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Journal of Biochemistry

Current research reports and chronological list of recent articles..

The international scientific Journal of Biochemistry publishes the results of original research in the fields of Biochemistry, Molecular Biology, Cell, and Biotechnology.

The publishers are Oxford Journals and the Japanese Biochemical Society. The copyright and publishing rights of specialized products listed below are in this publishing house. This is also responsible for the content shown.

To search this web page for specific words type "Ctrl" + "F" on your keyboard (Command + "F" on a Mac). Then: type the word you are searching for in the window that pops up!

Additional research articles see Current Chemistry Research Articles. Magazines with similar content (biochemistry):

 - Annual Reviews of Biochemistry,

 - Biochemical Journal,

 - Biochemistry,

 - Biochimie,

 - ChemBioChem,

 - FEBS Journal,

 - PLoS One Biochemistry,

 - Trends in Biochemical Sciences.

Journal of Biochemistry - Abstracts

Molecular connections between circadian clock and health/ageing

For decades, considerable efforts have been expended for solving the molecular mechanisms of disease progression. An important clue to tackle this question is the circadian clock. Recent findings have uncovered previously unknown molecular connections between circadian clock and disease incidence, consequently causing the ageing process. Furthermore, ‘chronotherapy’ is emerging as a new concept of optimizing the time of the day for drug administration according to target gene expressions in order to maximize therapeutic efficacy and minimize the side effects. This concept will help cure patients and prevent them from suffering evitable pain and side effects. This JB special issue ‘Molecular connections between circadian clock and health/aging’ discusses how the circadian clocks link to health and ageing from molecular to organismal levels.

Datum: 06.04.2022

Erratum to: Structural insights into the enhanced thermostability of cysteine substitution mutants of L-histidine decarboxylase from Photobacterium phosphoreum

J. Biochem. 2021. doi:10.1093/jb/mvab103
Datum: 08.03.2022

The circadian clock and cancer: links between circadian disruption and disease Pathology

There is growing evidence that disruption of our 24-h clock increases our risk for acquiring several diseases and disorders. One of these diseases is cancer. While the mechanistic links between circadian clock disruption and cancer initiation or progression are an active area of study, significantly more work needs to be done to understand the molecular substrates involved. Of particular complexity remains the functions of the clock in individual cells during the process of transformation (cancer initiation) versus the functions of the clock in tumour-surrounding stroma in the process of tumour progression or metastasis. Indeed, the nexus of cellular circadian dynamics, metabolism and carcinogenesis is drawing more attention, and many new studies are now highlighting the critical role of circadian rhythms and clock proteins in cancer prevention. In this brief review, we cover some of the basic mechanisms reported to link circadian disruption and cancer at the level of gene expression and metabolism. We also review some of the human studies addressing circadian disruption and cancer incidence as well as some controlled laboratory studies connecting the two in pre-clinical models. Finally, we discuss the tremendous opportunity to use circadian approaches for future prevention and treatment in the context of cancer in specific organs.

Datum: 22.02.2022

Visualization of Reelin Secretion from Primary Cultured Neurons by Bioluminescence Imaging

Reelin is a secreted glycoprotein important for brain development and synaptic plasticity in the adult brain. Some reports suggest that Reelin is secreted from the nerve terminals and functions as a neurotransmitter. However, the mechanism of Reelin secretion is unknown. In this study, we visualized Reelin secretion by bioluminescence imaging using a fusion protein of Reelin and Gaussia luciferase (GLase-Reelin). GLase-Reelin expressed in HEK293T cells was correctly processed and secreted. Luminescence signals from the secreted GLase-Reelin of primary cultured neurons were visualized by bioluminescence microscopy. Reelin secretory events were observed at neurites and cell bodies. Bioluminescence imaging was also performed before and after KCl depolarization to compare the secretory events of Reelin and brain-derived neurotrophic factor (BDNF). The secretion of BDNF increased markedly shortly after depolarization. In contrast, the frequency of Reelin secretion did not change significantly by depolarization. Thus, Reelin secretion from neurites might not be regulated in a neuronal activity-dependent manner.

