Insight into the Role of an α-Helix Cluster in Protoporphyrinogen IX Oxidase.

Protoporphyrinogen IX oxidase (PPO) is the last common enzyme in chlorophyll and heme biosynthesis pathways. In humans, point mutations on PPO are responsible for the dominantly inherited disorder disease variegate porphyria (VP). It is found that several VP-causing mutation sites are located on an α-helix cluster (consisting of α-5, α-6, and α-7 helix, named the G169 helix cluster) of human PPO, although these mutation sites are outside the active site of the human PPO. In this work, we investigated the role of the G169 helix cluster via site-directed mutagenesis, enzymatic kinetics, and computational studies. Kinetic studies showed that mutations on the G169 helix cluster affect the activity of PPO. The MD simulation showed that mutations on the G169 helix cluster reduced the activity of PPO by affecting the proper orientation of substrate protoporphyrinogen within the active site of PPO and possibly the dipole moment of the G169 helix cluster. Moreover, the mutation abolished the interaction between the mutated site and other residues, thus affecting the secondary structure and hydrogen bond interactions within the G169 helix cluster. These results indicated that the integrity of the G169 helix cluster is important for the stabilization of protoporphyrinogen within the active site of PPO to facilitate the interaction between protoporphyrinogen and cofactor FAD and provide a proper electrostatic environment for the activity of PPO. Our result provides new insight into understanding the relationship between the structure and function of PPO.

Meta-analysis of changes in thiol-disulfide homeostasis during preeclampsia.

The present study systematically assessed alterations in thiol-disulfide homeostasis among women with preeclampsia (PE) through meta-analysis. This was conducted as such changes are believed to be associated with the oxidative stress underlying this condition. A comprehensive search of Medline, Web of Science, and Embase databases was conducted from their inception until 22 March 2023, to identify studies comparing levels of native thiol, total thiol, and disulfide between pregnant women with PE and those without PE. Results were pooled using a random-effects model to account for study heterogeneity. The analysis included a total of 631 women diagnosed with PE and 668 healthy pregnant women, encompassing 13 case-control studies and 1 prospective study. Pooled outcomes revealed that women with PE had significantly lower blood levels of native thiol, (mean difference [MD] -51.42 umol/L; 95% confidence interval [CI] -79.75 to -23.10 umol/L; P < 0.001; I2 = 0% and total thiol (MD -65.56 umol/L; 95% CI -104.97 to -26.15 umol/L; P = 0.001; I2 = 0%) compared to the control group. In contrast, no significant difference was observed in blood disulfide levels between the two groups (MD -1.10 umol/L; 95% CI -4.41 to -2.21 umol/L; P = 0.51; I2 = 0%). Subgroup analyses indicated that the results were consistent across studies matched by gestational age and body mass index, as well as those with varying quality scores (P for subgroup differences all > 0.05). In conclusion, women with PE are associated with significantly reduced blood levels of native and total thiols but show no change in blood disulfide levels, suggesting a state of reduced antioxidants in PE.

A Comprehensive Study of Heterogeneous Mismatch Repair Expression in Solid Tumors Reveals Different Immunohistochemical Patterns and Distinct Genetic Mechanisms.

