protein accumulation
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2022 ◽  
Vol 15 ◽  
Author(s):  
Nguyen Thanh Nhu ◽  
Shu-Yun Xiao ◽  
Yijie Liu ◽  
V. Bharath Kumar ◽  
Zhen-Yang Cui ◽  
...  

Neural mitochondrial dysfunction, neural oxidative stress, chronic neuroinflammation, toxic protein accumulation, and neural apoptosis are common causes of neurodegeneration. Elamipretide, a small mitochondrially-targeted tetrapeptide, exhibits therapeutic effects and safety in several mitochondria-related diseases. In neurodegeneration, extensive studies have shown that elamipretide enhanced mitochondrial respiration, activated neural mitochondrial biogenesis via mitochondrial biogenesis regulators (PCG-1α and TFAM) and the translocate factors (TOM-20), enhanced mitochondrial fusion (MNF-1, MNF-2, and OPA1), inhibited mitochondrial fission (Fis-1 and Drp-1), as well as increased mitophagy (autophagy of mitochondria). In addition, elamipretide has been shown to attenuate neural oxidative stress (hydrogen peroxide, lipid peroxidation, and ROS), neuroinflammation (TNF, IL-6, COX-2, iNOS, NLRP3, cleaved caspase-1, IL-1β, and IL-18), and toxic protein accumulation (Aβ). Consequently, elamipretide could prevent neural apoptosis (cytochrome c, Bax, caspase 9, and caspase 3) and enhance neural pro-survival (Bcl2, BDNF, and TrkB) in neurodegeneration. These findings suggest that elamipretide may prevent the progressive development of neurodegenerative diseases via enhancing mitochondrial respiration, mitochondrial biogenesis, mitochondrial fusion, and neural pro-survival pathway, as well as inhibiting mitochondrial fission, oxidative stress, neuroinflammation, toxic protein accumulation, and neural apoptosis. Elamipretide or mitochondrially-targeted peptide might be a targeted agent to attenuate neurodegenerative progression.


2022 ◽  
Author(s):  
Xinlong Xiao ◽  
Jieqiong Zhang ◽  
Viswanathan Satheesh ◽  
Fanxiao Meng ◽  
Wenlan Gao ◽  
...  

Abstract Coordinated distribution of Pi between roots and shoots is an important process that plants use to maintain Pi homeostasis. SHR (SHORT-ROOT) is well-characterized for its function in root radial patterning1-3. Here, we demonstrate a new role of SHR in controlling phosphate (Pi) allocation from roots to shoots by regulating PHOSPHATE1 (PHO1) in the root differentiation zone. We recovered a weak mutant allele of SHR in Arabidopsis which accumulates much less Pi in the shoot and shows constitutive Pi starvation response (PSR) under Pi-sufficient condition. Besides, Pi starvation suppresses SHR protein accumulation and releases its inhibition on the HD-ZIP Ⅲ transcription factor PHB. PHB accumulates and directly binds the promoter of PHO2 to upregulate its transcription, resulting in PHO1 degradation in the xylem-pole pericycle cells. Our findings reveal a previously unrecognized mechanism of how plants repress Pi translocation from roots to shoots in response to Pi starvation.


2022 ◽  
Vol 12 ◽  
Author(s):  
Satyanarayana Tatineni ◽  
Jeff Alexander ◽  
Feng Qu

