Effects and safety of Ginkgo biloba on depression: a systematic review and meta-analysis.

Background: Because depression is a major factor contributing to the global disease burden, we tried to analyze the effects and safety of Ginkgo biloba (GKB) on patients with depression. Methods: We conducted a literature search for articles published between January 2002 and May 2022 in seven online databases (PubMed, Scopus, Embase, Google Scholar, Web of Sciences, Cochrane Library, and China National Knowledge Infrastructure). A systematic literature review and meta-analysis were performed to compare the effects and safety of GKB on patients with depression, including subjective and objective indicators of depression evaluation. Results: In total, 21 eligible articles with nine indicators among 2074 patients were included. Several outcomes showed a difference, and the GKB group had better results than the control group, including the Hamilton Depression Scale (HAMD), after taking GKB for 4 weeks (MD = -2.86, 95%CI [-4.27, -1.46], p < 0.01), 6 weeks (mean difference (MD) = -3.36, 95%CI [-4.05, -2.67], p < 0.01), and 8 weeks (MD = -4.58, 95% CI [-6.11, -3.05], p < 0.01), modified Barthel index (MBI) (MD = 14.86, 95%CI [12.07, 17.64], p < 0.01), modified Edinburgh-Scandinavian stroke scale (MESSS) (MD = -4.57, 95%CI [-6.34, -2.79], p < 0.01), brain-derived neurotrophic factor (BDNF) (MD = 16.35, 95%CI [7.34, 25.36], p < 0.01), 5-hydroxytryptamine (5-HT) (MD = 4.57, 95%CI [3.08, 6.05], p < 0.01), and clinical efficacy (risk ratio, RR = 1.24, 95%CI [1.17, 1.32], p < 0.01). However, there were no differences in adverse events between GKB and controls. Conclusion: In conclusion, the main finding was that patients treated with GKB had better MBI, MESSS, BDNF, 5-HT, and HAMD values after 4 weeks, 6 weeks, and 8 weeks than the control group. GKB might reduce the risk of depression or depressive symptoms with safe clinical efficacy. Systematic Review Registration: identifier (INPLASY2023100052).

Atypical and delayed spinal cord MRI features of COVID-19-associated myelopathies: a report of four cases and literature review.

We reported four patients with coronavirus disease 2019 (COVID-19)-associated myelopathies, highlighting the delayed and atypical spinal cord magnetic resonance imaging (MRI) features and the literature review. All four patients were males, aged 37 to 72 years old. The latencies from COVID-19 to the onset of myelitis were 5, 15, 30, and 80 days. The initial symptoms were numbness and weakness of lower limbs in three cases, and back pain with weakness of lower limbs in one case. The peak symptoms included paraplegia, sphincter dysfunction, sensory disturbance level, and spastic gait. The EDSS scores were 7.5, 9.0, 9.0, and 7.5, respectively. Magnetic resonance imaging (MRI) showed delayed atypical spinal cord lesions at onset, i.e., two cases without lesions, one with linear spinal meningeal enhancement, and one with punctate lesions on T2-weighted imaging (T2WI). During the follow-up period, punctate, linear, and cloudy lesions in the lateral and posterior funiculus were seen on T2WI in the peak stage. The prominent features of spinal cord lesions were linear spinal meningeal enhancement, the mismatch of deteriorated clinical symptoms, and inapparent MRI findings. All four patients were left with an obvious disability, with two patients completely bedridden and two who could stand with support. This report highlights the recognition of COVID-19-associated myelopathy even months after initial infection, especially in patients with delayed and atypical spinal cord findings on MRI.

Effects of tau on Aß-induced synaptic damage in a Drosophila model of Alzheimer's disease.