OBJECTIVE: Immunohistochemistry is routinely performed to detect mismatch repair deficiency in solid tumors. Heterogeneous MMR expression (MMR-het) has been reported occasionally but not systemically studied. METHODS: In this study, we depicted MMR-het patterns of 40 tumors of different anatomical sites and analyzed MMR genetic alterations and tumor mutational burdens (TMB) through comprehensive genomic profiling. RESULTS: The MMR-het patterns were classified into 4 subgroups: "single-loss" (3 cases), "MLH1/PMS2 double-loss" (16 cases), "MSH2/MSH6 double-loss" (8 cases), and "triple/tetra-loss" (13 cases). Seventeen MMR-het cases exhibited histological heterogeneity, in which MMR protein loss was generally confined to either poorly differentiated or well-differentiated tumor areas. All "single-loss" tumors had MMR somatic mutations and coexisting POLE exonuclease domain mutations. "MLH1/PMS2 double-loss" tumors unexceptionally harbored MLH1 hypermethylation without MMR germline mutations. In the "MSH2/MSH6 double-loss" subgroup, 4 cases had MSH2/MSH6 germline mutations, while another 4 cases had multiple MSH2/MSH6 somatic mutations. Additional POLE exonuclease domain mutations were identified in 2 cases. Tumors in the "triple/tetra-loss" subgroup generally had MLH1 abnormalities (8 MLH1 hypermethylation, 4 MLH1 germline mutation, 1 MLH1 double somatic mutations), and coexistent somatic mutations on MSH2/MSH6 . Thirty-one cases (83.8%) were TMB-H, and all POLE -mutated cases exhibited ultra-high TMB (111.4 to 524.2 mut/Mb). CONCLUSION: Our findings highlighted the importance of accurately interpreting heterogeneous MMR protein staining patterns for developing a more efficient personalized genetic investigation strategy.

Risk Factors for Breast Cancer-Related Lymphedema: An Umbrella Review.

BACKGROUND: Identification of risk factors facilitates the prevention of breast cancer-related lymphedema (BCRL). Several published systematic reviews have already addressed the risk factors for BCRL. This study aimed to systematically identify potential risk factors for BCRL and evaluate the quality of evidence. METHODS: The study followed methodologic guidance from the Joanna Briggs Institute, and the Cochrane Handbook. The following electronic databases were systematically searched from inception to 15 November 2022: PubMed, Embase, CINAHL, Web of Science, Scopus, CNKI, SinoMed, Wanfang, JBI Database, Cochrane Database, ProQuest, and PROSPERO. Two authors independently screened studies, extracted data, and assessed methodologic quality using AMSTAR2, risk of bias using ROBIS, and evidence quality using GRADE. The study evaluated overlap, assessed the small-study effect, and calculated the I2 statistic and Egger's P value as needed. RESULTS: The study included 14 publications comprising 10 meta-analyses and 4 systematic reviews. The authors identified 39 factors and 30 unique meta-analyses. In the study, 13 innate personal trait-related risk factors, such as higher body mass index (BMI) and axillary lymph nodes dissection, showed statistically significant associations with BCRL incidence. Breast reconstruction was found to be a protective factor. The methodologic quality was low or critically low. The majority of the systematic reviews and/or meta-analyses were rated as having a high risk of bias. Evidence quality was low for 22 associations and moderate for 8 associations. CONCLUSIONS: The currently identified risk factors for BCRL all are innate personal trait-related factors. Future well-designed studies and robust meta-analyses are needed to explore potential associations between behavioral-, interpersonal-, and environmental-related factors and BCRL, as well as the role of genetic variations and pathophysiologic factors.

Identification of novel serum protein biomarkers in the context of 3P medicine for intravenous leiomyomatosis: a data-independent acquisition mass spectrometry-based proteomics study.

