Jinlong Yuan, Degang Wu, Haibin Dai, Zong Zhuang.

  The nucleotide-binding oligomerization domain (NOD)-like receptor family pyrin domain containing 3 (NLRP3) inflammasome-mediated immuno-inflammatory response plays a critical role in exacerbating early brain injury (EBI) after subarachnoid hemorrhage (SAH). Salvianolic acid B (SalB) has previously been shown to suppress neuroinflammatory responses in many disorders. Meanwhile, a previous study has demonstrated that SalB mitigated oxidative damage and neuronal degeneration in a prechiasmatic injection model of SAH. However, the therapeutic potential of SalB on immuno-inflammatory responses after SAH remains unclear. In the present study, we explored the therapeutic effects of SalB on neuroinflammatory responses in an endovascular perforation SAH model. We observed that SalB ameliorated SAH-induced functional deficits. Additionally, SalB significantly mitigated microglial activation, pro-inflammatory cytokines release, and neuronal injury. Mechanistically, SalB inhibited NLRP3 inflammasome activation and increased sirtuin 1 (SIRT1) expression after SAH. Administration of EX527, an inhibitor of SIRT1, abrogated the anti-inflammatory effects of SalB against SAH and further induced NLRP3 inflammasome activation. In contrast, MCC950, a potent and selective NLRP3 inflammasome inhibitor, reversed the detrimental effects of SIRT1 inhibition by EX527 on EBI. These results indicated that SalB effectively repressed neuroinflammatory responses and neuronal damage after SAH. The action of SalB appeared to be mediated by blocking NLRP3 inflammasome and promoting SIRT1 signaling.

Keywords:  MCC950; NLRP3; salvianolic acid B; sirtuin 1; subarachnoid hemorrhage

DOI:  https://doi.org/10.3389/fimmu.2023.1159958
Am J Physiol Regul Integr Comp Physiol. 2023 Aug 07.

Clock genes regulate skeletal muscle energy metabolism through NAMPT/NAD+/SIRT1 following heavy-load exercise.

Yu Xia, Binyu Yao, Zeting Fu, Lunyu Li, Songlin Jin, Bo Qu, Ying Huang, Haili Ding.

  The biological clock is an invisible "clock" in the organism, which can regulate behavior, physiology, and biochemical reactions. However, the relationship between clock genes and energy metabolism in post-exercise skeletal muscle is not well known. The purpose of this study was to determine the mechanisms through which peripheral clock genes regulate energy metabolism in skeletal muscle. We analyzed the rhythm of mRNA content of the clock genes Bmal1 and Clock in skeletal muscle following heavy-load exercise and measured related indicators of mitochondrial structure and function. We obtained the following experimental results: Heavy load exercise induced loss of circadian rhythm of Bmal1 between ZT0 and ZT24, and the circadian rhythm of Clock was not restored between ZT0 and ZT72. Analysis of mitochondrial morphology in group E showed abnormal swelling and ridge structure damage at ZT0, which recovered somewhat at ZT24 and ZT48, and the damage had essentially disappeared by ZT72. The expression of NAMPT/NAD+/SIRT1 signaling axis proteins in group E was abnormal at ZT0, the content of NAMPT and the activity of SIRT1 significantly increased, and the content of NAD+ significantly decreased. The expression of Bmal1 and PGC-1α in group E significantly increased, while the ATP and ADP content, as well as the activities of COXII and COXIV, were significantly changed. The co-localization of BMAL1 and SIRT1 in group E was significantly upregulated at ZT0. These results suggest that the skeletal muscle clock gene Bmal1 may regulate the energy metabolism level of skeletal muscle after exercise through the NAMPT/NAD+/SIRT1 signaling pathway.

Keywords:  Clock genes; Energy metabolism; Heavy-load exercise

DOI:  https://doi.org/10.1152/ajpregu.00261.2022
Ecotoxicol Environ Saf. 2023 Aug 07. pii: S0147-6513(23)00835-7. [Epub ahead of print]262 115331

Salidroside ameliorates acetaminophen-induced acute liver injury through the inhibition of endoplasmic reticulum stress-mediated ferroptosis by activating the AMPK/SIRT1 pathway.

Jun Xu, Luying Zhao, Xiangting Zhang, Kanglei Ying, Ruoru Zhou, Weimin Cai, Xiao Wu, Haoran Jiang, Qian Xu, Dan Miao, Yuan Zeng, Fujun Yu.