OBJECTIVES: The etiology and pathologic mechanism underlying Alzheimer's disease (AD) are not clear. This study determined the effects of tau on amyloid-beta peptide(Aß)-induced synaptic damages in a Drosophila model of AD. METHODS: Galactose-regulated upstream promoter element 4(Gal4) and an upstream active sequence system was used to establish four kinds of Aß transgenic Drosophila models of AD. Behavioral evaluation and immunohistochemical localization were performed in Aß transgenic Drosophila models. Tau mutants were introduced into arctic mutant Aß1-42 (arctic mutant Aß [Aßarc]) Drosophila. The P{Gal4}A307 Drosophila strain was used as a control group; 12 strains were obtained to determine the effects of tau with or without Aßarc. Electrophysiologic records of the tau mutant groups were created. RESULTS: The flight and crawling ability of Aß transgenic Drosophila were gradually weakened compared to the control group, and the life span was significantly shorter than the control group. Aß was specifically expressed in the Drosophila giant fiber pathway and further accumulated in neuronal cell bodies based on immunohistochemistry. The percentage of the excitatory junctional potential (EJP) response in transgenic Drosophila expressing Aßarc was significantly decreased, which was approximately 40% lower than the control group. The tau deletion mutation alleviated the synaptic transmission disorder caused by Aß and improved the viability of Drosophila. CONCLUSION: The tau deletion mutation significantly improved the synaptic damage caused by Aß, and tau protein played an indispensable role in the synaptic dysfunction caused by Aß, suggesting that Aß and tau have close interactions in the pathogenesis of AD.

MoS2 Decorated Silver Nanowire-Reduced Graphene Oxide Aerogel Micro-Particle for Thermally Conductive Polymer Composites with Enhanced Flame Retardancy.

Multifunctional polymer composites with efficient heat dissipation and flame retardancy are highly desirable in the electronic industry. Here, by the combination of hydrothermal reaction and in situ fragmentation, molybdenum disulfide (MoS2 ) decorated silver nanowires (AgNWs) and 3D reduced graphene oxide (RGO) (AgNW-RGO@MoS2 ) aerogel micro-particles (AMPs) are successfully prepared. When the above AMP is introduced to epoxy (EP) resin by the simple blending method, a polymer composite with continuous thermally conductive pathways and flame barrier layers is achieved. With an AMP loading of 4.0 vol.%, the polymer composite displays superior enhancement in thermal conductivity up to 420%. Compared to neat EP, the peak heat release rate and total heat release decreases by 61.1% and 58.8%, respectively. This work provides new insights into the design and large-scale fabrication of multifunctional polymer composites for efficient thermal management materials.

Plant AFC2 kinase desensitizes thermomorphogenesis through modulation of alternative splicing.

High ambient temperatures have adverse impacts on crop yields. Although a few plant thermosensors have been reported, these sensors directly or indirectly impact PIF4-controlled transcriptional regulation. Moreover, high temperatures also trigger a number of post-transcriptional alternative splicing events in plants and even in animals. Here, we show that LAMMER kinase AFC2 in Arabidopsis controls high-temperature-triggered alternative splicing. Plants without AFC2 exhibited distorted splicing patterns at a high ambient temperature. Further investigations revealed that high temperatures triggered alternative splicing in the majority of PIF4 target genes as a means of desensitizing PIF4 signaling. Consistently, the afc2 mutants exhibited more exaggerated high ambient temperature responses in a PIF4-dependent manner. AFC2 directly phosphorylated the serine/arginine-rich protein splicing factor RSZ21, and AFC2 kinase activity decreased with increasing temperature, indicating that the AFC2 itself may sense temperature changes. In summary, we report that alternative splicing is a safe-guard mechanism when plants encounter high temperature.

Plant responses to high temperature: a view from pre-mRNA alternative splicing.

KEY MESSAGE: This review focused on the recent breakthroughs in plant high temperature responses from an alternative splicing angle. With the inevitable global warming, high temperature triggers plants to change their growth and developmental programs for adapting temperature increase. In the past decades, the signaling mechanisms from plant thermo-sensing to downstream transcriptional cascades have been extensively studied. Plenty of elegant review papers have summarized these breakthroughs from signal transduction to cross-talk within plant hormones and environmental cues. Precursor messenger RNA (pre-mRNA) splicing enables plants to produce a series of functional un-related proteins and thus enhances the regulation flexibility. Plants take advantage of this strategy to modulate their proteome diversity under high ambient temperature and elicit developmental plasticity. In this review, we particularly focus on pre-mRNA splicing regulation underlying plant high temperature responses, and will shed new light on the understanding of post-transcriptional regulation on plant growth and development.

PIF4 and HOOKLESS1 Impinge on Common Transcriptome and Isoform Regulation in Thermomorphogenesis.