Background: Intravenous leiomyomatosis (IVL) is a rare endocrine-associated tumor with unique characteristics of intravascular invasion. This study aimed to identify reliable biomarkers to supervise the development or recurrence of IVL in the context of predictive, preventive, and personalized medicine (PPPM/3PM). Methods: A total of 60 cases were recruited to detect differentially expressed proteins (DEPs) in serum samples from IVL patients. These cases included those with recurrent IVL, non-recurrent IVL, uterine myoma, and healthy individuals without uterine myoma, with 15 cases in each category. Then, weighted gene co-expression network analysis (WGCNA), lasso-penalized Cox regression analysis (Lasso), trend clustering, and a generalized linear regression model (GLM) were utilized to screen the hub proteins involved in IVL progression. Results: First, 93 differentially expressed proteins (DEPs) were determined from 2582 recognizable proteins, with 54 proteins augmented in the IVL group, and the remaining proteins declined. These proteins were enriched in the modulation of the immune environment, mainly by activating the function of B cells. After the integrated analyses mentioned above, a model based on four proteins (A0A5C2FUE5, A0A5C2GPQ1, A0A5C2GNC7, and A0A5C2GBR3) was developed to efficiently determine the potential of IVL lesions to progress. Among these featured proteins, our results demonstrated that the risk factor A0A5C2FUE5 was associated with IVL progression (OR = 2.64). Conversely, A0A5C2GPQ1, A0A5C2GNC7, and A0A5C2GBR3 might act in a protective manner and prevent disease development (OR = 0.32, 0.60, 0.53, respectively), which was further supported by the multi-class receiver operator characteristic curve analysis. Conclusion: Four hub proteins were eventually identified based on the integrated bioinformatics analyses. This study potentiates the promising application of these novel biomarkers to predict the prognosis or progression of IVL by a 3PM approach. Supplementary Information: The online version contains supplementary material available at 10.1007/s13167-023-00338-0.

Acute Salinity Stress Disrupts Gut Microbiota Homeostasis and Reduces Network Connectivity and Cooperation in Razor Clam Sinonovacula constricta.

Accumulating evidence demonstrates that it is of great importance to maintain a stable and functional gut microbial community for host's growth and health. However, gut microenvironment is constantly affected by diverse environmental factors. Salinity can cause stress, including hypersaline or hyposaline stress to aquatic species, thereby affecting their growth conditions. Razor clam (Sinonovacula constricta), an economically important bivalve species, inhabits in intertidal and estuarine zones and constantly experiences salinity stress. Yet little is known about how and to what extent clam gut microbiota is affected by salinity stress, while this knowledge is fundamental for clam aquaculture health management. To address this concern, this study compared the temporal differences of gut bacterial signatures and community assembly of S. constricta under normal salinity (NS), low salinity (LS), and high salinity (HS) conditions. Acute salinity stress affected the compositions, structures, and functional potentials of clam gut microbial community, of which salinity stress, hours post stress, and their interaction respectively constrained 7.6%, 16.4%, and 7.9% of community variation. Phylogenetic bin-based null model result revealed that the gut bacterial assembly of three salinity groups seemed to be largely driven by stochastic processes. Network analysis indicated that gut bacterial interspecies interaction exhibited less connected and lower cooperative activity under the conditions of LS and HS compared with NS. Notably, some pathogenic bacteria, including Vibrio and Pseudoalteromonas, were identified as keystone taxa of gut microbial networks in LS and HS groups. Above findings suggest that the clams under LS and HS conditions might be at a higher risk of developing disease. Our findings enhance the mechanism understanding of gut microbial assembly in S. constricta under abiotic factor challenge, which has important implications for clam health control from a microbial ecological perspective.

The neuroprotective effects of Liuwei Dihuang medicine in the APP/PS1 mouse model are dependent on the PI3K/Akt signaling pathway.

Alzheimer's disease (AD) is an age-related neurodegenerative disease that progressively impairs cognitive function and memory. The occurrence and development of Alzheimer's disease involves many processes. In response to the complex pathogenesis of AD, the Traditional Chinese medicine formula Liuwei Dihuang Pill (LWD) has been shown to improve the cognitive function of AD animal models. However, the active ingredients and mechanism of action of LWD have not been fully elucidated. In this study, network pharmacological analysis predicted 40 candidate compounds in LWD, acting on 227 potential targets, of which 185 were associated with AD. Through network pharmacological analysis, the mechanism of action of LWD therapy AD is related to the inhibition of inflammatory response, regulation of neuronal state, and autophagy. In this experiment, LWD was detected in the APP/PS1 transgenic mouse model. The objective was to observe the effects of LWD on hippocampal learning and memory ability, Aß clearance, autophagy and inflammatory response in APP/PS1 mice. The results showed that LWD improved long-term memory and working memory in APP/PS1 mice compared with the WT group. At the same time, LWD can increase the expression of hippocampal autophagy biomarkers, reduce the precipitation of Aß, and the activation of microglia and astrocytes. Its mechanism may be related to the regulation of the PI3K/Akt signaling pathway. Thus, we demonstrate for the first time that LWD has a neuroprotective effect on APP/PS1 mice and provide theoretical foundation for the development of a new clinical treatment for AD.