Field-grown wheat (Triticum aestivum L.) plants can be co-infected by multiple viruses, including wheat streak mosaic virus (WSMV), Triticum mosaic virus (TriMV), brome mosaic virus (BMV), and barley stripe mosaic virus (BSMV). These viruses belong to four different genera in three different families and are, hence, genetically divergent. However, the impact of potential co-infections with two, three, or all four of them on the viruses themselves, as well as the wheat host, has yet to be examined. This study examined bi-, tri-, and quadripartite interactions among these viruses in wheat for disease development and accumulation of viral genomic RNAs, in comparison with single virus infections. Co-infection of wheat by BMV and BSMV resulted in BMV-like symptoms with a drastic reduction in BSMV genomic RNA copies and coat protein accumulation, suggesting an antagonism-like effect exerted by BMV toward BSMV. However, co-infection of either BMV or BSMV with WSMV or TriMV led to more severe disease than singly infected wheat, but with a decrease or no significant change in titers of interacting viruses in the presence of BMV or BSMV, respectively. These results were in stark contrast with exacerbated disease phenotype accompanied with enhanced virus titers caused by WSMV and TriMV co-infection. Co-infection of wheat by WSMV, TriMV, and BMV or BSMV resulted in enhanced synergistic disease accompanied by increased accumulation of TriMV and BMV but not WSMV or BSMV. Quadripartite interactions in co-infected wheat by all four viruses resulted in very severe disease synergism, leading to the death of the most infected plants, but paradoxically, a drastic reduction in BSMV titer. Our results indicate that interactions among different viruses infecting the same plant host are more complex than previously thought, do not always entail increases in virus titers, and likely involve multiple mechanisms. These findings lay the foundation for additional mechanistic dissections of synergistic interactions among unrelated plant viruses.


2022 ◽  
Vol 17 (1) ◽  
Author(s):  
Peng Xu ◽  
Minghui Wang ◽  
Won-min Song ◽  
Qian Wang ◽  
Guo-Cheng Yuan ◽  
...  

Abstract Background Cellular senescence is a complex stress response that impacts cellular function and organismal health. Multiple developmental and environmental factors, such as intrinsic cellular cues, radiation, oxidative stress, oncogenes, and protein accumulation, activate genes and pathways that can lead to senescence. Enormous efforts have been made to identify and characterize senescence genes (SnGs) in stress and disease systems. However, the prevalence of senescent cells in healthy human tissues and the global SnG expression signature in different cell types are poorly understood. Methods This study performed an integrative gene network analysis of bulk and single-cell RNA-seq data in non-diseased human tissues to investigate SnG co-expression signatures and their cell-type specificity. Results Through a comprehensive transcriptomic network analysis of 50 human tissues in the Genotype-Tissue Expression Project (GTEx) cohort, we identified SnG-enriched gene modules, characterized SnG co-expression patterns, and constructed aggregated SnG networks across primary tissues of the human body. Our network approaches identified 51 SnGs highly conserved across the human tissues, including CDKN1A (p21)-centered regulators that control cell cycle progression and the senescence-associated secretory phenotype (SASP). The SnG-enriched modules showed remarkable cell-type specificity, especially in fibroblasts, endothelial cells, and immune cells. Further analyses of single-cell RNA-seq and spatial transcriptomic data independently validated the cell-type specific SnG signatures predicted by the network analysis. Conclusions This study systematically revealed the co-regulated organizations and cell type specificity of SnGs in major human tissues, which can serve as a blueprint for future studies to map senescent cells and their cellular interactions in human tissues.


Cancers ◽  
2022 ◽  
Vol 14 (2) ◽  
pp. 282
Author(s):  
W. Quinn O’Neill ◽  
Xiujie Xie ◽  
Shanying Gui ◽  
Heping Yu ◽  
Jacqueline Davenport ◽  
...  

Human papillomavirus-associated head and neck squamous cell carcinoma (HPV+ HNSCC) is recognized as a distinct disease with unique etiology and clinical features. Current standard of care therapeutic modalities are identical for HPV+ and HPV− HNSCC and thus, there remains an opportunity to develop innovative pharmacologic approaches to exploit the inherent vulnerabilities of HPV+ HNSCC. In this study, using an inducible HPVE6E7 knockdown system, we found that HPV+ HNSCC cells are addicted to HPVE6E7, such that loss of these viral oncogenes impaired tumorigenicity in vitro and in vivo. A number of druggable pathways, including PPAR and Wnt, were modulated in response to HPVE6E7 loss. Fenofibrate showed significant anti-proliferative effects in a panel of HPV+ cancer cell lines. Additionally, fenofibrate impaired tumor growth as monotherapy and potentiated the activity of cisplatin in a pre-clinical HPV+ animal model. Systemic fenofibrate treatment induced p53 protein accumulation, and surprisingly, re-programmed the tumor-immune microenvironment to drive immune cell infiltration. Since fenofibrate is FDA-approved with a favorable long-term safety record, repositioning of this drug, as a single agent or in combination with cisplatin or checkpoint blockade, for the HPV+ HNSCC setting should be prioritized.


