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Objective To evaluate the clinical effect of Tension-free laparoscopic lateral suspension with mesh for pelvic organ prolapse. Methods A total of 85 patients who underwent pelvic organ prolapse were selected as the study group, and 40 patients underwent Laparoscopic sacral fixation surgery(LSC) as the control group in Henan Provincial People's Hospital from March 1, 2021 to October 31, 2023. The patients were divided into two subgroups' uterine preservation group and uterine resection group and followed up until April 30, 2024. The intraoperative conditions and postoperative complications were recorded and analyzed. POP quantitative staging(POP-Q) scores were used for evaluation. Preoperative and postoperative quality of life and therapeutic effect were evaluated using the pelvic floor distress inventory short form-20(PFDI-20), urinary distress inventory-6 (UDI-6), colorectalanal distress inventory-8 (CRADI-8), pelvic organ prolapse distress inventory-6(POPDI-6), pelvic floor impact questionnaire-7(PFIQ-7), prolapse and Incontinence sexual function questionnaire short form(PISQ-12). Results The median follow-up time for patients in the study group is 13.13 months, with an objective cure rate of 96.47% and a reoperation rate of 1.18%. The perioperative complication rates are 6.45% for uterine resection and 4.35% for uterine preservation, while the mesh exposure rate is 1.61% for uterine resection. In comparison, the median follow-up time for patients in the control group is slightly longer at 13.76 months, with an objective cure rate of 92.5% and a reoperation rate of 2.5%. The perioperative complication rates are higher at 14.71% for uterine resection and as high as 33.33% for uterine preservation, while the mesh exposure rate is also elevated at 8.82% for uterine resection. Despite these differences, there was no significant disparity in objective cure rates or reoperation rates between the study group and the control group. Furthermore, it was observed that the study group experienced shorter operation times, less bleeding, faster postoperative recovery, shorter hospitalization periods, lower perioperative complications, and reduced mesh exposure rates -especially among patients with uterine preservation. Additionally, intra-group comparisons revealed significant improvements in all POP-Q indicators one year after surgery (P < 0.05), along with significantly lower scores on PFDI-20, UDI-6, CRADI-8, POPDI-6, PFIQ-7, and PISQ-12 scales compared to pre-surgery levels (P < 0.05). However, no significant inter-group differences were noted. Conclusions Tension-free laparoscopic lateral suspension with mesh proves to be an effective surgical approach for treating anteriorand middle pelvic organ prolapse. It demonstrates few perioperative complications while significantly improving prolapse symptoms and enhancing patient qualityof life. It stands as a viable alternative to sacrocolpopexy, particularly beneficial for patients with a preserved uterus. [ABSTRACT FROM AUTHOR]

The aryl hydrocarbon receptor (AhR) is a transcription factor that regulates the immune system through complicated transcriptional programs. Genistein, an AhR ligand, exhibits anti-inflammatory properties. However, its role in modulating immune responses via the AhR signaling pathway remains unclear. In this study, 360 male Arbor Acre broilers (1-day-old) were fed a basal diet supplemented with 40 or 80 mg/kg genistein and infected with or without Clostridium perfringens (Cp). Our results demonstrated that genistein ameliorated Cp-induced intestinal damage, as reflected by the reduced intestinal lesion scores and improved intestinal morphology and feed-to-gain ratio. Moreover, genistein increased intestinal sIgA, TGF-β, and IL-10, along with elevated serum IgG, IgA, and lysozyme levels. Genistein improved intestinal AhR and cytochrome P450 family 1 subfamily A member 1 (CYP1A1) protein levels and AhR+ cell numbers in Cp-challenged broilers. The increased number of AhR+CD163+ cells in the jejunum suggested a potential association between genistein-induced AhR activation and anti-inflammatory effects mediated through M2 macrophage polarization. In IL-4-treated RAW264.7 cells, genistein increased the levels of AhR, CYP1A1, CD163, and arginase (Arg)-1 proteins, as well as IL-10 mRNA levels. This increase was attenuated by the AhR antagonist CH223191. In summary, genistein activated the AhR signaling pathway in M2 macrophages, which enhanced the secretion of anti-inflammatory cytokines and attenuated intestinal damage in Cp-infected broilers Cp. [ABSTRACT FROM AUTHOR]

DJ‐1, also known as Parkinson's disease protein 7 (Park7), is a multifunctional protein that regulates oxidative stress and mitochondrial function. Dysfunction of DJ‐1 is implicated in the pathogenesis of Parkinson's disease (PD). Hyperhomocysteinemia is associated with an increased risk of PD. Here we show that homocysteine thiolactone (HTL), a reactive thioester of homocysteine (Hcy), covalently modifies DJ‐1 on the lysine 182 (K182) residue in an age‐dependent manner. The N‐homocysteinylation (N‐hcy) of DJ‐1 abolishes its neuroprotective effect against oxidative stress and mitochondrial dysfunction, exacerbating cell toxicity. Blocking the N‐hcy of DJ‐1 restores its protective effect. These results indicate that the N‐hcy of DJ‐1 abolishes its neuroprotective effect and promotes the progression of PD. Inhibiting the N‐hcy of DJ‐1 may exert neuroprotective effect against PD. [ABSTRACT FROM AUTHOR]