Breast cancer survivors' experiences of barriers and facilitators to lymphedema self-management behaviors: a theory-based qualitative study.

PURPOSE: Lifelong self-management plays a critical role in the prevention and management of lymphedema among breast cancer survivors. However, adherence to lymphedema self-management behaviors has remained suboptimal. Hence, we adopted a theory-informed method to elucidate the facilitators and barriers of lymphedema self-management for breast cancer survivors. METHODS: In-depth semi-structured interviews were conducted between August and October 2022 in the lymphedema nursing clinic of a tertiary cancer hospital. The maximum variation sampling technique was used to ensure a diverse sample. The ITHBC (Integrated Theory of Health Behavior Change) framework was used to inform the interview outline and data analysis. Interview transcripts were coded line-by-line and mapped to domains in accordance with the ITHBC, using both deductive and inductive content analysis. RESULTS: A total of 16 participants were interviewed (aged 35 to 67). Twenty-three themes (12 facilitators and 11 barriers) were mapped onto the three domains (knowledge and belief, social facilitation, and self-regulation skill and ability) of ITHBC as facilitators and barriers to lymphedema self-management. Three additional themes including limited treatment resources for lymphedema, inconvenience of lymphedema management, boredom and tedium of lymphedema self-management were categorized under the domain of other barriers. CONCLUSIONS: Incorporating these findings into the ITHBC framework allows for a more systematic selection of theory-based strategies that may improve the design of effective lymphedema self-management interventions for breast cancer survivors. IMPLICATIONS FOR CANCER SURVIVORS: Elucidating impact factors, especially facilitators and barriers, for lymphedema self-management adherence is essential for developing effective intervention programs to enhance breast cancer survivors' lymphedema self-management behaviors.

A Dual GLP-1/GIP Receptor Agonist Is More Effective than Liraglutide in the A53T Mouse Model of Parkinson's Disease.

Parkinson's disease (PD) is a complex syndrome with many elements, such as chronic inflammation, oxidative stress, mitochondrial dysfunction, loss of dopaminergic neurons, build-up of alpha-synuclein (α-syn) in cells, and energy depletion in neurons, that drive the disease. We and others have shown that treatment with mimetics of the growth factor glucagon-like peptide 1 (GLP-1) can normalize energy utilization, neuronal survival, and dopamine levels and reduce inflammation. Liraglutide is a GLP-1 analogue that recently showed protective effects in phase 2 clinical trials in PD patients and in Alzheimer disease patients. We have developed a novel dual GLP-1/GIP receptor agonist that can cross the blood-brain barrier and showed good protective effects in animal models of PD. Here, we test liraglutide against the dual GLP-1/GIP agonist DA5-CH (KP405) in the A53T tg mouse model of PD which expresses a human-mutated gene of α-synuclein. Drug treatment reduced impairments in three different motor tests, reduced levels of α-syn in the substantia nigra, reduced the inflammation response and proinflammatory cytokine levels in the substantia nigra and striatum, and normalized biomarker levels of autophagy and mitochondrial activities in A53T mice. DA5-CH was superior in almost all parameters measured and therefore may be a better drug treatment for PD than liraglutide.

Cholecystokinin Signaling can Rescue Cognition and Synaptic Plasticity in the APP/PS1 Mouse Model of Alzheimer's Disease.

