Κυριακή 11 Σεπτεμβρίου 2022

LAMP‐2A ablation in hippocampal CA1 astrocytes confers cerebroprotection and ameliorates neuronal injury after global brain ischemia

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LAMP-2A ablation in hippocampal CA1 astrocytes confers cerebroprotection and ameliorates neuronal injury after global brain ischemia

Hippocampal astrocytic LAMP-2A knockdown inhibits astrocyte activation, maintains the integrity of neuronal morphology, and ameliorates cognitive deficits after transient global cerebral ischemia.


Abstract

Reactive astrogliosis and neuronal death are major features of brain tissue damage after transient global cerebral ischemia/reperfusion (I/R). The CA1 subfield in the hippocampus is particularly susceptible to cell death after I/R. Recently, attention has focused on the relationship between the autophagy–lysosomal pathway and cerebral ischemia. Lysosomal-associated membrane protein type-2A (LAMP-2A) is a key protein in chaperone-mediated autophagy (CMA). However, LAMP-2A expression in astrocytes of the hippocampus and its influence on brain injury following I/R remain unknown. Here, we show that LAMP-2A is elevated in astrocytes of the CA1 hippocampal subfield after I/R and in primary cultured astrocytes after transient oxygen–glucose deprivation (OGD). Conditional LAMP-2A knockdown in CA1 astrocytes inhibited astrocyte activation and prevented neuronal death by inhibiting the mitochondrial pathway of apoptosis after I/R, suggesting that elevated astrocytic LAMP-2A contributes to regional ischemic vulnerability. Furthermore, astrocytic LAMP-2A ablation ameliorated the spatial learning and memory deficits caused by I/R. Conditional astrocytic LAMP-2A knockdown also prevented the loss of hippocampal synapses and dendritic spines, improved the synaptic ultrastructure, and inhibited the reduced expression of synaptic proteins after ischemia. Thus, our findings demonstrate that astrocytic LAMP-2A expression increases upon I/R and that LAMP-2A ablation specifically in hippocampal astrocytes contributes to cerebroprotection, suggesting a novel neuroprotective strategy for patients with global ischemia.
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Improving causal inference of mediation analysis with multiple mediators using interventional indirect effects

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Abstract

Mediation analysis is indispensable for investigating how a treatment causally affects an outcome via intervening variables. Existing discussions on the validity of causal inference drawn from mediation analysis have prioritized single mediator settings. In this article, we focus on improving causal inference when investigating multiple mediators. We pay particular attention to the prevalent practice of exploring mediated effects along various paths linking several mediators. Such approaches are fraught with stringent—yet often overlooked—causal assumptions that predicate valid inference of indirect or mediated effects. To mitigate the risk of incorrect inference, we introduce a conceptually and substantively novel approach from the causal inference literature: interventional indirect effects. Interventional indirect effects focus on the contributions of each distinct mediator to the treatment effect on the outcome. An appealing feature of this approach is that valid causal in ference of mediation analysis with multiple mediators can be attained without assuming a (correct) causal structure among the mediators. Using a social psychology experiment as a running example, we illustrate how researchers can readily estimate and interpret the proposed interventional effects in practice. We hope this article will encourage explaining and substantiating the causal assumptions underpinning mediation analysis with multiple mediators to fortify causal inference in psychology research.
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Quantification of Patient-Reported Pain Locations: Development of an Automated Measurement Method

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imagePatient-reported pain locations are critical for comprehensive pain assessment. Our study aim was to introduce an automated process for measuring the location and distribution of pain collected during a routine outpatient clinic visit. In a cross-sectional study, 116 adults with sickle cell disease–associated pain completed PAINReportItⓇ. This computer-based instrument includes a two-dimensional, digital body outline on which patients mark their pain location. Using the ImageJ software, we calculated the percentage of the body surface area marked as painful and summarized data with descriptive statistics and a pain frequency map. The painful body areas most frequently marked were the left leg-front (73%), right leg-front (72%), upper back (72%), and lower back (70%). The frequency of pain marks in each of the 48 body segments ranged from 3 to 79 (mean, 33.2 ± 21.9). The mean percentage of painful body surface area per segment was 10.8% ± 7.5% (ranging from 1.3% to 33.1%). Patient-reported pain locations can be easily analyzed from digital drawings using an algorithm created via the free ImageJ software. This method may enhance comprehensive pain assessment, facilitating research and personalized care over time for patients with various pain conditions.
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Potential associations between alterations in gut microbiome and obesity‐related traits after the bariatric surgery

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Abstract

Aim

This study aimed to examine the effects of both obesity and bariatric surgery on gut microbiome, dietary intake, as well as metabolic and inflammatory parameters.

