Recent developments in the chemical biology of amyloid-ß oligomer targeting.

Aggregation of amyloid-ß (Aß) peptides is characteristic of Alzheimer's disease (AD), which is the most common neurodegenerative disorder. Increasing evidence shows that Aß oligomers, the intermediates during aggregation, rather than the fully mature fibrils are the most toxic species of Aß and the key contributors to neurodegeneration. Aß oligomers have been considered as both biomarkers and drug targets for the diagnosis and treatment of AD. However, the high heterogeneity and metastability of oligomers make it difficult to determine their exact pathogenic mechanisms. Recent developments in Aß oligomer-targeting agents and techniques have provided great opportunities for overcoming the existing limitations. This review introduces the formation, structure, and toxicity of Aß oligomers and categorizes the Aß oligomer-targeting agents based on their chemical biological applications, including recognition and detection of Aß oligomers for diagnosis, intervention of Aß oligomerization for treatment, and stabilization of Aß oligomers for pathogenic studies. The design strategies and working mechanisms of the representative examples published in the past five years are highlighted. Finally, future development directions and challenges of Aß oligomer targeting are tentatively proposed.

sLRP1 (Soluble Low-Density Lipoprotein Receptor-Related Protein 1): A Novel Biomarker for P2Y12 (P2Y Purinoceptor 12) Receptor Expression in Atherosclerotic Plaques.

OBJECTIVE: Recent studies suggest that the P2Y12 (P2Y purinoceptor 12) receptor of vascular smooth muscle cells in atherosclerotic plaques aggravates atherosclerosis, and P2Y12 receptor inhibitors such as CDL (clopidogrel) may effectively treat atherosclerosis. It is imperative to identify an effective biomarker for reflecting the P2Y12 receptor expression on vascular smooth muscle cells in plaques. Approach and Results: We found that there was a positive correlation between the level of circulating sLRP1 (soluble low-density lipoprotein receptor-related protein 1) and the number of LRP1+ α-SMA+ (α-smooth muscle actin), P2Y12+, or P2Y12+ LRP1+ cells in plaques from apoE-/- mice fed a high-fat diet. Furthermore, activation of the P2Y12 receptor increased the expression and shedding of LRP1 in vascular smooth muscle cells by inhibiting cAMP (3'-5'-cyclic adenosine monophosphate)/PKA (protein kinase A)/SREBP-2 (sterol regulatory element binding transcription factor 2). Conversely, genetic knockdown or pharmacological inhibition of the P2Y12 receptor had the opposite effects. Additionally, CDL decreased the number of lesional LRP1+ α-SMA+ cells and the levels of circulating sLRP1 by activating cAMP/PKA/SREBP-2 in apoE-/- mice fed a high-fat diet. CONCLUSIONS: Our study suggests that sLRP1 may be a biomarker that reflects the P2Y12 receptor level in plaques and has the potential to be an indicator for administering P2Y12 receptor inhibitors for patients with atherosclerosis.

[Mechanisms of histamine ameliorating memory impairment induced by pentylenetetrazole-kindling epilepsy in rats].

Objective: To investigate the effects of neuronal histamine on spatial memory acquisition impairment in rats with pentylenetetrazole-kindling epilepsy, and to explore its mechanisms. Methods: A subconvulsive dose of pentylenetetrazole (35 mg/kg) was intraperitoneally injected in rats every 48 h to induce chemical kindling until fully kindled. Morris water maze was used to measure the spatial memory acquisition of the rats one week after fully pentylenetetrazole-kindled, and the histamine contents in different brain areas were measured spectrofluorometrically. Different dosages of hitidine (the precursor of histamine), pyrilamine (H1 receptor antagonist), and zolantidine (H2 receptor antagonist) were intraperitoneally injected, and their effects on spatial memory acquisition of the rats were observed. Results: Compared with control group, escape latencies were significantly prolonged on Morris water maze training day 2 and day 3 in pentylenetetrazole-kindling epilepsy rats (all P<0.05); and the histamine contents in hippocampus, thalamus and hypothalamus were decreased significantly (all P<0.05). Escape latencies were markedly shortened on day 3 by intraperitoneally injected with histidine 500 mg/kg, and on day 2 and day 3 by intraperitoneally injected with histidine 1000 mg/kg in pentylenetetrazole-kindling epilepsy rats (all P<0.05). The protection of histidine was reversed by zolantidine (10 and 20 mg/kg), but not by pyrilamine. Conclusion: Neuronal histamine can improve the spatial memory acquisition impairment in rats with pentylenetetrazole-kindling epilepsy, and the activation of H2 receptors is possibly involved in the protective effects of histamine.