Synaptic impairment and loss are an important pathological feature of Alzheimer's disease (AD). Memory is stored in neural networks through changes in synaptic activity, and synaptic dysfunction can cause cognitive dysfunction and memory loss. Cholecystokinin (CCK) is one of the major neuropeptides in the brain, and plays a role as a neurotransmitter and growth factor. The level of CCK in the cerebrospinal fluid is decreased in AD patients. In this study, a novel CCK analogue was synthesized on the basis of preserving the minimum bioactive fragment of endogenous CCK to investigate whether the novel CCK analogue could improve synaptic plasticity in the hippocampus of the APP/PS1 transgenic mouse model of AD and its possible molecular biological mechanism. Our study found that the CCK analogue could effectively improve spatial learning and memory, enhance synaptic plasticity in the hippocampus, normalize synapse numbers and morphology and the levels of key synaptic proteins, up-regulate the PI3K/Akt signaling pathway and normalize PKA, CREB, BDNF and TrkB receptor levels in APP/PS1 mice. The amyloid plaque load in the brain was reduced by CCK, too. The use of a CCKB receptor antagonist and targeted knockdown of the CCKB receptor (CCKBR) attenuated the neuroprotective effect of the CCK analogue. These results demonstrate that the neuroprotective effect of CCK analogue is achieved by activating the PI3K/Akt as well as the PKA/CREB-BDNF/TrkB signaling pathway that leads to protection of synapses and cognition.

Design, synthesis and in vitro/in vivo anticancer activity of tranylcypromine-based triazolopyrimidine analogs as novel LSD1 inhibitors.

Histone lysine specific demethylase 1 (LSD1) is responsible for the demethylation of mono-/dimethylated lysine residue on histone proteins. LSD1 plays an extensive and essential role in the pathogenesis and progression of many human diseases such as cancers, and thus is becoming an attractive therapeutic target for cancer treatment. Tranylcypromine (TCP) is an important chemical template for developing irreversible LSD1 inhibitors, representing a major chemotype of clinical candidates. Here we report a novel pool of TCP derivatives with triazolopyrimidine as a privileged heterocylic motif. Starting from ticagrelor, a clinically available antiplatelet agent, as a hit compound, our medicinal efforts have led to the identification of compound 9j with nanomolar inhibitory potency against LSD1 as well as broad-spectrum antiproliferative activities against tumor cells. Enzyme studies show that compound 9j is selective over MAO-A/B enzymes, and also cellular active to elevate the expression of H3K4me2 by inhibiting LSD1 in cells. Furthermore, in a H1650 xenograft mouse model, oral administration of compound 9j at low 10 and 20 mg/kg dosages could enable a significant reduction in tumor size and a remarkable extension of survival. The current work is expected to provide an additional strategy to achieve new TCP-based LSD1 inhibitors.

Risk factors of breast cancer-related lymphoedema: protocol of an umbrella review.

INTRODUCTION: Breast cancer-related lymphoedema (BCRL) is a progressive and debilitating complication post-breast cancer treatment. Identifying potential risk factors facilitates the prevention and management of BCRL. Multiple systematic reviews have been conducted to address the variables correlated with the occurrence of BCRL. This study aims to identify and examine factors predicting the development of BCRL, to clarify the predicting mechanism of these factors, as well to determine the credibility of risk factors for BCRL. METHODS AND ANALYSIS: This umbrella review will be conducted with the methodological guidance of the Joanna Briggs Institute and the Cochrane handbook. A comprehensive systematic search will be performed in ten databases: PubMed, Embase, CINAHL, Web of Science, Scopus, CNKI, SinoMed, Wangfang database, the JBI Database of Systematic Reviews, Cochrane Database of Systematic Reviews. The search for unpublished studies will include ProQuest and the PROSPERO register. Reference lists will also be hand searched. Two reviewers will independently screen the studies, extract data and assess the methodological quality using the Methodological Quality of Systematic Reviews-2 and the Risk of Bias in Systematic Reviews. The degree of overlap between included reviews will be assessed by calculating the Corrected Covered Area. The credibility of the associations between risk factors and lymphoedema will be graded into four classes: convincing, highly suggestive, suggestive and weak, referring to the classification system of recent umbrella reviews. A descriptive, narrative synthesis and suggestions for clinical practice and future research will be made based on included systematic reviews, considering the quality of the evidence. ETHICS AND DISSEMINATION: Ethical approval is not required for this umbrella review. We will seek to submit the results for publication in a peer-reviewed journal or present it at conferences. PROSPERO REGISTRATION NUMBER: CRD42022375710.