The bridging integrator 1 (BIN1) gene is an important risk locus for late-onset Alzheimer's disease (AD). BIN1 protein has been reported to mediate tau pathology, but the underlying molecular mechanisms remain elusive. Here, we show that neuronal BIN1 is cleaved by the cysteine protease legumain at residues N277 and N288. The legumain-generated BIN1 (1–277) fragment is detected in brain tissues from AD patients and tau P301S transgenic mice. This fragment interacts with tau and accelerates its aggregation. Furthermore, the BIN1 (1–277) fragment promotes the propagation of tau aggregates by enhancing clathrin-mediated endocytosis (CME). Overexpression of the BIN1 (1–277) fragment in tau P301S mice facilitates the propagation of tau pathology, inducing cognitive deficits, while overexpression of mutant BIN1 that blocks its cleavage by legumain halts tau propagation. Furthermore, blocking the cleavage of endogenous BIN1 using the CRISPR/Cas9 gene-editing tool ameliorates tau pathology and behavioral deficits. Our results demonstrate that the legumain-mediated cleavage of BIN1 plays a key role in the progression of tau pathology. Inhibition of legumain-mediated BIN1 cleavage may be a promising therapeutic strategy for treating AD. [ABSTRACT FROM AUTHOR]

The aggregation of α‐synuclein plays a pivotal role in the pathogenesis of Parkinson's disease (PD). Epidemiological evidence indicates that high level of homocysteine (Hcy) is associated with an increased risk of PD. However, the molecular mechanisms remain elusive. Here, we report that homocysteine thiolactone (HTL), a reactive thioester of Hcy, covalently modifies α‐synuclein on the K80 residue. The levels of α‐synuclein K80Hcy in the brain are increased in an age‐dependent manner in the TgA53T mice, correlating with elevated levels of Hcy and HTL in the brain during aging. The N‐homocysteinylation of α‐synuclein stimulates its aggregation and forms fibrils with enhanced seeding activity and neurotoxicity. Intrastriatal injection of homocysteinylated α‐synuclein fibrils induces more severe α‐synuclein pathology and motor deficits when compared with unmodified α‐synuclein fibrils. Increasing the levels of Hcy aggravates α‐synuclein neuropathology in a mouse model of PD. In contrast, blocking the N‐homocysteinylation of α‐synuclein ameliorates α‐synuclein pathology and degeneration of dopaminergic neurons. These findings suggest that the covalent modification of α‐synuclein by HTL promotes its aggregation. Targeting the N‐homocysteinylation of α‐synuclein could be a novel therapeutic strategy against PD. [ABSTRACT FROM AUTHOR]

Aims: Alterations in neuronal activity and cerebral hemodynamics have been reported in idiopathic generalized epilepsy (IGE) patients, possibly resulting in neurovascular decoupling; however, no neuroimaging evidence confirmed this disruption. This study aimed to investigate the possible presence of neurovascular decoupling and its clinical implications in childhood IGE using resting‐state fMRI and arterial spin labeling imaging. Methods: IGE patients and healthy participants underwent resting‐state fMRI and arterial spin labeling imaging to calculate degree centrality (DC) and cerebral blood flow (CBF), respectively. Across‐voxel CBF‐DC correlations were analyzed to evaluate the neurovascular coupling within the whole gray matter, and the regional coupling of brain region was assessed with the CBF/DC ratio. Results: The study included 26 children with IGE and 35 sex‐ and age‐matched healthy controls (HCs). Compared with the HCs, the IGE group presented lower across‐voxel CBF‐DC correlations, higher CBF/DC ratio in the right posterior cingulate cortex/precuneus, middle frontal gyrus, and medial frontal gyrus (MFG), and lower ratio in the left inferior frontal gyrus. The increased CBF/DC ratio in the right MFG was correlated with lower performance intelligence quotient scores in the IGE group. Conclusion: Children with IGE present altered neurovascular coupling, associated with lower performance intelligence quotient scores. The study shed a new insight into the pathophysiology of epilepsy and provided potential imaging biomarkers of cognitive performances in children with IGE. [ABSTRACT FROM AUTHOR]