Identification of diagnose related therapeutic targets of Danggui buxue decoction in Parkinson's disease.

BACKGROUND: Parkinson's disease (PD) is the fastest growing neurological disease. Currently, there is no disease-modifying therapy to slow the progression of the disease. Danggui buxue decoction (DBD) is widely used in the clinic because of its therapeutic effect. However, little is known about the molecular mechanism of DBD against PD. This study intends to explore the possible molecular mechanisms involved in DBD treatment of PD based on network pharmacology, and provide potential research directions for future research. METHODS: Firstly, the active components and target genes of DBD were screened from the traditional Chinese medicine systems pharmacology (TCMSP), DrugBank and UniProt database. Secondly, target genes of PD were identified from the (GEO) dataset, followed by identification of common target genes of DBD and PD. Thirdly, analysis of protein-protein interaction (PPI), functional enrichment and diagnosis was performed on common target genes, followed by correlation analysis between core target genes, immune cell, miRNAs, and transcription factors (TFs). Finally, molecular docking between core target genes and active components, and real-time PCR were performed. RESULTS: A total of 72 common target genes were identified between target genes of DBD and target genes of PD. Among which, 11 target genes with potential diagnostic value were further identified, including TP53, AKT1, IL1B, MMP9, NOS3, RELA, MAPK14, HMOX1, TGFB1, NOS2, and ERBB2. The combinations with the best docking binding were identified, including kaempferol-AKT1/HMOX1/NOS2/NOS3, quercetin-AKT1/ERBB2/IL1B/HMOX1/MMP9/TP53/NOS3/TGFB1. Moreover, IL1B and NOS2 respectively positively and negatively correlated with neutrophil and Type 1 T helper cell. Some miRNA-core target gene regulatory pairs were identified, such as hsa-miR-185-5p-TP53/TGFB1/RELA/MAPK14/IL1B/ERBB2/AKT1 and hsa-miR-214-3p-NOS3. These core target genes were significantly enriched in focal adhesion, TNF, HIF-1, and ErbB signaling pathway. CONCLUSION: Diagnostic TP53, AKT1, IL1B, MMP9, NOS3, RELA, MAPK14, HMOX1, TGFB1, NOS2, and ERBB2 may be considered as potential therapeutic targets of DBD in the treatment of PD.

A case report of fatal familial insomnia with cerebrospinal fluid leukocytosis during the COVID-19 epidemic and review of the literature.

Fatal familial insomnia (FFI) is a rare autosomal dominant genetic neurodegenerative disease. Generally, FFI patients will develop rapidly progressive dementia, sleep disturbance, autonomic dysfunction, and so on. Cerebrospinal fluid examination of FFI patients normally shows no obvious abnormalities. Here, we report a young male patient who was diagnosed with FFI during the COVID-19 epidemic. Clinical symptoms include psychobehavioral abnormality, cognitive decline, sleep disturbance, and autonomic dysfunction. No abnormalities were found in routine examinations after admission. However, the number of white blood cells in the cerebrospinal fluid increased. Though the patient was treated with anti-infection and immunotherapy, the symptoms were not relieved. A lumbar puncture was performed again, and it was found that the total Tau protein in the cerebrospinal fluid was elevated, and PET results showed that brain metabolism decreased. Finally, a genetic test was used to confirm the diagnosis of FFI. This case suggests that patients with FFI may also have elevated white blood cells in cerebrospinal fluid and timely detection of Tau protein in cerebrospinal fluid is helpful for early identification of FFI. And precise diagnosis relies on genetic testing.

A terbium(III) complex-based time-resolved luminescent probe for selenocysteine as an inhibitor of selenoproteins.

A terbium(III) complex-based time-resolved luminescence probe for selenocysteine can inhibit selenoprotein activity via a selenolate-triggered cleavage reaction of sulfonamide bonds in living cells.

[Sequential enteral nutrition support for patients with severe cerebral stroke].