Methods

All participants (15 with morbid obesity who had bariatric surgery, 8 with morbid obesity and 11 non-obese) were followed-up for a 6-month period with the interviews at baseline (M0), at the end of 3 (M3) and 6 months (M6). Dietary assessment was done, and blood and faecal samples were collected.

Results

Dietary energy and nutrient intakes as well as serum levels glucose, total cholesterol, LDL-cholesterol, and hs-CRP levels decreased by surgery (p<0.05, for each). Participants with morbid obesity had higher levels of Firmicutes and lower levels of Bacteroidetes at M0 compared to non-obese participants. The abundances of Bacteroidetes increased (p=0.02) while Firmicutes decreased (p>0.05) by the surgery, leading a significant decrease in Firmicutes/Bacteroidetes ratio (p=0.01). At sub-phylum level, the abundances of Lactobacillus and Bifidobacterium decreased while Akkermansia increased by the surgery (p<0.01, for each). Although participants who are morbidly obese had a distinct profile according to ß-diversity indices at M0, it became similar with the profile of non-obese participants (p>0.05) at M3 and M6. Similarly, α-diversity indices were lower in subjects with morbid obesity at M0, but became similar to levels in non-obese controls at M6.

Conclusion

This study confirmed that bariatric surgery has substantial impacts on gut microbiome composition and diversity, as well as anthropometrical measurements and biochemical parameters, which were associated with the alterations in dietary intake patterns.

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SARS‐CoV‐2‐encoded Inhibitors of Human LINE‐1 Retrotransposition

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Abstract

The ongoing pandemic of severe acute respiratory coronavirus 2 (SARS-CoV-2) is causing a devastating impact on public health worldwide. However, details concerning the profound impact of SARS-CoV-2 on host cells remain elusive. Here, we investigated the effects of SARS-CoV-2-encoded viral proteins on the intracellular activity of long interspersed element 1 (L1) retrotransposons using well-established reporter systems. Several non-structural or accessory proteins (Nsps) of SARS-CoV-2 (i.e., Nsp1, Nsp3, Nsp5, and Nsp14) significantly suppress human L1 mobility, and these viral L1 inhibitors generate a complex network that modulates L1 transposition. Specifically, Nsp1 and Nsp14 inhibit the intracellular accumulation of L1 open reading frame proteins (ORF1p), whereas Nsp3, Nsp5, and Nsp14 repress the reverse transcriptase activity of L1 ORF2p. Given recent findings concerning the roles of L1 in antiviral immune activation and host genome instability, the anti- L1 activities mediated by SARS-CoV-2-encoded inhibitors suggest that SARS-CoV-2 employs different strategies to optimize the host genetic environment.

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ADMET study, spectroscopic characterization and effect of synthetic nitro chalcone in combination with Norfloxacin, Ciprofloxacin and Ethidium Bromide against Staphylococcus aureus efflux pumps

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Abstract

Chalcones are present in a wide variety of plants, having in their structure two aromatic rings that are linked together by a chain composed of three carbon atoms with α, β-unsaturated to carbonyl system. Bacteria have several drug resistance mechanisms, among them the Efflux Pump, this mechanism when active, is able to expel different compounds from inside bacterial cells. Several efflux pumps have already been identified for Staphylococcus aureus bacteria, including MepA and NorA. Many chalcones have been isolated and identified with various activities, such as antimicrobial. In view of this, this article aimed to evaluate the antibiotic modifying effect of chalcone (E)-1-(2-hydroxyphenyl)-3-(3-nitrophenyl)prop-2-en-1-one against Staphylococcus aureus carrier of NorA and MepA efflux pump. Regarding the antibiotic, there was a synergism when associated with Ciprofloxacin in SA-K2068 strain, showing this chalcone as an alternative to reverse the resistance to this medicine. The physicochemical properties calculated were fundamental in the description of the predicted pharmacokinetic properties. Despite the mutagenic risk caused by the metabolic activation of nitrochalcone, it is possible to notice a pharmacological principle in a longer half-life for the performance of biological activities. The compound has a good bioavailability, as it is highly absorbed in the intestine and easily transported by plasma proteins, in addition to not presenting neurotoxic, hepatotoxic and cardiotoxic damage.
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Overexpression of NIMA related kinase 2 in multiple myeloma and its relevance with disease features and prognosis to bortezomib treatment

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Overexpression of NIMA related kinase 2 in multiple myeloma and its relevance with disease features and prognosis to bortezomib treatment

A total of 76 multiple myeloma (MM) patients and 30 health donors (HDs) were enrolled to collect bone marrow plasma cells for NIMA related kinase 2 (NEK2) detection using RT-qPCR. Meanwhile, NEK2 siRNA was transfected into the RPMI-8226 and KMS-11 cells (MM cell lines), subsequently their cell viability was evaluated using CCK8 reagent. NEK2 expression was higher in MM patients compared with HDs. Besides, elevated NEK2 expression associated with the occurrence of the bone lesion and t (4; 14). Additionally, elevated NEK2 expression correlated with declined objective response rate (ORR) and shorter progression-free survival (PFS). What is more, NEK2 silence decreased the cell viability under bortezomib treatment and the IC50 value of bortezomib in RPMI-8226 and KMS-11 cells (MM cell lines).


