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Neurological symptoms are prevalent in both the acute and post-acute phases of coronavirus disease 2019 (COVID-19), and they are becoming a major concern for the prognosis of COVID-19 patients. Accumulation evidence has suggested that metal ion disorders occur in the central nervous system (CNS) of COVID-19 patients. Metal ions participate in the development, metabolism, redox and neurotransmitter transmission in the CNS and are tightly regulated by metal ion channels. COVID-19 infection causes neurological metal disorders and metal ion channels abnormal switching, subsequently resulting in neuroinflammation, oxidative stress, excitotoxicity, neuronal cell death, and eventually eliciting a series of COVID-19-induced neurological symptoms. Therefore, metal homeostasis-related signaling pathways are emerging as promising therapeutic targets for mitigating COVID-19-induced neurological symptoms. This review provides a summary for the latest advances in research related to the physiological and pathophysiological functions of metal ions and metal ion channels, as well as their role in COVID-19-induced neurological symptoms. In addition, currently available modulators of metal ions and their channels are also discussed. Collectively, the current work offers a few recommendations according to published reports and in-depth reflections to ameliorate COVID-19-induced neurological symptoms. Further studies need to focus on the crosstalk and interactions between different metal ions and their channels. Simultaneous pharmacological intervention of two or more metal signaling pathway disorders may provide clinical advantages in treating COVID-19-induced neurological symptoms. [ABSTRACT FROM AUTHOR]

Abstract Methyl protodioscin (MPD) is reported to relieve angina pectoris and myocardial ischemia, and mitochondrial E3 ubiquitin ligase 1 (Mul1) plays a key role in maintaining mitochondrial functions. Bioinformatic analysis shows potential interactions between MPD and Mul1. This study aims to explore whether MPD could protect rat brain against ischemia/reperfusion (I/R) injury through regulation of Mul1/ superoxide dismutase 2 (SOD2) pathway. The SD rat brains were subjected to 2 h of ischemia following by 24 h of reperfusion, which showed I/R injury (increase in neurological deficit score and infarct volume), up-regulation of Mul1 and down regulation of SOD2, these phenomena were attenuated by MPD treatment (3 or 10 mg/kg, i.g.). Consistently, in cultured HT22 cells, hypoxia-reoxygenation (H/R) treatment induced cellular injury (apoptosis and LDH release) concomitant with up-regulation of Mul1 and down regulation of SOD2, these phenomena were blocked in the presence of MPD (5 μM). Knockdown of Mul1 could also decrease SOD2 protein levels in HT22 cells accompanied by alleviation of H/R injury (reduction of apoptosis and LDH release). In agreement with the change of SOD2, reactive oxygen species generation was increased in H/R-treated HT22 cells while decreased in the presence of MPD. Based on these observations, we conclude that upregulation of Mul1 in rat brain contributes to cerebral I/R injury via suppression of SOD2 and that MPD protects rat brain from I/R injury through a mechanism involving regulation of Mul1/SOD2 pathway. Graphical abstract fx1 [ABSTRACT FROM AUTHOR]

Metal homeostasis is critical to normal neurophysiological activity. Metal ions are involved in the development, metabolism, redox and neurotransmitter transmission of the central nervous system (CNS). Thus, disturbance of homeostasis (such as metal deficiency or excess) can result in serious consequences, including neurooxidative stress, excitotoxicity, neuroinflammation, and nerve cell death. The uptake, transport and metabolism of metal ions are highly regulated by ion channels. There is growing evidence that metal ion disorders and/or the dysfunction of ion channels contribute to the progression of neurodegenerative diseases, such as Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS). Therefore, metal homeostasis-related signaling pathways are emerging as promising therapeutic targets for diverse neurological diseases. This review summarizes recent advances in the studies regarding the physiological and pathophysiological functions of metal ions and their channels, as well as their role in neurodegenerative diseases. In addition, currently available metal ion modulators and in vivo quantitative metal ion imaging methods are also discussed. Current work provides certain recommendations based on literatures and in-depth reflections to improve neurodegenerative diseases. Future studies should turn to crosstalk and interactions between different metal ions and their channels. Concomitant pharmacological interventions for two or more metal signaling pathways may offer clinical advantages in treating the neurodegenerative diseases. • Metal ions play a key role in maintaining the normal functions of brain. • Various ion channels are involved in keeping the metal homeostasis of brain. • Disturbance of metal homeostasis commonly occurs in neurodegenerative diseases. • Ion modulators possess the potential to treat neurodegenerative diseases. [ABSTRACT FROM AUTHOR]