OBJECTIVE: To evaluate the efficacy of sequential enteral nutrition support in patients with severe cerebral stroke. METHODS: Forty-nine patients with severe cerebral stroke met the inclusion criteria were randomly divided into sequential enteral nutrition group (Group A, n=24) and conventional enteral nutrition group (Group B, n=25). Patients in Group A received short-peptide-based enteral nutrition support first, then gradually transferred to intact protein enteral nutrition. Meanwhile, patients in Group B constantly received intact protein enteral nutrition support. The nutritional indexes and the rate of complications were compared between two groups. RESULTS: The nutritional indexes were decreased in both groups within 4 weeks after admission, but the decreasing levels of hemoglobin and albumin in Group A were significantly lower than those in Group B (P<0.05), and the incidence of infections and gastrointestinal hemorrhage in Group A was also lower than that in Group B (P<0.05). However, there were no significant differences in body weight, BMI, triceps skinfold thickness, biceps circumference, arm muscle circumference between two groups (P>0.05). CONCLUSION: Sequential enteral nutritional support can improve the nutritional status and decrease the incidence of complications in critical patients with cerebral stroke.

Bibliometric analysis and visualized study of research on autophagy in ischemic stroke.

Aims: To summarize and clarify the current research status and indicate possible future directions in the field of autophagy in ischemic stroke, we performed a comprehensive and multidimensional bibliometric analysis of the literature in this field published from 2011 to 2022. Methods: We retrieved articles on the field of autophagy in ischemic stroke published between 2011 and 2022 from Web of Science Core Collection (WOSCC). VOSviewer (version 1.6.19) and CiteSpace (version 6.2.R2 Basic) were used to identify the leading topics as well as generate visual maps of Countries/regions, organizations, authors, journals, and keyword networks in the related field. Results: A total of 568 publications were contained in this research. The journal with the most publications were Front Pharmacol, Mol Neurobiol, and Neuroscience. China was the most productive country with respect to co-authorship, with the Capital Med Univ being the organization with the most. co-authorships. In terms of authorship analysis, eight of the top 10 most contributive authors were from China. The co-occurring author keywords can be divided into three main clusters, including "protective effect of autophagy in ischemic stroke," "autophagy-targeted therapy for ischemic stroke," and "mitochondrial function in cerebral ischemia-reperfusion injury". Conclusion: This bibliometric analysis helps us reveal the current research hotspots in the research field of autophagy in ischemic stroke and guide future research directions. Subsequent trends in this special field are likely to identify and develop novel autophagy-targeted therapy strategies to effectively prevent and treat ischemic stroke.

Recent progress of small-molecule-based theranostic agents in Alzheimer's disease.

Alzheimer's disease (AD) is the most common form of neurodegenerative dementia. As a multifactorial disease, AD involves several etiopathogenic mechanisms, in which multiple pathological factors are interconnected with each other. This complicated and unclear pathogenesis makes AD lack effective diagnosis and treatment. Theranostics, exerting the synergistic effect of diagnostic and therapeutic functions, would provide a promising strategy for exploring AD pathogenesis and developing drugs for combating AD. With the efforts in small drug-like molecules for both diagnosis and treatment of AD, small-molecule-based theranostic agents have attracted significant attention owing to their facile synthesis, high biocompatibility and reproducibility, and easy clearance from the body through the excretion systems. In this review, the small-molecule-based theranostic agents reported in the literature for anti-AD are classified into four groups according to their diagnostic modalities. Their design rationales, chemical structures, and working mechanisms for theranostics are summarized. Finally, the opportunities for small-molecule-based theranostic agents in AD are also proposed.

Corrigendum: The dual role of low-density lipoprotein receptor-related protein 1 in atherosclerosis.

[This corrects the article DOI: 10.3389/fcvm.2021.682389.].

Sensorimotor network connectivity correlates with motor improvement after repetitive transcranial magnetic stimulation in patients with Parkinson's disease.

BACKGROUND: Emerging evidence suggests that repetitive transcranial magnetic stimulation (rTMS) generally improves Parkinson's disease (PD) motor symptoms. However, personal responses to rTMS might be different. In this study, we explore the connectivity changes in PD patients with different responses to rTMS. METHODS: Among PD patients, 25 were treated with 10Hz-rTMS and seven were with sham rTMS over the supplementary motor area for 10 days. Resting-state functional connectivity magnetic resonance imaging (rs-fMRI) was performed in PD patients before and after rTMS stimulation. Neuropsychological scales such as Unified Parkinson's Disease Rating Scale Part III (UPDRS-III) were collected synchronously with rs-fMRI. To explore the connectivity changes after rTMS, degree centrality was calculated. RESULTS: 13 out of 25 participants were responsive to 10Hz rTMS. Degree centrality patterns in the left sensorimotor regions are primarily responsible for the differences between responsive and non-responsive individuals. Improvement in motor symptoms was substantially related to the baseline degree centrality in the left PreCG and the left PoCG. The performance in distinguishing non-responders from responders was further validated by the ROC analysis utilizing DC characteristics. Lastly, we found that connectivity increased in left PreCG and PoCG in patients with a better response to the rTMS. CONCLUSION: Taken together, these results suggest that the sensorimotor network is involved in the motor improvement following rTMS treatment, with patients with lower sensorimotor connectivity showing a tendency for greater motor improvement to HF-rTMS.