High temperature activates the transcription factor PHYTOCHROME-INTERACTING FACTOR4 (PIF4) to stimulate auxin signaling, which causes hypocotyl elongation and leaf hyponasty (thermomorphogenesis). HOOKLESS1 (HLS1) is a recently reported positive regulator of thermomorphogenesis, but the molecular mechanisms by which HLS1 regulates thermomorphogenesis remain unknown. In this study, we initially compared PIF4- and/or HLS1-dependent differential gene expression (DEG) upon high-temperature treatment. We found that a large number of genes are coregulated by PIF4 and HLS1, especially genes involved in plant growth or defense responses. Moreover, we found that HLS1 interacts with PIF4 to form a regulatory module and that, among the HLS1-PIF4-coregulated genes, 27.7% are direct targets of PIF4. We also identified 870 differentially alternatively spliced genes (DASGs) in wild-type plants under high temperature. Interestingly, more than half of these DASG events (52.4%) are dependent on both HLS1 and PIF4, and the spliceosome-defective mutant plantsexhibit a hyposensitive response to high temperature, indicating that DASGs are required for thermomorphogenesis. Further comparative analyses showed that the HLS1/PIF4-coregulated DEGs and DASGs exhibit almost no overlap, suggesting that high temperature triggers two distinct strategies to control plant responses and thermomorphogenesis. Taken together, these results demonstrate that the HLS1-PIF4 module precisely controls both transcriptional and posttranscriptional regulation during plant thermomorphogenesis.

Emerging Plant Thermosensors: From RNA to Protein.

How plants sense temperature is an important question. Here, we highlight recent achievements in identifying plant thermosensors, including RNA switch and protein-DNA binding ability. Finally, we borrow an idea from one recent mammalian study and propose a putative temperature-sensitive kinase as a thermosensory mechanism.

Levodopa/Benserazide PLGA Microsphere Prevents L-Dopa-Induced Dyskinesia via Lower ß-Arrestin2 in 6-Hydroxydopamine Parkinson's Rats.

Prolonged pulsatile administration of Levodopa (L-dopa) can generate L-dopa-induced dyskinesia (LID). Numerous research has reported that continuous dopamine delivery (CDD) was useful in reducing the severity of LID. 6-OHDA lesioned rats were divided into two groups to receive intermittent L-dopa stimulation (L-dopa/benserazide) or Levodopa/benserazide PLGA microsphere (LBPM) for 3 weeks. rAAV (recombinant adeno-associated virus) vector was used to overexpress and ablation of ß-arrestin2. We found that LBPM developed less AIM severity compared with standard L-dopa administration, whereas selective deletion of ß-arrestin2 in striatum neurons dramatically enhanced the severity of dyskinesia by LBPM. On the contrary, the effects of LBPM in terms of ALO AIM were further relieved by ß-arrestin2 overexpression. Furthermore, no significant change in motor behavior was seen either in inhibition or overexpression of ß-arrestin2. In short, our experiments provided evidence that LBPM's prevention of LID behavior was likely due to ß-arrestin2, suggesting that a therapy modulating ß-arrestin2 may offer a more efficient anti-dyskinetic method with a low risk of untoward effects.

Partial Depletion of Peripheral M1 Macrophages Reverses Motor Deficits in MPTP-Treated Mouse by Suppressing Neuroinflammation and Dopaminergic Neurodegeneration.

Background: Neuroinflammation plays an important role in the pathogenesis of Parkinson's disease (PD). Inflammatory cytokines in the peripheral immune system can induce neuroinflammation in central nervous system (CNS). Whether the peripheral immune system is involved in PD is unclear. The present study investigated the contribution of the peripheral immune system to the neuronal loss in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine(MPTP) model of PD. Methods: MPTP was intraperitoneally injected into mice to generate a PD model. Mice received clodronate liposomes every 3 days to deplete peripheral macrophages. The percentages of macrophages were measured by flow cytometry at 1, 3, and 7 days after MPTP injection. Neurobehavioral parameters, protein expression, inflammatory cytokines release, and microglia activation were measured by the open field test, western blotting, quantitative polymerase chain reaction (qPCR), and immunofluorescence staining, respectively at 7 days after MPTP injection. Results: Our study revealed that intraperitoneal injection of MPTP could increase peripheral M1 macrophages levels. It also can induce T cells infiltration and cytokine release. Depletion of M1 macrophages by clodronate liposomes suppressed these inflammatory effects and blunted the loss of TH+ nigral neurons and functional impairments caused by MPTP. Conclusion: Our results indicated the critical role of M1 macrophages in the pathogenesis of PD and proposed inhibition of M1 macrophages as a promising therapeutic approach for neurodegeneration.