2022 ◽  
Vol 9 (1) ◽  
Author(s):  
Ling-Zhuo Kong ◽  
Rui-Li Zhang ◽  
Shao-Hua Hu ◽  
Jian-Bo Lai

AbstractMilitary psychiatry, a new subcategory of psychiatry, has become an invaluable, intangible effect of the war. In this review, we begin by examining related military research, summarizing the related epidemiological data, neuropathology, and the research achievements of diagnosis and treatment technology, and discussing its comorbidity and sequelae. To date, advances in neuroimaging and molecular biology have greatly boosted the studies on military traumatic brain injury (TBI). In particular, in terms of pathophysiological mechanisms, several preclinical studies have identified abnormal protein accumulation, blood–brain barrier damage, and brain metabolism abnormalities involved in the development of TBI. As an important concept in the field of psychiatry, TBI is based on organic injury, which is largely different from many other mental disorders. Therefore, military TBI is both neuropathic and psychopathic, and is an emerging challenge at the intersection of neurology and psychiatry.


Antioxidants ◽  
2022 ◽  
Vol 11 (1) ◽  
pp. 117
Author(s):  
Phuong Linh Nguyen ◽  
Chang Hoon Lee ◽  
Heesoon Lee ◽  
Jungsook Cho

Chemotherapy has been a standard intervention for a variety of cancers to impede tumor growth, mainly by inducing apoptosis. However, development of resistance to this regimen has led to a growing interest and demand for drugs targeting alternative cell death modes, such as paraptosis. Here, we designed and synthesized a novel derivative of a pyrazolo[3,4-h]quinoline scaffold (YRL1091), evaluated its cytotoxic effect, and elucidated the underlying molecular mechanisms of cell death in MDA-MB-231 and MCF-7 breast cancer (BC) cells. We found that YRL1091 induced cytotoxicity in these cells with numerous cytoplasmic vacuoles, one of the distinct characteristics of paraptosis. YRL1091-treated BC cells displayed several other distinguishing features of paraptosis, excluding autophagy or apoptosis. Briefly, YRL1091-induced cell death was associated with upregulation of microtubule-associated protein 1 light chain 3B, downregulation of multifunctional adapter protein Alix, and activation of extracellular signal-regulated kinase 1/2 and c-Jun N-terminal kinase. Furthermore, the production of reactive oxygen species (ROS) and newly synthesized proteins were also observed, subsequently causing ubiquitinated protein accumulation and endoplasmic reticulum (ER) stress. Collectively, these results indicate that YRL1091 induces paraptosis in BC cells through ROS generation and ER stress. Therefore, YRL1091 can serve as a potential candidate for the development of a novel anticancer drug triggering paraptosis, which may provide benefit for the treatment of cancers resistant to conventional chemotherapy.


2021 ◽  
Vol 26 (6) ◽  
pp. 3137-3144
Author(s):  
HUAYOU CHEN ◽  
XIAOYU LIANG ◽  
KANGTAO CAI ◽  
BANGGUO WU ◽  
HONGCHENG WANG ◽  
...  