Recent Advances in Epigenetics of Age-Related Kidney Diseases.

Renal aging has attracted increasing attention in today's aging society, as elderly people with advanced age are more susceptible to various kidney disorders such as acute kidney injury (AKI) and chronic kidney disease (CKD). There is no clear-cut universal mechanism for identifying age-related kidney diseases, and therefore, they pose a considerable medical and public health challenge. Epigenetics refers to the study of heritable modifications in the regulation of gene expression that do not require changes in the underlying genomic DNA sequence. A variety of epigenetic modifiers such as histone deacetylases (HDAC) inhibitors and DNA methyltransferase (DNMT) inhibitors have been proposed as potential biomarkers and therapeutic targets in numerous fields including cardiovascular diseases, immune system disease, nervous system diseases, and neoplasms. Accumulating evidence in recent years indicates that epigenetic modifications have been implicated in renal aging. However, no previous systematic review has been performed to systematically generalize the relationship between epigenetics and age-related kidney diseases. In this review, we aim to summarize the recent advances in epigenetic mechanisms of age-related kidney diseases as well as discuss the application of epigenetic modifiers as potential biomarkers and therapeutic targets in the field of age-related kidney diseases. In summary, the main types of epigenetic processes including DNA methylation, histone modifications, non-coding RNA (ncRNA) modulation have all been implicated in the progression of age-related kidney diseases, and therapeutic targeting of these processes will yield novel therapeutic strategies for the prevention and/or treatment of age-related kidney diseases.

Pathogenic Role of MicroRNA Dysregulation in Podocytopathies.

MicroRNAs (miRNAs) participate in the regulation of various important biological processes by regulating the expression of various genes at the post-transcriptional level. Podocytopathies are a series of renal diseases in which direct or indirect damage of podocytes results in proteinuria or nephrotic syndrome. Despite decades of research, the exact pathogenesis of podocytopathies remains incompletely understood and effective therapies are still lacking. An increasing body of evidence has revealed a critical role of miRNAs dysregulation in the onset and progression of podocytopathies. Moreover, several lines of research aimed at improving common podocytopathies diagnostic tools and avoiding invasive kidney biopsies have also identified circulating and urine miRNAs as possible diagnostic and prognostic biomarkers for podocytopathies. The present review mainly aims to provide an updated overview of the recent achievements in research on the potential applicability of miRNAs involved in renal disorders related to podocyte dysfunction by laying particular emphasis on focal segmental glomerulosclerosis (FSGS), minimal change disease (MCD), membranous nephropathy (MN), diabetic kidney disease (DKD) and IgA nephropathy (IgAN). Further investigation into these dysregulated miRNAs will not only generate novel insights into the mechanisms of podocytopathies, but also might yield novel strategies for the diagnosis and therapy of this disease.

The Role of Oxidative Stress in Acute Ischemic Stroke-Related Thrombosis.

Acute ischemic stroke is a serious life-threatening disease that affects almost 600 million people each year throughout the world with a mortality of more than 10%, while two-thirds of survivors remain disabled. However, the available treatments for ischemic stroke are still limited to thrombolysis and/or mechanical thrombectomy, and there is an urgent need for developing new therapeutic target. Recently, intravascular oxidative stress, derived from endothelial cells, platelets, and leukocytes, has been found to be tightly associated with stroke-related thrombosis. It not only promotes primary thrombus formation by damaging endothelial cells and platelets but also affects thrombus maturation and stability by modifying fibrin components. Thus, oxidative stress is expected to be a novel target for the prevention and treatment of ischemic stroke. In this review, we first discuss the mechanisms by which oxidative stress promotes stroke-related thrombosis, then summarize the oxidative stress biomarkers of stroke-related thrombosis, and finally put forward an antithrombotic therapy targeting oxidative stress in ischemic stroke.