Idebenone Alleviates Neuroinflammation and Modulates Microglial Polarization in LPS-Stimulated BV2 Cells and MPTP-Induced Parkinson's Disease Mice.

Background: Idebenone is an antioxidant and a coenzyme Q10 analog that has been used to treat neurodegeneration disease. Some studies show idebenone exerts anti-inflammatory effects. However, whether idebenone can be used to reduce the neuroinflammation in Parkinson's disease (PD) has been little studied. Methods: The study investigated the potential anti-inflammatory effects of idebenone in vitro and in vivo, using cell models of Lipopolysaccharide (LPS)-simulated BV2 cells and animal models of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD with or without idebenone. To verify how idebenone exerts its effects on the BV2 cell activation and PD model, we performed the mechanistic studies in vitro and in vivo. Results: In vitro study showed that pretreatment with idebenone could attenuate the production of pro-inflammatory factors in LPS-stimulated BV2 cells and promoted a phenotypic switch from the M1 state to the M2 state. Mechanistically, idebenone reduced the activation of the MAPK and NF-κB signaling pathway upon LPS stimulation. Furthermore, in vivo experiments confirmed that pretreatment with idebenone could ameliorate MPTP-induced neurodegeneration and modulate microglia phenotypes through inhibition of the MAPK and NF-κB signaling pathway in the SN. Conclusion: These results suggest that idebenone ameliorates the neurological deficits related to PD and this effect is partly mediated by inhibiting the neuroinflammation and modulating microglia phenotypes.

Lipoic acid alleviates L­DOPA­induced dyskinesia in 6­OHDA parkinsonian rats via anti­oxidative stress.

Levodopa (L­DOPA) is the gold standard for symptomatic treatment of Parkinson's disease (PD); however, long­term therapy is associated with the emergence of L­DOPA­induced dyskinesia (LID). Nigral dopaminergic cell loss determines the degree of drug exposure and time required for the initial onset of LID. Accumulating evidence indicates that α­lipoic acid (ALA) decreases this nigral dopaminergic cell loss. However, until now, the precise mechanisms of ALA have only been partially understood in LID. Chronic L­DOPA treatment was demonstrated to develop intense AIM scores to assess dyskinetic symptoms. Rats in the LID group were administrated twice daily with L­DOPA + benserazide for 3 weeks to induce a rat model of dyskinesia. Moreover, other 6­OHDA­lesioned rats were treatment with ALA (31.5 mg/kg or 63 mg/kg) in combination with L­DOPA treatment. Furthermore, the authors investigated the level of malondialdehyde (MDA) and glutathione (GSH) activity, as well as IBa­1, caspase­3 and poly (ADP-ribose) polymerase (PARP) in substantia nigra by the way of western blotting and immunofluorescence. ALA reduced LID in a dose­dependent manner without compromising the anti­PD effect of L­DOPA. Moreover, ALA reduced the level of MDA and upregulated the GSH activity, as well as ameliorated IBa­1 positive neurons in the substantia nigra. Finally, it was identified that ALA could reduce L­DOPA­induced cleaved­caspase­3 and PARP overexpression in the substantia nigra. Based on the present findings, ALA could be recommended as a promising disease­modifying therapy when administered with L­DOPA early in the course of PD. The exact mechanism for this action, although incompletely understood, appears to relate to anti­oxidative stress and anti­apoptosis.

Antidyskinetic Treatment with MTEP Affects Multiple Molecular Pathways in the Parkinsonian Striatum.