The aggregation and prion-like propagation of α-synuclein are involved in the pathogenesis of Parkinson's disease. However, the underlying mechanisms regulating the assembly and spreading of α-synuclein fibrils remain poorly understood. Tau co-deposits with α-synuclein in the brains of Parkinson's disease patients, suggesting a pathological interplay between them. Here we show that tau interacts with α-synuclein and accelerates its aggregation. Compared with pure α-synuclein fibrils, the tau-modified α-synuclein fibrils show enhanced seeding activity, inducing mitochondrial dysfunction, synaptic impairment and neurotoxicity in vitro. Injection of the tau-modified α-synuclein fibrils into the striatum of mice induces more severe α-synuclein pathology, motor dysfunction and cognitive impairment when compared with the mice injected with pure α-synuclein fibrils. Knockout of tau attenuates the propagation of α-synuclein pathology and Parkinson's disease-like symptoms both in mice injected with α-syn fibrils and α-syn A53T transgenic mice. In conclusion, tau facilitates α-synuclein aggregation and propagation in Parkinson's disease. [ABSTRACT FROM AUTHOR]

Background: Studies have demonstrated that adults with idiopathic generalized epilepsy (IGE) have functional abnormalities; however, the neuropathological pathogenesis differs between adults and children. This study aimed to explore alterations in the cerebral blood flow (CBF) and functional connectivity (FC) to comprehensively elucidate the neuropathological mechanisms of IGE in children. Methods: We obtained arterial spin labeling (ASL) and resting state functional magnetic resonance imaging data of 28 children with IGE and 35 matched controls. We used ASL to determine differential CBF regions in children with IGE. A seed-based whole-brain FC analysis was performed for regions with significant CBF changes. The mean CBF and FC of brain areas with significant group differences was extracted, then its correlation with clinical variables in IGE group was analyzed by using Pearson correlation analysis. Results: Compared to controls, children with IGE had CBF abnormalities that were mainly observed in the right middle temporal gyrus, right middle occipital gyrus (MOG), right superior frontal gyrus (SFG), left inferior frontal gyrus (IFG), and triangular part of the left IFG (IFGtriang). We observed that the FC between the left IFGtriang and calcarine fissure (CAL) and that between the right MOG and bilateral CAL were decreased in children with IGE. The CBF in the right SFG was correlated with the age at IGE onset. FC in the left IFGtriang and left CAL was correlated with the IGE duration. Conclusion: This study found that CBF and FC were altered simultaneously in the left IFGtriang and right MOG of children with IGE. The combination of CBF and FC may provide additional information and insight regarding the pathophysiology of IGE from neuronal and vascular integration perspectives. [ABSTRACT FROM AUTHOR]

Synaptic dysfunction is a key feature of Alzheimer's disease (AD). However, the molecular mechanisms underlying synaptic dysfunction remain unclear. Here, we show that synapsin Ⅰ, one of the most important synaptic proteins, is fragmented by the cysteine proteinase asparagine endopeptidase (AEP). AEP cleaves synapsin at N82 in the brains of AD patients and generates the C‐terminal synapsin Ⅰ (83–705) fragment. This fragment is abnormally distributed in neurons and induces synaptic dysfunction. Overexpression of AEP in the hippocampus of wild‐type mice results in the production of the synapsin Ⅰ (83–705) fragment and induces synaptic dysfunction and cognitive deficits. Moreover, overexpression of the AEP‐generated synapsin Ⅰ (83–705) fragment in the hippocampus of tau P301S transgenic mice and wild‐type mice promotes synaptic dysfunction and cognitive deficits. These findings suggest a novel mechanism of synaptic dysfunction in AD. [ABSTRACT FROM AUTHOR]

Netrin‐1 is a chemotropic cue mediating axon growth and neural migration in neuronal development, and its receptors deletion in colorectal cancer and UNC5s act as dependence receptors regulating neuronal apoptosis. Asparagine endopeptidase (AEP) is an age‐dependent protease that cuts human alpha‐synuclein (α‐Syn) at N103 and triggers its aggregation and neurotoxicity. In the current study, it is reported that UNC5C receptor is cleaved by AEP in Parkinson's disease (PD) and facilitates dopaminergic neuronal loss. UNC5C is truncated by active AEP in human α‐SNCA transgenic mice in an age‐dependent manner or induced by neurotoxin rotenone. Moreover, UNC5C is fragmented by AEP in PD brains, inversely correlated with reduced netrin‐1 levels. Netrin‐1 deprivation in primary cultures induces AEP and caspase‐3 activation, triggering UNC5C proteolytic fragmentation and enhancing neuronal loss. Noticeably, blocking UNC5C cleavage by AEP attenuates netrin‐1 deprivation‐elicited neuronal death and motor disorders in netrin flox/flox mice. Overexpression of AEP‐truncated UNC5C intracellular fragment strongly elicits α‐Syn aggregation and dopaminergic loss, locomotor deficits in α‐SNCA transgenic mice. Hence, the findings demonstrate that netrin‐1 reduction and UNC5C truncation by AEP contribute to PD pathogenesis. [ABSTRACT FROM AUTHOR]