Datum: 16.02.2022

Diurnal shift of mouse activity by the deficiency of an ageing-related gene Lmna

Nuclear lamina is a fundamental structure of the cell nucleus and regulates a wide range of molecular pathways. Defects of components of the nuclear lamina cause ageing-like physiological disorders, called laminopathy. Generally, ageing and diseases are often associated with perturbation of various time-of-day–dependent regulations, but it remains elusive whether laminopathy induces any changes of the circadian clock and physiological rhythms. Here, we demonstrated that deficiency of Lmna gene in mice caused an obvious shift of locomotor activities to the daytime. The abnormal activity profile was accompanied by a remarkable change in phase angle between the central clock in the suprachiasmatic nucleus (SCN) and the lung peripheral clocks, leaving the phase of the SCN clock unaffected by the mutation. These observations suggest that Lmna deficiency causes a change of the habitat from nocturnal to diurnal behaviours. On the other hand, molecular oscillation and its phase resetting mechanism were intact in both the Lmna-deficient cells and progeria-mimicking cells. Intriguingly, high-fat diet feeding extended the short lifespan and ameliorated the abnormalities of the behaviours and the phase of the peripheral clock in the Lmna-deficient mice. The present study supports the important contribution of the energy conditions to a shift between the diurnal and nocturnal activities.

Datum: 08.02.2022

NRF2 pathway activation attenuates ageing-related renal phenotypes due to α-klotho deficiency

Oxidative stress is one of the major causes of the age-related functional decline in cells and tissues. The KEAP1–NRF2 system plays a central role in the regulation of redox balance, and NRF2 activation exerts antiageing effects by controlling oxidative stress in aged tissues. α-Klotho was identified as an ageing suppressor protein based on the premature ageing phenotypes of its mutant mice, and its expression is known to gradually decrease during ageing. Because α-klotho has been shown to possess antioxidant function, ageing-related phenotypes of α-klotho mutant mice seem to be attributable to increased oxidative stress at least in part. To examine whether NRF2 activation antagonizes ageing-related phenotypes caused by α-klotho deficiency, we crossed α-klotho–deficient (Kl−/−) mice with a Keap1-knockdown background, in which the NRF2 pathway is constitutively activated in the whole body. NRF2 pathway activation in Kl−/− mice extended the lifespan and dramatically improved ageing-related renal phenotypes. With elevated expression of antioxidant genes accompanied by an oxidative stress decrease, the antioxidant effects of NRF2 seem to make a major contribution to the attenuation of ageing-related renal phenotypes of Kl−/− mice. Thus, NRF2 is expected to exert an antiageing function by partly compensating for the functional decline of α-Klotho during physiological ageing.

Datum: 07.02.2022

CEBPB is required for NRF2-mediated drug resistance in NRF2-activated non-small cell lung cancer cells

NRF2 is a transcription activator that plays a key role in cytoprotection against oxidative stress. Although increased NRF2 activity is principally beneficial for our health, NRF2 activation in cancer cells is detrimental, as it drives their malignant progression. We previously found that CCAAT/enhancer-binding protein B (CEBPB) cooperates with NRF2 in NRF2-activated lung cancer and enhances tumour-initiating activity by promoting NOTCH3 expression. However, the general contribution of CEBPB in lung cancer is rather controversial, probably because the role of CEBPB depends on cooperating transcription factors in each cellular context. To understand how NRF2 shapes the function of CEBPB in NRF2-activated lung cancers and its biological consequence, we comprehensively explored NRF2-CEBPB–coregulated genes and found that genes involved in drug metabolism and detoxification were characteristically enriched. Indeed, CEBPB and NRF2 cooperatively contribute to the drug resistance. We also found that CEBPB is directly regulated by NRF2, which is likely to be advantageous for the coexpression and cooperative function of NRF2 and CEBPB. These results suggest that drug resistance of NRF2-activated lung cancers is achieved by the cooperative function of NRF2 and CEBPB.