Necroptosis has been demonstrated to contribute to brain injury in ischemic stroke, whereas A20 can exert anti-necroptosis effect via deubiquitinating receptor-interacting protein kinase (RIPK3) at k63 and it can be cleaved by MALT1. This study aims to explore whether MALT1 is upregulated in the brain during ischemic stroke and promotes brain cell necroptosis through enhancing the degradation of A20. Ischemic stroke model was established in Sprague Dawley rats by occlusion of the middle cerebral artery (MCA) for 2 h, followed by 24 h reperfusion, which showed brain injury (increase in neurological deficit score and infarct volume) concomitant with an upregulation of MALT1, a decrease in A20 level, and increases in necroptosis-associated protein levels [RIPK3, mixed lineage kinase domain-like protein (MLKL) and p-MLKL] and k63-ubiquitination of RIPK3 in brain tissues. Administration of MALT1 inhibitor (Ml-2) at 8 or 15 mg/kg (i.p.) at 1 h after ischemia significantly improved neurological function and reduced infarct volume together with a downregulation of MALT1, an increase in A20 level and decreases in necroptosis-associated protein levels and k63-ubiquitination of RIPK3. Similarly, knockdown of MALT1 could also reduce oxygen-glucose deprivation/reoxygenation (OGD/R)-induced injury in the cultured HT22 cells coincident with an increase in A20 level and decreases in necroptosis-associated protein levels and k63-ubiquitination of RIPK3. Based on these observations, we conclude that MALT1 promotes necroptosis in stroke rat brain via enhancing the degradation of A20, which leads to a decrease in the capability of A20 to deubiquitinate RIPK3 at k63 and a subsequent compromise in counteraction against the brain cell necroptosis. Upregulation of MALT1 in ischemic stroke rat brain contributes to neuronal cell necroptosis and brain injury through promoting the degradation of A20, which leads to a decrease in the capability of A20 to deubiquitinate RIPK3 at k63. [Display omitted] • Inhibition of MALT1 exerts beneficial effect on ischemic stroke rats. • MALT1 promotes necroptosis in stroke rat brain via enhancing the degradation of A20. • Ubiquitination of RIPK3 at k63 leads to a compromise in counteraction against the brain cell necroptosis. [ABSTRACT FROM AUTHOR]

[Display omitted] Mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1) is a multifunctional protein. MALT1 functions as an adaptor protein to assemble and recruit proteins such as B-cell lymphoma 10 (BCL10) and caspase-recruitment domain (CARD)-containing coiled-coil protein 11 (CARD11). Conversely it also acts as a paracaspase to cleave specified substrates. Because of its involvement in immunity, inflammation and cancer through its dual functions of scaffolding and catalytic activity, MALT1 is becoming a promising therapeutic target in B cell- and T cell-related diseases. There is growing evidence that the function of MALT1 is subtly modulated via post-translational modifications. This review summarized recent progress in relevant studies regarding the physiological and pathophysiological functions of MALT1, post-translational modifications of MALT1 and its role in B cell- and T cell- related diseases. In addition, the current available MALT1 inhibitors were also discussed. [ABSTRACT FROM AUTHOR]

The article presents a study on measuring the drought-tolerance ability of transgenic tobacco and rice plants using salt-and drought-induced ring-finger 1 (SDIR1). Screening of independent transgenic lines, determination of the expression levels, RNA gel blot analysis and water loss assay are performed to the crop plants. It was found out that overexpressions of SDIR1 improves the drought tolerance ability and regulates the stress-related genes of transgenic tobacco and rice.

The dysregulation of nuclear factor erythroid 2-related factor 2 (Nrf2) and/or solute carrier family 7 member 11 (SLC7A11) is believed to contribute to ferroptosis in the hearts suffered ischemia/reperfusion (I/R), but the mechanisms behind the dysregulation of them are not fully elucidated. Mucosa associated lymphoid tissue lymphoma translocation gene 1 (MALT1) can function as a paracaspase to cleave specified substrates and it is predicted to interact with Nrf2. This study aims to explore whether targeting MALT1 can reduce I/R-induced ferroptosis via enhancing the Nrf2/SLC7A11 pathway. The SD rat hearts were subjected to 1h-ischemia plus 3h-reperfusion to establish the I/R injury model, which showed myocardial injuries (increase in infarct size and creatine kinase release) and up-regulation of MALT1 while downregulation of Nrf2 and SLC7A11 concomitant with the increased ferroptosis, reflecting by an increase in glutathione peroxidase 4 (GPX4) level while decreases in the levels of acyl-CoA synthetase long chain family member 4 (ACSL4), total iron, Fe2+ and lipid peroxidation (LPO); these phenomena were reversed in the presence of MI-2, a specific inhibitor of MALT1. Consistently, similar results were achieved in the cultured cardiomyocytes subjected to 8h-hypoxia plus 12h-reoxygenation. Furthermore, micafungin, an antifungal drug, could also exert beneficial effect on mitigating myocardial I/R injury via inhibition of MALT1. Based on these observations, we conclud that inhibition of MALT1 can reduce I/R-induced myocardial ferroptosis through enhancing the Nrf2/SLC7A11 pathway; and MALT1 may be used as a potential target to seek novel or existing drugs (such as micafungin) for treating myocardial infarction. [Display omitted] • Upregulation of MALT1 occurs in rat hearts suffered ischemia/reperfusion. • Inhibition of MALT1 reduces I/R-induced ferroptosis via enhancing the Nrf2/SLC7A11 pathway. • Micafungin mitigate myocardial I/R injury via inhibition of MALT1. [ABSTRACT FROM AUTHOR]