Parkinson's disease is characterized by dopaminergic neuron loss and dopamine (DA) depletion in the striatum. Standard treatment is still focused on the restoration of dopamine with exogenous L-Dopa, which however causes L-Dopa-induced dyskinesia (LID). Several studies have shown that antagonism of the metabotropic glutamate receptor 5 alleviates LID, but the underlying mechanisms have remained unclear. We set out to determine where this alleviation may depend on restoring the equilibrium between the two main striatofugal pathways. For this purpose, we examined molecular markers of direct and indirect pathway involvement (prodynorphin and proenkephalin, resp.) in a rat model of LID treated with the mGluR5 antagonist MTEP. Our results show that MTEP cotreatment significantly attenuates the upregulation of prodynorphin mRNA induced by L-Dopa while also decreasing the expression levels of proenkephalin mRNA. We also examined markers of the mGluR5-related PKC/MEK/ERK1/2 signaling pathway, finding that both the expression of PKC epsilon and the phosphorylation of MEK and ERK1/2 had decreased significantly in the MTEP-treated group. Taken together, our results show that pharmacological antagonism of mGluR5 normalizes several abnormal molecular responses in the striatum in this experimental model of LID.

Current Experimental Studies of Gene Therapy in Parkinson's Disease.

Parkinson's disease (PD) was characterized by late-onset, progressive dopamine neuron loss and movement disorders. The progresses of PD affected the neural function and integrity. To date, most researches had largely addressed the dopamine replacement therapies, but the appearance of L-dopa-induced dyskinesia hampered the use of the drug. And the mechanism of PD is so complicated that it's hard to solve the problem by just add drugs. Researchers began to focus on the genetic underpinnings of Parkinson's disease, searching for new method that may affect the neurodegeneration processes in it. In this paper, we reviewed current delivery methods used in gene therapies for PD, we also summarized the primary target of the gene therapy in the treatment of PD, such like neurotrophic factor (for regeneration), the synthesis of neurotransmitter (for prolong the duration of L-dopa), and the potential proteins that might be a target to modulate via gene therapy. Finally, we discussed RNA interference therapies used in Parkinson's disease, it might act as a new class of drug. We mainly focus on the efficiency and tooling features of different gene therapies in the treatment of PD.

Inhibition of Glycogen Synthase Kinase-3ß (GSK-3ß) as potent therapeutic strategy to ameliorates L-dopa-induced dyskinesia in 6-OHDA parkinsonian rats.

Levodopa (L-dopa) is the dominating therapy drug for exogenous dopaminergic substitution and can alleviate most of the manifestations of Parkinson's disease (PD), but long-term therapy is associated with the emergence of L-dopa-induced dyskinesia (LID). Evidence points towards an involvement of Glycogen Synthase Kinase-3ß (GSK-3ß) in development of LID. In the present study, we found that animals rendered dyskinetic by L-dopa treatment, administration of TDZD8 (2mg/kg) obviously prevented the severity of AIM score, as well as improvement in motor function (P < 0.05). Moreover, the TDZD8-induced reduction in dyskinetic behavior correlated with a reduction in molecular correlates of LID. TDZD8 reduced the phosphorylation levels of tau, DARPP32, ERK and PKA protein, which represent molecular markers of LID, as well as reduced L-dopa-induced FosB mRNA and PPEB mRNA levels in the lesioned striatum. In addition, we found that TDZD8 antidyskinetic properties were overcome by D1 receptor, as pretreatment with SKF38393 (5 mg/kg, 10 mg/kg, respectively), a D1 receptor agonist, blocked TDZD8 antidyskinetic actions. This study supported the hypothesis that GSK-3ß played an important role in the development and expression of LID. Inhibition of GSK-3ß with TDZD8 reduced the development of ALO AIM score and associated molecular changes in 6-OHDA-lesioned rats.

Intraneuronal accumulation of Aß42 induces age-dependent slowing of neuronal transmission in Drosophila.

Beta amyloid (Aß42)-induced dysfunction and loss of synapses are believed to be major underlying mechanisms for the progressive loss of learning and memory abilities in Alzheimer's disease (AD). The vast majority of investigations on AD-related synaptic impairment focus on synaptic plasticity, especially the decline of long-term potentiation of synaptic transmission caused by extracellular Aß42. Changes in other aspects of synaptic and neuronal functions are less studied or undiscovered. Here, we report that intraneuronal accumulation of Aß42 induced an age-dependent slowing of neuronal transmission along pathways involving multiple synapses.