Predictive value of different bilirubin subtypes for clinical outcomes in patients with acute ischemic stroke receiving thrombolysis therapy.

AIMS: To explore the association of total bilirubin (TBIL), direct bilirubin (DBIL), and indirect bilirubin (IBIL) levels with, as well as the incremental predictive value of different bilirubin subtypes for, poor outcomes in acute ischemic stroke patients after thrombolysis. METHODS: We analyzed 588 individuals out of 718 AIS participants, and all patients were followed up at 3 months after thrombolysis. The primary outcome was 3-month death and major disability (modified Rankin Scale (mRS) score of 3-6). The secondary outcomes were 3-month mortality (mRS score of 6), moderate-severe cerebral edema, and symptomatic intracranial hemorrhage (sICH), respectively. RESULTS: Elevated DBIL pre-thrombolysis was associated with an increased risk of primary outcome (OR 3.228; 95% CI 1.595-6.535; p for trend = 0.014) after fully adjustment. Elevated TBIL pre-thrombolysis showed the similar results (OR 2.185; 95% CI 1.111-4.298; p for trend = 0.047), while IBIL pre-thrombolysis was not significantly associated with primary outcome (OR 1.895; 95% CI 0.974-3.687; p for trend = 0.090). Multivariable-adjusted spline regression model showed a positive linear dose-response relationship between DBIL pre-thrombolysis and risk of primary outcome (p for linearity = 0.004). Adding DBIL pre-thrombolysis into conventional model had greater incremental predictive value for primary outcome, with net reclassification improvement (NRI) 95% CI = 0.275 (0.084-0.466) and integrated discrimination improvement (IDI) 95% CI = 0.011 (0.001-0.024). Increased DBIL post-thrombolysis had an association with primary outcome (OR 2.416; 95%CI 1.184-4.930; p for trend = 0.039), and it also elevated the incremental predictive value for primary outcome, with NRI (95% CI) = 0.259 (0.066-0.453) and IDI (95% CI) = 0.025 (0.008-0.043). CONCLUSION: Increased DBIL pre-thrombolysis had a stronger association with, as well as greater incremental predictive value for, poor outcomes than TBIL and IBIL did in AIS patients after thrombolysis, which should be understood in the context of retrospective design. The effect of DBIL on targeted populations should be investigated in further researches.

The Dual Role of Low-Density Lipoprotein Receptor-Related Protein 1 in Atherosclerosis.

Low-density lipoprotein receptor-related protein-1 (LRP1) is a large endocytic and signaling receptor belonging to the LDL receptor (LDLR) gene family and that is widely expressed in several tissues. LRP1 comprises a large extracellular domain (ECD; 515 kDa, α chain) and a small intracellular domain (ICD; 85 kDa, ß chain). The deletion of LRP1 leads to embryonic lethality in mice, revealing a crucial but yet undefined role in embryogenesis and development. LRP1 has been postulated to participate in numerous diverse physiological and pathological processes ranging from plasma lipoprotein homeostasis, atherosclerosis, tumor evolution, and fibrinolysis to neuronal regeneration and survival. Many studies using cultured cells and in vivo animal models have revealed the important roles of LRP1 in vascular remodeling, foam cell biology, inflammation and atherosclerosis. However, its role in atherosclerosis remains controversial. LRP1 not only participates in the removal of atherogenic lipoproteins and proatherogenic ligands in the liver but also mediates the uptake of aggregated LDL to promote the formation of macrophage- and vascular smooth muscle cell (VSMC)-derived foam cells, which causes a prothrombotic transformation of the vascular wall. The dual and opposing roles of LRP1 may also represent an interesting target for atherosclerosis therapeutics. This review highlights the influence of LRP1 during atherosclerosis development, focusing on its dual role in vascular cells and immune cells.

Morinda officinalis oligosaccharides alleviate depressive-like behaviors in post-stroke rats via suppressing NLRP3 inflammasome to inhibit hippocampal inflammation.