Alkaline pretreatment is essential in lignin degradation, but the inhibitors produced in this process affect microbial growth. To overcome the impacts of the phenolic compounds, detoxification was applied to corn stalk pretreated with calcium hydroxide.The results showed that ferulic acid degradation rate can reach 85.11% by laccase at the optimal conditions. Phanerochaete chrysosporium degraded most vanillin (77.19%) and p-hydroxybenzaldehyde (63.82%) but the degradation of ferulic acid (15.34%) was relatively weak. Laccase combined with Phanerochaete chrysosporium detoxified most of the phenolic compounds including 2- methoxy-4-vinylphenol (88.46%) and salicylic acid (58.13%) that hardly decompose alone after calcium hydroxide pretreatment in this study. These results inferred that Phanerochaete chrysosporium might generate some substance during the spore germination and growth period which may cooperate with laccase to decompose the phenolic compounds. After the fermentation of detoxified corn stalk by Neurospora crassa, the true protein content was increased by 2.73 times, and 21.17% lignin was degraded.


Life ◽  
2021 ◽  
Vol 12 (1) ◽  
pp. 42
Author(s):  
Funmilayo O. Adeshakin ◽  
Adeleye O. Adeshakin ◽  
Zhao Liu ◽  
Jian Cheng ◽  
Pengchao Zhang ◽  
...  

Metastasis arises owing to tumor cells’ capacity to evade pro-apoptotic signals. Anoikis—the apoptosis of detached cells (from the extracellular matrix (ECM)) is often circumvented by metastatic cells as a result of biochemical and molecular transformations. These facilitate cells’ ability to survive, invade and reattach to secondary sites. Here, we identified deregulated glucose metabolism, oxidative phosphorylation, and proteasome in anchorage-independent cells compared to adherent cells. Metformin an anti-diabetic drug that reduces blood glucose (also known to inhibit mitochondrial Complex I), and proteasome inhibitors were employed to target these changes. Metformin or proteasome inhibitors alone increased misfolded protein accumulation, sensitized tumor cells to anoikis, and impaired pulmonary metastasis in the B16F10 melanoma model. Mechanistically, metformin reduced cellular ATP production, activated AMPK to foster pro-apoptotic unfolded protein response (UPR) through enhanced expression of CHOP in ECM detached cells. Furthermore, AMPK inhibition reduced misfolded protein accumulation, thus highlight relevance of AMPK activation in facilitating metformin-induced stress and UPR cell death. Our findings provide insights into the molecular biology of anoikis resistance and identified metformin and proteasome inhibitors as potential therapeutic options for tumor metastasis.


2021 ◽  
Author(s):  
Ruth R. Finkelstein ◽  
Tim Lynch ◽  
Guillaume Nee ◽  
Avan Chu ◽  
Thorben Krüger ◽  
...  

Overexpression of ABI5/ABF interacting proteins (AFPs) results in extreme ABA resistance of seeds and failure to acquire desiccation tolerance, at least in part through effects on chromatin modification. This study tests the hypothesis that the AFPs promote germination by also functioning as adapters for E3 ligases that ubiquitinate ABI5, leading to its degradation. Interactions between AFPs and two well-characterized classes of E3 ligases targeting ABI5, DWD HYPERSENSITIVE TO ABA (DWA)s and KEEP ON GOING (KEG), were analyzed by yeast two-hybrid, bimolecular fluorescence complementation, and genetic assays. Although the AFPs and E3 ligases showed weak direct interactions, loss of function for the E3 ligases did not impair ABA-resistance conferred by overexpression of the YFP-AFP2 fusion. Comparison of ABI5 and AFP2 levels in these lines showed that AFP2 accumulation increased during germination, but that ABI5 degradation followed germination, demonstrating that AFP2 controls ABA sensitivity during germination independently of ABI5 degradation. Surprisingly, AFP2 overexpression in the dwa1 dwa2 mutant background produced the unusual combination of extreme ABA resistance and desiccation tolerance, creating an opportunity to separate the underlying biochemical characteristics of ABA sensitivity and desiccation tolerance that we investigated by quantitative proteomics. Our analysis identified at least three-fold more differentially accumulated seed proteins than previous studies. Comparison of dry seed proteomes of the different genotypes allowed us to separate and refine the changes in protein accumulation patterns correlating with desiccation tolerance independently of ABA sensitivity, or vice versa, to a subset of cold-induced and defense stress-responsive proteins and signaling regulators.


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