Datum: 07.02.2022

Autophagy-independent cytoprotection by optineurin from toxicity of aggregates formed by mutant huntingtin and mutant ataxin-3

An important feature of several neurodegenerative diseases is the formation of pathological structures containing aggregated proteins. The autophagy receptor optineurin/OPTN is frequently observed in these structures. The role played by optineurin in these aggregates is not clear. In this study, we explored whether optineurin has a cytoprotective role in the cells having mutant protein aggregates. We overexpressed mutant huntingtin having 97 glutamine repeats (mHtt) and mutant ataxin-3 having 130 glutamine repeats (mAtax-3) in wild-type and optineurin-deficient neuronal (N2A) and non-neuronal cells (Optn−/− mouse embryonic fibroblasts) and determined the percentage of dead cells with mutant protein aggregates. Optineurin-deficient cells having mHtt or mAtax-3 aggregates showed higher cell death as compared to wild-type cells having mutant protein aggregates. Confocal microscopy revealed that optineurin formed a shell around mHtt and mAtax-3 aggregates through its C-terminal domain. The C-terminal domain of optineurin, which lacks LC3-interacting region required for autophagy, was necessary and sufficient to reduce cytotoxicity of mHtt and mAtax-3 aggregates. Our results show that in the absence of optineurin, mutant protein aggregates are highly toxic, revealing an autophagy-independent cytoprotective function of optineurin, which is mediated by its C-terminal domain.

Datum: 04.02.2022

Sialyl-Tn antigen facilitates extracellular vesicle-mediated transfer of FAK and enhances motility of recipient cells

Protein glycosylation plays a pivotal role in tumour development by modulating molecular interactions and cellular signals. Sialyl-Tn (sTn) antigen is a tumour-associating carbohydrate epitope whose expression correlates with metastasis and poor prognosis of various cancers; however, its pathophysiological function is poorly understood. Extracellular vesicles (EVs) derived from cancer cells act as a signal mediator amongst tumour microenvironments by transferring cargo molecules. sTn antigen has been found in the glycans of EVs, thereby the functional relevance of sTn antigen to the regulation of tumour microenvironments could be expected. In the present study, we showed that sTn antigen induced TP53 and tumour suppressor–activated pathway 6 (TSAP6) and consequently enhanced EV production. Besides, the genetic attenuation of TSAP6 resulted in the reduction of the EV production in the sTn antigen expressing cells. The enhanced EV production in the sTn antigen–expressing cells consequently augmented the delivery of EVs to recipient cells. The produced EVs selectively and abundantly encased focal adhesion kinase and transferred it to EV-recipient cells, and thus, their cellular motility was enhanced. These findings would contribute to facilitate the elucidation of the pathophysiological significance of the sTn antigen in the tumour microenvironments and tumour development.

Datum: 01.02.2022

Basis for diurnal exacerbation of neuropathic pain hypersensitivity and its application for drug development

In addition to diurnal rhythms in physiology and behavior, a variety of pathological conditions also exhibit marked day–night changes in symptom intensity, exemplified by allergic rhinitis, arthritis, asthma, myocardial infarction, congestive heart failure, stroke and chronic pain disorders. Currently, novel therapeutic approaches are facilitated by the development of chemical compounds targeted to key proteins that cause diurnal exacerbation of pathological events. Neuropathic pain is a chronic condition that occurs by tumor-induced nerve compression, cancer cell infiltration into the nerve, diabetes and herpes virus infection. One troublesome hallmark symptom of neuropathic pain is hypersensitivity to normally innocuous stimuli known as ‘mechanical allodynia’ that is often refractory to common analgesic therapies. Millions of patients worldwide presently endure neuropathic pain. We summarize the recent insights gained into the mechanism of diurnal exacerbation of neuropathic pain hypersensitivity and introduce the strategy of circadian clock-based drug development.