Abstract

What is Known and Objective

NIMA related kinase 2 (NEK2) promotes the malignant transformation and enhances the chemoresistance to proteasome inhibitor in multiple myeloma (MM) cell lines. The current study aimed to further investigate its correlation with clinical features and responsiveness to bortezomib treatment in MM patients.

Methods

Totally, 76 MM patients and 30 health donors (HDs) were enrolled to collect bone marrow plasma cells for NEK2 detection using reverse transcription quantitative polymerase chain reaction (RT-qPCR). Meanwhile, NEK2 siRNA was transfected into the RPMI-8226 and KMS-11 cells, subsequently their cell viability was evaluated using Cell Counting Kit-8 reagent after treatment with different doses of bortezomib.

Results and Discussion

NEK2 expression was higher in MM patients compared with HDs (Z = −5.123, p < 0.001). Besides, elevated NEK2 expression was associated with the occurrence of the bone lesion (χ 2 = 4.610, p = 0.032) and t (4; 14) (χ 2 = 3.971, p = 0.046). Additionally, elevated NEK2 expression was correlated with declined objective response rate (ORR) (χ 2 = 4.808, p = 0.028), but not with complete response (CR) (χ 2 = 2.341, p = 0.126). More importantly, elevated NEK2 expression was correlated with shorter progression-free survival (PFS) (χ 2 = 8.352, p = 0.039), but not with overall survival (OS) (χ 2 = 5.624, p = 0.131), What is more, NEK2 silence decreased the cell viability under bortezomib treatment and the inhibitory concentration (IC50) value of bortezomib in RPMI-8226 and KMS-11 cell lines (all p < 0.05).

What is New and Conclusion

NEK2 overexpression links with occurrence of bone lesion, t (4; 14), and poor prognosis to bortezomib treatment in MM patients.
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Relationships between squamous cell carcinoma antigen and cytokeratin 19 fragment values and renal function in oral cancer patients

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Squamous cell carcinoma antigen (SCC-Ag) and cytokeratin 19 fragment (CYFRA) are used to screen and monitor oral cancer patients. However, recent studies have reported that tumour markers become elevated as renal function decreases, regardless of tumour progression. A retrospective study was performed of 423 oral cancer patients who underwent blood testing for these tumour markers and other blood analytes during a 10-year period. The values of SCC-Ag and CYFRA increased significantly with decreasing renal function (P   (Source: International Journal of Oral and Maxillofacial Surgery)
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Glycerol strengthens probiotic effect of Limosilactobacillus reuteri in oral biofilms: a synergistic synbiotic approach

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Abstract

Both in vitro and in vivo studies have shown that the probiotic Limosilactobacillus reuteri can improve oral health. L. reuteri species are known to produce the antimicrobial 'reuterin' from glycerol. In order to further increase its antimicrobial activity, this study evaluated the effect of the combined use of glycerol and Limosilactobacillus reuteri (ATCC PTA 5289) in view of using a synergistic synbiotic over a probiotic. An antagonistic agar growth and a multispecies biofilm model showed that the antimicrobial potential of the probiotic was significantly enhanced against periodontal pathobionts and anaerobic commensals when supplemented with glycerol. Synbiotic biofilms also showed a significant reduction in inflammatory expression of human oral keratinocytes (HOK-18A), but only when the keratinocytes were preincubated with the probiotic. Probiotic preincubation of keratinocytes or probiotic- and synbiotic treatment of biofilms alone were insufficient to significantly reduce inflammatory expression. Overall, this study shows that combining glycerol with the probiotic L. reuteri into a synergistic synbiotic can greatly improve the effectiveness of the latter.

One sentence summary: The use of a synbiotic formulation of Limosilactobacillus reuteri with glycerol over the probiotic improves antimicrobial effects and reduced inflammatory response to oral biofilms.

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Association between human papillomavirus infection and malignant transformation of sinonasal inverted papilloma: A systematic review and meta-analysis

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Publication date: Available online 11 September 2022

Source: American Journal of Otolaryngology

Author(s): Fabio Ferreli, Matteo Di Bari, Antoine Moya-Plana, Federica Canzano, Emanuela Morenghi, Armando De Virgilio, Giuseppe Mercante, Giuseppe Spriano, Giovanni Colombo
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