Purpose. To investigate the correlation between sonographic and computed tomography and pathological features of basal cell adenomas (BCAs) of the parotid gland. Methods. This retrospective study included 41 patients (43 tumors) with BCAs. The tumors were divided into three types based on their location in the parotid gland and their imaging features. The features of the tumors were analyzed. Results. Imaging manifestations and corresponding pathological results of most BCAs of the parotid glands resembled those of benign parotid gland tumors. Malignant transformation occurred in membranous BCAs and in those with extensive cribriform structures. Type-II and type-III tumors accounted for 82.93% of the total proportion. Thirteen tumors showed cystic degeneration with 30.23%, among which type-III tumors could easily develop cystic degeneration. These cystic areas might correspond to cystic degeneration or focal necrosis. Cystic change was not dependent on the tumor size. The pathological features of the tumors were correlated to their imaging manifestations. Conclusion. Most BCAs of the parotid glands have imaging manifestations similar to those of benign parotid gland tumors. BCAs with extensive cribriform structures and of the membranous type can show malignant transformation and should be treated with caution in clinical practice. [ABSTRACT FROM AUTHOR]

Background: The accessory spleen has no anatomical or vascular relationship with the normal spleen, The tissue structure and physiological function of the accessory spleen are the same as those of the normal spleen, which usually locate in the splenic hilum and the tail of the pancreas. The aims of this manuscript are to present a rare case of the gastric accessory spleen and a review of the literature.Case Presentation: A 19-year-old male patient was sent to the emergency department with stomach bleeding after drinking alcohol. The computed tomographic scan showed a 1.2 cm × 1.7 cm mass at the lesser curvature of the gastric fundus. Gastrointestinal endoscopy displayed a submucosal elevated lesion on the gastric fundus, and gastrectomy was performed. Postoperative pathological examination proved an accessory spleen in the stomach. The postoperative course was uneventful, and the patient was discharged on the 6th day after the surgery.Conclusions: The accessory spleen at the fundus of stomach is extremely rare, especially in this case, which is accompanied by acute gastric bleeding, and it is difficult to diagnosis before operation. Many literatures reported that it was misdiagnosis as tumor, so it is necessary to diagnose accessory spleen correctly. [ABSTRACT FROM AUTHOR]

Cerebral oedema is a major pathological change of acute carbon monoxide (CO) poisoning, the pathogenesis of which is still unclear. In the aquaporin (AQP) water channel family, AQP1 and AQP4 play critical roles in the progress of cerebral oedema of various neuropathological events. However, their functions in CO poisoning have not been demonstrated. In this study, we investigated the expressions of AQPs and associated mechanisms of brain injury in an acute CO poisoning rat model. Compared with the control injected intraperitoneally with equal volume of air, the dry weight/wet weight (DW/WW) ratio of brain water content, levels of AQP1, AQP4, phosph‐p38 mitogen‐activated protein kinase (p‐p38 MAPK) and astrocyte marker, glial fibrillary acidic protein (GFAP) in the frontal cortex and hippocampal CA1 of acute CO poisoning group significantly increased at 6, 12, 24 hours after CO injection. Intracerebroventricular injection with a p38 MAPK inhibitor, SB203580 (200 µmol/L/kg/d), before CO injection reduced water content in the brain tissues and significantly decreased levels of AQP1, AQP4, p‐p38 MAPK and GFAP. Therefore, our study showed that the overexpressions of AQP1 and AQP4 were involved in the development of CO poisoning‐induced cerebral oedema, which could be attenuated by inhibition of p‐p38 MAPK signalling. Manipulation of AQPs and p38 MAPK may be a new therapeutic strategy for acute CO poisoning. [ABSTRACT FROM AUTHOR]

7,8-Dihydroxyflavone (7,8-DHF) is thought to be a promising therapeutic agent for various neurodegenerative diseases. The major purpose of this study was to investigate the neuroprotective effects of 7,8-DHF on the rotenone-induced motor deficit of Parkinson's disease. Nine-month-old rats were treated with rotenone (2 mg/kg/day, i.h.) for 5 weeks to establish the animal model of Parkinson's disease (PD), and 7,8-DHF (5 mg/kg, i.p.) was administrated daily throughout the whole period of rotenone injection. Five weeks later, an open field test was used to assess the motor ability of the animals. TH immunostaining was performed to evaluate rotenone-induced neurotoxicity on substantia nigra (SN) dopaminergic neurons and the DA terminals in the striatum. Western blot analyses were used to examine the expressions of TH, BDNF/TrkB signaling cascades, phospho-α-synuclein (Ser129), α-synuclein, and phospho-tau (Ser396) in SN. The results revealed that treatment with 7,8-DHF improved PD model's behavioral performance and reduced dopaminergic neuron loss in the SN and striatum, associated with the activation of TrkB receptors and its signaling cascades, and reduced p-MAPK, p-α-synuclein, and p-tau. Collectively, these results indicated that 7,8-DHF displayed prominent neuroprotective properties, providing a promising therapeutic strategy for PD treatment. [ABSTRACT FROM AUTHOR]