AIMS: Morinda officinalis oligosaccharides (MOOs), a traditional Chinese medicine, have been used to treat mild and moderate depressive episodes. In this study, we investigated whether MOOs can ameliorate depressive-like behaviors in post-stroke depression (PSD) rats and further explored its mechanism by suppressing microglial NLRP3 inflammasome activation to inhibit hippocampal inflammation. METHODS: Behavioral tests were performed to evaluate the effect of MOOs on depressive-like behaviors in PSD rats. The effects of MOOs on the expression of IL-18, IL-1ß, and nucleotide-binding domain leucine-rich repeat (NLR) family pyrin domain containing 3 (NLRP3) inflammasome were measured in both PSD rats and lipopolysaccharide (LPS) and adenosine triphosphate (ATP) stimulated primary rat microglia by reverse transcription polymerase chain reaction (RT-PCR), immunofluorescence and Western blot analysis. Adeno-associated virus (AAV) was injected into the hippocampus to regulate NLRP3 inflammasome expression. The detailed molecular mechanism underlying the effects of MOOs was analyzed by Western blot and immunofluorescence. RESULTS: MOOs can alleviate depressive-like behaviors in PSD rats. PSD rats showed increased expression of IL-18, IL-1ß, and NLRP3 inflammasome in the ischemic hippocampus, while MOOs reversed the elevation. NLRP3 downregulation ameliorated depressive-like behaviors and hippocampal inflammation response in PSD rats, while NLRP3 upregulation inhibited the effect of MOOs on depressive-like behaviors and hippocampal inflammation response in PSD rats. Moreover, we found that NLRP3 was mainly expressed on microglia. In vitro, MOOs effectively inhibited the expression of IL-18, IL-1ß, and NLRP3 inflammasome in LPS + ATP treated primary rat microglia. We also showed that modulation of NLRP3 inflammasome by MOOs was associated with the IκB/NF-κB p65 signaling pathway. CONCLUSION: Overall, our study reveals the antidepressive effect of MOOs on PSD rats through modulation of microglial NLRP3 inflammasome. We also provide a novel insight into hippocampal inflammation response in PSD pathology and put forward NLRP3 inflammasome as a potential therapeutic target for PSD.

The P2RY12 receptor promotes VSMC-derived foam cell formation by inhibiting autophagy in advanced atherosclerosis.

Vascular smooth muscle cells (VSMCs) are an important source of foam cells in atherosclerosis. The mechanism for VSMC-derived foam cell formation is, however, poorly understood. Here, we demonstrate that the P2RY12/P2Y12 receptor is important in regulating macroautophagy/autophagy and VSMC-derived foam cell formation in advanced atherosclerosis. Inhibition of the P2RY12 receptor ameliorated lipid accumulation and VSMC-derived foam cell formation in high-fat diet-fed apoe-/- mice (atherosclerosis model) independent of LDL-c levels. Activation of the P2RY12 receptor blocked cholesterol efflux via PI3K-AKT, while genetic knockdown or pharmacological inhibition of the P2RY12 receptor inhibited this effect in VSMCs. Phosphoproteomic analysis showed that the P2RY12 receptor regulated the autophagy pathway in VSMCs. Additionally, activation of the P2RY12 receptor inhibited MAP1LC3/LC3 maturation, SQSTM1 degradation, and autophagosome formation in VSMCs. Genetic knockdown of the essential autophagy gene Atg5 significantly attenuated P2RY12 receptor inhibitor-induced cholesterol efflux in VSMCs. Furthermore, activation of the P2RY12 receptor led to the activation of MTOR through PI3K-AKT in VSMCs, whereas blocking MTOR activity (rapamycin) or reducing MTOR expression reversed the inhibition of cholesterol efflux mediated by the P2RY12 receptor in VSMCs. In vivo, inhibition of the P2RY12 receptor promoted autophagy of VSMCs through PI3K-AKT-MTOR in advanced atherosclerosis in apoe-/- mice, which could be impeded by an autophagy inhibitor (chloroquine). Therefore, we conclude that activation of the P2RY12 receptor decreases cholesterol efflux and promotes VSMC-derived foam cell formation by blocking autophagy in advanced atherosclerosis. Our study thus suggests that the P2RY12 receptor is a therapeutic target for treating atherosclerosis.Abbreviations: 2-MeSAMP: 2-methylthioadenosine 5'-monophosphate; 8-CPT-cAMP: 8-(4-chlorophenylthio)-adenosine-3',5'-cyclic-monophosphate; ABCA1: ATP binding cassette subfamily A member 1; ABCG1: ATP binding cassette subfamily G member 1; ACTB: actin beta; ADPßs: adenosine 5'-(alpha, beta-methylene) diphosphate; ALs: autolysosomes; AMPK: AMP-activated protein kinase; APOA1: apolipoprotein A1; APs: autophagosomes; ATG5: autophagy related 5; ATV: atorvastatin; AVs: autophagic vacuoles; CD: chow diet; CDL: clopidogrel; CQ: chloroquine; DAPI: 4',6-diamidino-2-phenylindole; dbcAMP: dibutyryl-cAMP; DIL-oxLDL: dioctadecyl-3,3,3,3-tetramethylin docarbocyanine-oxLDL; EIF4EBP1/4E-BP1: eukaryotic translation initiation factor 4E binding protein 1; EVG: elastic van gieson; HE: hematoxylin-eosin; HDL: high-density lipoprotein; HFD: high-fat diet; KEGG: Kyoto Encyclopedia of Genes and Genomes; LDL-c: low-density lipoprotein cholesterol; LDs: lipid droplets; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; Masson: masson trichrome; MCPT: maximal carotid plaque thickness; MK2206: MK-2206 2HCL; NBD-cholesterol: 22-(N-[7-nitrobenz-2-oxa-1,3-diazol-4-yl] amino)-23,24-bisnor-5-cholen-3ß-ol; OLR1/LOX-1: oxidized low density lipoprotein receptor 1; ORO: oil Red O; ox-LDL: oxidized low-density lipoprotein; SQSTM1/p62: sequestosome 1; TEM: transmission electron microscopy; TIC: ticagrelor; ULK1: unc-51 like autophagy activating kinase 1; VSMCs: vascular smooth muscle cells.