  Acetaminophen (APAP) overdose has long been considered a major cause of drug-induced liver injury. Ferroptosis is a type of programmed cell death mediated by iron-dependent lipid peroxidation. Endoplasmic reticulum (ER) stress is a systemic response triggered by the accumulation of unfolded or misfolded proteins in the ER. Ferroptosis and ER stress have been proven to contribute to the progression of APAP-induced acute liver injury (ALI). It was reported that salidroside protects against APAP-induced ALI, but the potential mechanism remain unknown. In this study, male C57BL/6 J mice were intraperitoneally (i.p.) injected APAP (500 mg/kg) to induce an ALI model. Salidroside was i.p. injected at a dose of 100 mg/kg 2 h prior to APAP administration. Mice were sacrificed 12 h after APAP injection and the liver and serum of the mice were obtained for histological and biochemistry analysis. AML12 cells were used in in vitro assays. The results indicated that salidroside mitigated glutathione degradation via inhibiting cation transport regulator homolog 1 (CHAC1) to attenuate ferroptosis, and simultaneously suppressing PERK-eIF2α-ATF4 axis-mediated ER stress, thus alleviating APAP-induced ALI. However, PERK activator CCT020312 and overexpression of ATF4 inhibited the protective function of salidroside on CHAC1-mediated ferroptosis. Besides this, activation of the AMPK/SIRT1 signaling pathway by salidroside was demonstrated to have a protective effect against APAP-induced ALI. Interestingly, selective inhibition of SIRT1 ameliorated the protective effects of salidroside on ER stress and ferroptosis. Overall, salidroside plays a significant part in the mitigation of APAP-induced ALI by activating the AMPK/SIRT1 signaling to inhibit ER stress-mediated ferroptosis in the ATF4-CHAC1 axis.

Keywords:  AMP-activated protein kinase; Acute liver injury; Endoplasmic reticulum stress; Ferroptosis; SIRT1; Salidroside

DOI:  https://doi.org/10.1016/j.ecoenv.2023.115331
NPJ Parkinsons Dis. 2023 Aug 08. 9(1): 120

Parkinson's disease neurons exhibit alterations in mitochondrial quality control proteins.

Chun Chen, David McDonald, Alasdair Blain, Emily Mossman, Kiera Atkin, Michael F Marusich, Roderick Capaldi, Laura Bone, Anna Smith, Andrew Filby, Daniel Erskine, Oliver Russell, Gavin Hudson, Amy E Vincent, Amy K Reeve.

Mitochondrial dysfunction has been suggested to contribute to Parkinson's disease pathogenesis, though an understanding of the extent or exact mechanism of this contribution remains elusive. This has been complicated by challenging nature of pathway-based analysis and an inability simultaneously study multiple related proteins within human brain tissue. We used imaging mass cytometry (IMC) to overcome these challenges, measuring multiple protein targets, whilst retaining the spatial relationship between targets in post-mortem midbrain sections. We used IMC to simultaneously interrogate subunits of the mitochondrial oxidative phosphorylation complexes, and several key signalling pathways important for mitochondrial homoeostasis, in a large cohort of PD patient and control cases. We revealed a generalised and synergistic reduction in mitochondrial quality control proteins in dopaminergic neurons from Parkinson's patients. Further, protein-protein abundance relationships appeared significantly different between PD and disease control tissue. Our data showed a significant reduction in the abundance of PINK1, Parkin and phosphorylated ubiquitinSer65, integral to the mitophagy machinery; two mitochondrial chaperones, HSP60 and PHB1; and regulators of mitochondrial protein synthesis and the unfolded protein response, SIRT3 and TFAM. Further, SIRT3 and PINK1 did not show an adaptive response to an ATP synthase defect in the Parkinson's neurons. We also observed intraneuronal aggregates of phosphorylated ubiquitinSer65, alongside increased abundance of mitochondrial proteases, LONP1 and HTRA2, within the Parkinson's neurons with Lewy body pathology, compared to those without. Taken together, these findings suggest an inability to turnover mitochondria and maintain mitochondrial proteostasis in Parkinson's neurons. This may exacerbate the impact of oxidative phosphorylation defects and ageing related oxidative stress, leading to neuronal degeneration. Our data also suggest that that Lewy pathology may affect mitochondrial quality control regulation through the disturbance of mitophagy and intramitochondrial proteostasis.

DOI: https://doi.org/10.1038/s41531-023-00564-3