Thyrotropin-releasing hormone (TRH) and its analogs are able to stimulate the release of the endogenic dopamine (DA) in the central nervous system. However, this effect has not been tested in the Parkinson's disease (PD), which is characterized by the DA deficiency due to the dopaminergic neurons loss in the substantia nigra. Here, we investigated the therapeutic effect of Taltirelin, a long-acting TRH analog on 6-hydroxydopamine-lesioned hemi-Parkinsonian rat model. 1–10 mg/kg Taltirelin i.p. administration significantly improved the locomotor function and halted the electrophysiological abnormities of PD animals without inducing dyskinesia even with high-dose for 7 days treatment. Microdialysis showed that Taltirelin gently and persistently promoted DA release in the cortex and striatum, while L-DOPA induced a sharp rise of DA especially in the cortex. The DA-releasing effect of Taltirelin was alleviated by reserpine, vanoxerine (GBR12909) or AMPT, indicating a mechanism involving vesicular monoamine transporter-2 (VMAT-2), dopamine transporter (DAT) and tyrosine hydroxylase (TH). The in vivo and in vitro experiments further supported that Taltirelin affected the regulation of TH expression in striatal neurons, which was mediated by p-ERK1/2. Together, this study demonstrated that Taltirelin improved motor function of hemi-PD rats without inducing dyskinesia, thus supporting a further exploration of Taltirelin for PD treatment. [ABSTRACT FROM AUTHOR]

Vascular cognitive impairment (VCI) encompasses all causes of cerebrovascular disease that lead to cognitive decline, or overt dementia, atherosclerotic disease being the most common contributor. However, few rodent models that mimic the pathology of VCI replicated the clinical cerebrovascular atherosclerosis. Here we aimed to investigate the mechanism underlying VCI in an Apolipoprotein E knockout (ApoE -KO) mouse model fed with western style food with implantation of bilateral shear stress modifiers. We established a cognitive decline in spatial learning and memory developed in the bilateral modifier treated mice. Brain imaging and pathological examinations demonstrated reduced glucose intake and neuronal loss in hippocampus. Although no amyloid plaques or neurofibrillary tangles (NFTs) were observed, tau pathology including hyperphosphorylation, paired helical filament formation and pathologic truncation were found at considerable higher extent in the bilateral modifier group 8 weeks post the procedure. In addition, gliosis and microglia activation were confirmed in corpus callosum (CC) and ventral striatum. Thus, this ApoE -KO mouse model faithfully replicates the stenosis of common carotid artery (CCA) and cognitive impairment following atherosclerotic deposition and global cerebral hypoperfusion. The close correlation of cognitive decline and tau pathology indicates the toxic tau species could be at least partially responsible for the neurodegenerative changes induced by the chronic hypoxia/ischemia. [ABSTRACT FROM AUTHOR]

Undifferentiated carcinoma with osteoclast-like giant cells of the pancreas (UCOGCP) is a rare pancreatic tumor that accounts for <1% of all primary pancreatic malignant tumors. Although the tumor is considered a variant of pancreatic ductal adenocarcinoma, there are substantial differences in the clinicopathological characteristics between UCOGCP and pancreatic ductal adenocarcinoma. Imaging examinations are useful in making a correct diagnosis, and providing a reasonable and effective surgical treatment regimen; however, the imaging characteristics of UCOGCP require further investigation. The present report describes a rare case of UCOGCP with rapid progression and poor prognosis. The patient could not undergo surgery and received chemotherapy drugs only. Chemotherapy did not markedly improve the outcome, and a follow-up 6 months after discharge showed that the patient had died. The present report describes this case and summarizes the available imaging findings to increase awareness, and to improve early diagnosis of this rare disease and therapeutic outcomes. [ABSTRACT FROM AUTHOR]

L-DOPA-induced dyskinesias (LID) remain a major problem of long-term therapy of Parkinson’s disease. Levetiracetam, a new antiepileptic drug, has been shown to reduce LID, but the mechanisms underlying its effects are unknown. In this study, we assessed the effect of levetiracetam on key mediators of LID in rats with 6-hydroxydopamine (6-OHDA) lesions. Following chronic administration of L-DOPA (12 mg/kg, twice daily for 14 days), rats developed abnormal involuntary movements (AIMs), but co-administration of levetiracetam (15, 30, and 60 mg/kg) with equivalent L-DOPA dosing significantly reduced AIMs scores in a dose dependent manner. The effects of levetiracetam were associated with changes in striatal expression of ΔFosB, phosphorylated extracellular signal-regulated kinases 1 and 2 (p-ERK1/2), and phosphorylated cAMP-regulated phosphoprotein of 32 kDa (p-DARPP-32). These data support that levetiracetam acts at multiple sites in the pathogenetic cascade of LID, and that further understanding of these actions of antiepileptics may contribute to developing new LID therapies. [ABSTRACT FROM AUTHOR]

(Z)-1,2-Disubstituted vinyl sulfones can be stereoselectively synthesized in one pot under mild conditions, in good yields, by the palladium-catalyzed hydrostannylation of acetylenic sulfones with tributyltin hydride, followed by Stille coupling with aryl iodides. [ABSTRACT FROM AUTHOR]