Cryptococcal meningitis in patients with lupus nephritis.

OBJECTIVE: Cryptococcal meningitis (CM) is a rare condition in patients with lupus nephritis (LN). Here, we describe the clinical characteristics, possible risk factors, and outcomes of LN patients with CM. METHODS: A systematic review of medical records from16 LN patients with CM admitted to our hospital was performed. A total of 32 cases were randomly selected as controls from LN patients without infection during the same period. RESULTS: The mean age of patients with CM at presentation was 35.1 years, and the female-to-male ratio was 15:1.The most common clinical manifestation was headache (93.7%); patients with CM had a significantly higher prednisone dose at the time of hospitalization, a higher SLE Disease Activity Index (SLEDAI), a higher urine protein/creatinine ratio, and a lower CD4+ T cells count than those without infection (p < 0.05). Patients with CM also had significantly higher activity index and more moderate and severe mesangial proliferation than those without infections (p < 0.001 and p = 0.025, respectively). CONCLUSION: Serious renal pathological changes, mass proteinuria, higher SLEDAI, higher prednisone dose, and a decline in CD4+ T cells could be risk factors for CM in patients with LN. Key Points ⦁ LN patients with CM had more serious renal pathological changes than those without infections; serious renal pathological changes could be a major risk factor for CM in patients with LN.

Effects of thioperamide on seizure development and memory impairment induced by pentylenetetrazole-kindling epilepsy in rats.

BACKGROUND: Histamine H(3) receptor antagonists have been considered as potential drugs to treat central nervous system diseases. However, whether these drugs can inhibit epileptogenesis remains unclear. This study aimed to investigate the effects of thioperamide, a selective and potent histamine H(3) receptor antagonist, on the seizure development and memory impairment induced by pentylenetetrazole (PTZ)-kindling epilepsy in rats. METHODS: Chemical kindling was elicited by repeated intraperitoneal (ip) injections of a subconvulsant dose of PTZ (35 mg/kg) once every 48 hours for 12 times, and seizure activity of kindling was recorded for 30 minutes. Control rats were ip injected with saline instead of PTZ. Morris water maze was used to evaluate the spatial memory. Phosphorylated cyclic adenosine monophosphate response element binding protein (p-CREB) was tested by Western blotting in hippocampus. RESULTS: Intracerebroventricular (icv) injections with thioperamide (10 µg, 20 µg) 30 minutes before every PTZ injections, significantly prolonged the onset of PTZ-kindling and inhibited the seizure stages. PTZ-kindling seizures led to the impairment of spatial memory in rats, and thioperamide ameliorated the impairment of spatial learning and memory. Compared to non-kindling rats, there was a significant decrease in p-CREB level in hippocampus of the PTZ-kindling rats, which was reversed by thioperamide. CONCLUSIONS: Thioperamide plays a protective role in seizure development and cognitive impairment of PTZ-induced kindling in rats. The protection of thioperamide in cognitive impairment is possibly associated with the enhancement of CREB-dependent transcription.