Datum: 30.12.2021

MITOL regulates phosphatidic acid-binding activity of RMDN3/PTPIP51

The transfer of phospholipids from the endoplasmic reticulum (ER) to mitochondria via the mitochondria-ER contact site (MERCS) is essential for maintaining mitochondrial function and integrity. Here, we identified RMDN3/PTPIP51, possessing phosphatidic acid (PA)-transfer activity, as a neighbouring protein of the mitochondrial E3 ubiquitin ligase MITOL/MARCH5 by proximity-dependent biotin labelling using APEX2. We found that MITOL interacts with and ubiquitinates RMDN3. Mutational analysis identified lysine residue 89 in RMDN3 as a site of ubiquitination by MITOL. Loss of MITOL or the substitution of lysine 89 to arginine in RMDN3 significantly reduced the PA-binding activity of RMDN3, suggesting that MITOL regulates the transport of PA to mitochondria by activating RMDN3. Our findings imply that ubiquitin signalling regulates phospholipid transport at the MERCS.

Datum: 29.12.2021

Cellular senescence and its impact on the circadian clock

Ageing is one of the greatest risk factors for chronic non-communicable diseases, and cellular senescence is one of the major causes of ageing and age-related diseases. The persistent presence of senescent cells in late life seems to cause disarray in a tissue-specific manner. Ageing disrupts the circadian clock system, which results in the development of many age-related diseases such as metabolic syndrome, cancer, cardiac diseases and sleep disorders and an increased susceptibility to infections. In this review, we first discuss cellular senescence and some of its basic characteristics and detrimental roles. Then, we discuss a relatively unexplored topic on the link between cellular senescence and the circadian clock and attempt to determine whether cellular senescence could be the underlying factor for circadian clock disruption.

Datum: 20.10.2021

A circular RNA derived from FAT atypical cadherin 3 promotes lung cancer progression via forming a regulatory loop with oncogenic ELAV like RNA binding protein 1

Circular RNA (circRNA) is a covalently closed endogenous RNA that participates in disease progression. However, its role in lung cancer is largely undetermined. In the present study, we found an onctogenic circRNA in lung cancer, FAT atypical cadherin 3 (FAT3) circRNA (circ-FAT3) was remarkably upregulated in lung cancer in comparison to paired normal tissues. High circ-FAT3 was closely linked to larger tumour size, lymph node metastasis, later clinical stage, as well as dismal outcome. Stable knockdown of circ-FAT3 inhibited cell proliferation and metastasis both in vitro and in vivo. RNA binding protein ELAV like RNA binding protein 1 (HuR) was found to bind to introns flanking circ-FAT3, promoting the cyclization and generation of circ-FAT3. Further, circ-FAT3 was able to sponge miR-136-5p by acting as a competing endogenous RNA (ceRNA), alleviating the repressive effect of miR-136-5p on HuR mRNA at the transcriptional and post-transcriptional levels. Moreover, circ-FAT3 expression in lung cancer tissues was strongly positively and negatively correlated with HuR and miR-136-5p expression, respectively. Overall, our data reveal the previously uncharacterized regulatory loop of circ-FAT3/miR-136-5p/HuR in lung cancer and provide novel evidence for the importance of circRNA as a ceRNA in tumorigenesis.

Datum: 14.10.2021

Effects of cryptochrome-modulating compounds on circadian behavioural rhythms in zebrafish

The circadian clock controls daily rhythms of various physiological processes, and impairment of its function causes many diseases including sleep disorders. Chemical compounds that regulate clock function are expected to be applied for treatment of circadian clock-related diseases. We previously identified small-molecule compounds KL001, KL101 and TH301 that lengthen the period of cellular circadian clock by directly targeting clock proteins cryptochromes (CRYs) in mammals. KL001 targets both CRY1 and CRY2 isoforms, while KL101 and TH301 are isoform-selective compounds and require CRY C-terminal region for their effects. For further application of these compounds, the effects on locomotor activity rhythms at the organismal level need to be investigated. Here we used zebrafish larvae as an in vivo model system and found that KL001 lengthened the period of locomotor activity rhythms in a dose-dependent manner. In contrast, KL101 and TH301 showed no effect on the period. The amino acid sequences of CRY C-terminal regions are diverged in zebrafish and mammals, supporting the importance of this region for the effects of KL101 and TH301. This study demonstrated efficacy of CRY modulation for controlling circadian behavioural rhythms in organisms and suggested species-dependent differences in the effects of isoform-selective CRY-modulating compounds.

Datum: 16.09.2021


Category: Current Chemistry Research

Last update: 28.03.2018.

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