Recent studies indicated that the algal decomposition produces particulate and dissolved organic carbon (DOC), and can enhance denitrification in eutrophic lakes. However, the effects of the living cyanobacteria on nitrogen cycling in eutrophic lakes were still an unknown question. This study explores a new underlying mechanism of nitrate removal which is driven by living Microcystis . The results suggested that living Microcystis significantly enhanced the nitrate removal at sediment-water interface, with a nitrate removal rate of 0.54 d −1 , which was 2.57 times higher than the nitrate removal rate in the treatment without the addition of Microcystis . Measurements of Chl a and Fv/Fm confirmed that Microcystis was tolerant to the dark/anoxic condition, and the recovery experiments suggested that Microcystis could survive under such stress conditions for at least seven days. Meanwhile, DOC secreted by living Microcystis reached to 4.55 mg C mg −1 Chl a. These secretions were biodegradable hydrophilic and contained carbohydrates and proteins. Our study indicated that during blooms, sinking Microcystis cells could directly provide DOC as carbon source, then consequently enhanced the denitrification at sediment-water interface, and the interactive relationship between living cyanobacteria and permanent nitrate removal should be taken into account while studying nitrogen cycling in aquatic ecosystem. [ABSTRACT FROM AUTHOR]

Harmful cyanobacterial blooms (CyanoHABs) represent a serious threat to aquatic ecosystems. A beneficial use for these harmful microorganisms would be a promising resolution of this urgent issue. This study applied a simple method, nitrogen limitation, to cultivate cyanobacteria aimed at producing cyanobacterial carbon for denitrification. Under nitrogen-limited conditions, the common cyanobacterium, Microcystis, efficiently used nitrate, and had a higher intracellular C/N ratio. More importantly, organic carbons easily leached from its dry powder; these leachates were biodegradable and contained a larger amount of dissolved organic carbon (DOC) and carbohydrates, but a smaller amount of dissolved total nitrogen (DTN) and proteins. When applied to an anoxic system with a sediment-water interface, a significant increase of the specific NO X − -N removal rate was observed that was 14.2 times greater than that of the control. This study first suggests that nitrogen-limited cultivation is an efficient way to induce organic and carbohydrate accumulation in cyanobacteria, as well as a high C/N ratio, and that these cyanobacteria can act as a promising carbon source for denitrification. The results indicate that application as a carbon source is not only a new way to utilize cyanobacteria, but it also contributes to nitrogen removal in aquatic ecosystems, further limiting the proliferation of CyanoHABs. [ABSTRACT FROM AUTHOR]

Long-term l -DOPA treatment of Parkinson’s disease is accompanied with fluctuations of motor responses and l -DOPA-induced dyskinesia (LID). Phosphorylation of the dopamine and c-AMP regulated phosphoprotein of 32 kDa (DARPP-32) plays a role in the pathogenesis of LID, and thus dephosphorylation of this protein by activated calcineurin may help reduce LID. One important activator of calcineurin is the Ca 2+ ionophore ionomycin. Here, we investigated whether intrastriatal injection of ionomycin to hemiparkinsonian rats produced changes in l -DOPA responses including LID. We also analyzed the effects of ionomycin on key molecular mediators of LID. Results confirmed our hypothesis that ionomycin could downregulate the phosphorylation of DARPP32 at Thr-34 and reduce LID. Besides, ionomycin decreased two established molecular markers of LID, FosB/ΔFosB and phosphorylated ERK1/2. Ionomycin also decreased the phosphorylation of three main subunits of the NMDA receptor, NR1 phosphorylated at ser896, NR2A phosphorylated at Tyr-1325, and NR2B phosphorylated at Tyr-1472. Furthermore, the anti-LID effect of striatally injected ionomycin was not accompanied by reduction of the antiparkinsonian action of l -DOPA. These data indicate that ionomycin largely interacts with striatal mechanisms that are critical to the l -DOPA motor response highlighting the role of protein dephosphorylation by calcineurin. [ABSTRACT FROM AUTHOR]

Dopaminergic neurons loss in the substantia nigra (SN) and dopamine (DA) content loss in the striatum correlate well with disease severity in Parkinson's disease (PD). Brain-derived neurotrophic factor (BDNF) is a member of neurotrophin family and is necessary for the survival and development of DA neurons in the SN. Deficits in BDNF/TrkB receptors signaling contribute to the dysfunction of PD. Deoxygedunin, a derivative of gedunin produced from Indian neem tree, binds TrkB receptor and activates TrkB and its downstream signaling cascades in a BDNF-independent manner, and possesses neuroprotective effects in vitro and in vivo . In this study, we tested the neuroprotective effects of deoxygedunin in 6-hydroxydopamine (6-OHDA)-lesioned rat model and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced mice model of Parkinson's disease. Rats were treated with deoxygedunin 5 mg/kg (i.p.) for one month started two weeks before 6-OHDA lesion (pre-treatment), or for two weeks right after lesion (post-treatment), with isovolumetric vehicle as control and normal. Mice were given deoxygedunin 5 mg/kg (i.p.) for 2 weeks and administrated with MPTP twice at the dose of 20 mg/kg (i.p.) on day 7. The results revealed that pretreatment with deoxygedunin improved PD models' behavioral performance and reduced dopaminergic neurons loss in SN, associated with the activation of TrkB receptors and its two major signaling cascades involving mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K). Thus, our current study indicates that deoxygedunin, as a small molecule TrkB agonist, displays prominent neuroprotective properties, providing a novel therapeutic strategy for treating Parkinson's disease. [ABSTRACT FROM AUTHOR]