Summary In plants, the exogenous transgene transcribing inverted-repeat (exo- IR) sequences produces double-stranded RNAs that are processed by DCL4. The 21-nt small interfering RNAs generated function as mobile signals to trigger non-cell autonomous silencing of target endogenes in the neighboring 10-15 cells. The potential involvement of nuclear silencing pathway components in signal spreading or sensing in target cells is not clear. Here, we demonstrate that the exo- IR silencer (exo- Pdsi) is negatively autoregulated through methylation spreading, which acts in cis to reinforce the self-silencing of the silencer. Mutations affecting nuclear proteins DRD1 and Pol V (NRPE1 or NRPD2) relieved exo- Pdsi self-silencing, resulting in higher levels of Pdsi transcripts, which increased the non-cell autonomous silencing of endo- PDS. Our results suggest that in an experimental silencing pathway, methylation spreading on a silencer transgene may not have a direct endogenous plant counterpart when the protein-encoding gene is the target. DRD1-Pol V-dependent de novo methylation, by acting in cis to reinforce self-silencing of exo- IR, may play a role in restraining the inappropriate silencing of active protein-coding genes in plants. [ABSTRACT FROM AUTHOR]

Initiation of necroptosis has been considered as a promising strategy for anticancer therapies, especially for eradicating apoptosis-resistant malignant cells. Jujubisode B is a natural saponins extracted from the seeds of Zizyphi Spinosi Semen, and possesses multiple pharmacological activities, including antianxiety, anti-inflammation, antiplatelet aggregation and induction of apoptosis. This study aims to explore the effect of jujuboside B on acute leukemic cells and the underlying mechanisms. Our results showed that jujuboside B inhibited leukemia cell growth in a dose-dependent manner and attenuated the clonogenic ability of U937 cells, concomitant with activation of RIPK1/RIPK3/MLKL pathway; these phenomena were evidently blocked by necroptosis inhibitor (Nec-1). With the help of Molecular Operating Environment (MOE) program, we identified that RIPK1, RIPK3 and MLKL are potential targets of jujuboside B. To the best of our knowledge, this is the first study to provide evidence that jujuboside B possesses antileukemic activity via a mechanism involving activation of RIPK1/RIPK3/MLKL pathway. [ABSTRACT FROM AUTHOR]

Mitochondrial dysfunctions contribute to brain injury in ischemic stroke while disturbance of mitochondrial dynamics results in mitochondrial dysfunction. Mitochondrial E3 ubiquitin ligase 1 (Mul1) involves in regulation of mitochondrial fission and fusion. This study aims to explore whether Mul1 contributes to brain injury in ischemic stroke and the underlying mechanisms. First, a rat ischemic stroke model was established by middle cerebral artery occlusion (MCAO), which showed ischemic injuries (increase in neurological deficit score and infarct volume) and upregulation of Mul1 in brain tissues. Next, Mul1 siRNAs were injected intracerebroventricularly to knockdown Mul1 expression, which evidently attenuated brain injuries (decrease in neurological deficit score, infarct volume and caspase-3 activity), restored mitochondrial dynamics and functions (decreases in mitochondrial fission and cytochrome c release while increase in ATP production), and restored protein levels of dynamin-related protein 1 (Drp1, a mitochondrial fission protein) and mitofusin2 (Mfn2, a mitochondrial fusion protein) through suppressing their sumoylation and ubiquitination, respectively. Finally, PC12 cells were cultured under hypoxic condition to mimic the ischemic stroke. Consistently, knockdown of Mul1 significantly reduced hypoxic injuries (decrease in apoptosis and LDH release), restored protein levels of Drp1 and Mfn2, recovered mitochondrial dynamics and functions (decreases in mitochondrial fission, mitochondrial membrane potential, reactive oxygen species production and cytochrome c release while increase in ATP production). Based on these observations, we conclude that upregulation of Mul1 contributes to brain injury in ischemic stroke rats and disturbs mitochondrial dynamics through sumoylation of Drp1 and ubiquitination of Mfn2. Image 1 [ABSTRACT FROM AUTHOR]