L-DOPA-induced dyskinesia (LID) is a major complication of long-term dopamine replacement therapy in Parkinson's disease. Characteristic neural oscillation and abnormal activity of striatal projection neurons (SPNs) are typical pathological events of LID, which would be reliable biomarkers for assessment of novel anti-dyskinetic approach if fully profiled. Glutamate dysregulation plays a critical role in the development of LID, and the group II metabotropic glutamate receptors (mGluR2/3) is believed to regulate the release of glutamate on the presynaptic terminals and inhibits postsynaptic excitation. However, the anti-dyskinetic effect of modulating mGluR2/3 is still unclear. In this study, rats with unilateral dopaminergic lesion were injected with L-DOPA (12 mg/kg, i.p.) for seven days, while motor behavior was correlated with in vivo electrophysiology analyzing LFP and single-cell activity in both primary motor cortex and dorsolateral striatum. Our study showed that as LID established, high γ oscillation (hγ) predominated during LID, the number of unstable responses of SPN to dopamine increased, and the coherence between these patterns of oscillation and spiking activity also increased. We found that pretreatment of NMDA receptor antagonist, amantadine 60 mg/kg, i.p. (AMAN) significantly reduced abnormal involuntary movements (AIMs), in parallel with the reduction of hγ oscillation, and more markedly with a decrease in unstable responses of SPNs. In contrast, a mGluR2/3 agonist, LY354740 12 mg/kg, i.p. (LY) significantly shortened the duration of LID but merely exhibited a weak effect in diminishing the intensity of LID or reversing SPN responses. Together results indicate that AIMs in the rat model of PD are associated with abnormal corticostriatal signaling, which could be reversed by NMDAR antagonism more efficiently than mGluR2/3 agonism. • Amantadine reduces unstable responses of striatal projection neurons to dopamine. • Group II metabotropic glutamate receptors agonist LY354740 shortens LID duration. • The fluctuation of high γ oscillation is associated with LID duration. • The switch between high β and high γ oscillation suggests their distinct origins. [ABSTRACT FROM AUTHOR]

The histopathological hallmark of Parkinson's disease (PD) is the presence of fibrillar aggregates referred to as Lewy bodies (LBs), in which α-synuclein is the major component. Converging evidence supports the prion-like transmission of α-synuclein aggregates in the onset and progression of PD. Intracellular α-synuclein aggregates into pathological fibrils, which can be transferred from aggregate-producing cells to aggregate-free cells, triggering neuronal injury and the progression of pathology. However, the specific mechanisms mediating the aggregation and transmission of pathological α-synuclein remain unknown. Here we show that cofilin 1 binds to α-synuclein and promotes its aggregation. The mixed fibrils consist of cofilin 1 and α-synuclein are more compact and more potent than pure α-synuclein fibrils in seeding α-synuclein aggregation. Cofilin 1 also facilitates the uptake of α-synuclein fibrils and finally induces neuronal dysfunction. Together, these observations indicate that cofilin 1 acts as a crucial mediator in the aggregation and propagation of pathological α-synuclein, contributing to the pathogenesis of PD. • Cofilin 1 was highly expressed in human and mouse PD brains. • Cofilin 1 combined α-synuclein and promoted its aggregation. • Cofilin 1 facilitated the propagation of α-synuclein pathology. • Cofilin 1 enhanced the toxicity of α-synuclein fibrils. [ABSTRACT FROM AUTHOR]

Pathologic aggregation and prion-like propagation of α-synuclein (α-syn) are the hallmarks of Parkinson's disease (PD). Emerging evidence shows that type 2 diabetes mellitus (T2DM) is a risk factor for PD. Interestingly, T2DM is characterized by the amyloid deposition of islet amyloid polypeptide (IAPP) in the pancreas. Although T2DM and PD share pathological similarities, the underlying molecular mechanisms bridging these two diseases remain unknown. Here, we report that IAPP co-deposits with α-syn in the brains of PD patients. IAPP interacts with α-syn and accelerates its aggregation. In addition, the IAPP-seeded α-syn fibrils show enhanced seeding activity and neurotoxicity compared with pure α-syn fibrils in vitro and in vivo. Strikingly, intravenous injection of IAPP fibrils into α-syn A53T transgenic mice or human SNCA transgenic mice accelerated the aggregation of α-syn and PD-like motor deficits. Taken together, these findings support that IAPP acts as a trigger of α-syn pathology in PD, and provide a mechanistic explanation for the increased risk and faster progression of PD in patients with T2DM. • IAPP interacts with α-synuclein and accelerates its aggregation. • IAPP enhances the seeding activity and neurotoxicity of α-synuclein fibrils. • Administration of IAPP promotes α-synuclein pathology and PD-like phenotypes. [ABSTRACT FROM AUTHOR]

• AEP age-dependently cleaves γ-adducin at N357 in AD. • The AEP-generated γ-adducin (1-357) fragment translocates into nucleus and inhibits neurites growth. • γ-adducin (1-357) fragment induces neurites deficits and synaptic dysfunction by downregulating Rac2. • γ-adducin (1-357) fragment promotes AD-like pathology and cognitive impairments in vivo. Neurite deficits and synaptic dysfunction contribute to cognitive impairments in Alzheimer's disease (AD). However, the underlying molecular mechanisms remain unclear. Here, we show that γ-adducin, a cytoskeleton-associated protein that assembles the spectrin-actin framework, is cleaved by a lysosomal cysteine proteinase named asparagine endopeptidase (AEP). AEP is upregulated and activated during aging and cleaves γ-adducin at N357, disrupting spectrin-actin assembly. Moreover, γ-adducin (1-357) fragment downregulates the expression of Rac2, leading to defects in neurite outgrowth. Expression of the γ-adducin (1-357) fragment in the hippocampus of tau P301S transgenic mice resulted in significant AD-like pathology and cognitive deficits. In summary, AEP-mediated fragmentation of γ-adducin plays a vital role in AD. Blocking the activity of AEP might be a novel therapeutic target for AD. [ABSTRACT FROM AUTHOR]

Parkinson's disease (PD) is characterized by the pathologic aggregation and prion-like propagation of α-synuclein (α-syn). Emerging evidence shows that fungal infections increase the incidence of PD. However, the molecular mechanisms by which fungi promote the onset of PD are poorly understood. Here, we show that nasal infection with Saccharomyces cerevisiae ( S. cerevisiae ) in α-syn A53T transgenic mice accelerates the aggregation of α-syn. Furthermore, we found that Sup35, a prion protein from S. cerevisiae , is the key factor initiating α-syn pathology induced by S. cerevisiae . Sup35 interacts with α-syn and accelerates its aggregation in vitro. Notably, injection of Sup35 fibrils into the striatum of wild-type mice led to α-syn pathology and PD-like motor impairment. The Sup35-seeded α-syn fibrils showed enhanced seeding activity and neurotoxicity compared with pure α-syn fibrils in vitro and in vivo. Together, these observations indicate that the yeast prion protein Sup35 initiates α-syn pathology in PD.

Netrin-1 and its receptors play crucial roles in inducing axonal growth and neuronal migration during neuronal development. Their profound impacts then extend into adulthood to encompass the maintenance of neuronal survival and synaptic function. Increasing amounts of evidence highlight several key points: (1) Diminished Netrin-1 levels exacerbate pathological progression in animal models of Alzheimer's disease and Parkinson's disease, and potentially, similar alterations occur in humans. (2) Genetic mutations of Netrin-1 receptors increase an individuals' susceptibility to neurodegenerative disorders. (3) Therapeutic approaches targeting Netrin-1 and its receptors offer the benefits of enhancing memory and motor function. (4) Netrin-1 and its receptors show genetic and epigenetic alterations in a variety of cancers. These findings provide compelling evidence that Netrin-1 and its receptors are crucial targets in neurodegenerative diseases. Through a comprehensive review of Netrin-1 signaling pathways, our objective is to uncover potential therapeutic avenues for neurodegenerative disorders., (Copyright © 2025 Copyright: © 2025 Neural Regeneration Research.)

The aggregation and prion-like propagation of α-synuclein are involved in the pathogenesis of Parkinson's disease. However, the underlying mechanisms regulating the assembly and spreading of α-synuclein fibrils remain poorly understood. Tau co-deposits with α-synuclein in the brains of Parkinson's disease patients, suggesting a pathological interplay between them. Here we show that tau interacts with α-synuclein and accelerates its aggregation. Compared with pure α-synuclein fibrils, the tau-modified α-synuclein fibrils show enhanced seeding activity, inducing mitochondrial dysfunction, synaptic impairment and neurotoxicity in vitro. Injection of the tau-modified α-synuclein fibrils into the striatum of mice induces more severe α-synuclein pathology, motor dysfunction and cognitive impairment when compared with the mice injected with pure α-synuclein fibrils. Knockout of tau attenuates the propagation of α-synuclein pathology and Parkinson's disease-like symptoms both in mice injected with α-syn fibrils and α-syn A53T transgenic mice. In conclusion, tau facilitates α-synuclein aggregation and propagation in Parkinson's disease., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)