Migration behavior and dietary exposure risk assessment of pesticides residues in honeysuckle (Lonicera japonica Thunb.) based on modified QuEChERS method coupled with tandem mass spectrometry.

The honeysuckle was widely appreciated as tea beverage owing to the biological activities and the unique aroma and flavor. It is in urgent requirement to explore the migration behavior and dietary exposure as the pesticide residues would bring about potential risks through honeysuckle intake. The optimized QuEChERS procedure coupled with the HPLC-MS/MS and GC-MS/MS methods were employed to determine 93 pesticide residues of seven classifications including carbamates, pyrethroid, triazoles, neonicotinoids, organophosphorus, organochlorine, and others for 93 honeysuckle samples from four primary production bases. As a result, 86.02% of the samples were contaminated by at least one pesticide. Unexpectedly, the banned pesticide of carbofuran was also identified. The migration behavior of metolcarb was the highest, whereas thiabendazole contributed less risk to the infusion with relative lower transfer rate. Both the chronic and acute exposure yielded low risk for human health with five high risk pesticides of dichlorvos, cyhalothrin, carbofuran, ethomyl, and pyridaben. Besides, this study provides foundation of dietary exposure risk assessment for honeysuckle and other likewise products.

Chitinase Is Involved in the Fruiting Body Development of Medicinal Fungus Cordyceps militaris.

Cordyceps militaris is a famous traditional edible and medicinal fungus in Asia, and its fruiting body has rich medicinal value. The molecular mechanism of fruiting body development is still not well understood in C. militaris. In this study, phylogenetically analysis and protein domains prediction of the 14 putative chitinases were performed. The transcription level and enzyme activity of chitinase were significant increased during fruiting body development of C. militaris. Then, two chitinase genes (Chi1 and Chi4) were selected to construct gene silencing strain by RNA interference. When Chi1 and Chi4 genes were knockdown, the differentiation of the primordium was blocked, and the number of fruiting body was significantly decreased approximately by 50% compared to wild-type (WT) strain. The length of the single mature fruiting body was shortened by 27% and 38% in Chi1- and Chi4-silenced strains, respectively. In addition, the chitin content and cell wall thickness were significantly increased in Chi1- and Chi4-silenced strains. These results provide new insights into the biological functions of chitinase in fruiting body development of C. militaris.

Investigation on maternal and infant health literacy among lying-in women / 预防医学

Objective@#To investigate the level of maternal and infant health literacy and its influencing factors among lying-in women, so as to provide insights into formulating maternal and infant health education and promotion strategies. @*Methods@# Lying-in women were sampled from Children's Hospital of Shanxi using a cluster sampling method from March to September 2022. Demographic characteristics, maternal and infant health literacy, and health education demands were collected through a questionnaire survey. Factors affecting maternal and infant health literacy among lying-in women were identified using a multivariable logistic regression model. @*Results@#A total of 1 099 questionnaires were allocated, and 1 059 valid questionnaires were recovered, with an effective rate of 96.36%. Participants had a mean age of (30.93±4.01) years, 930 urban residents (87.82%), and 706 pluripara (66.67%). The overall prevalence of maternal and infant health literacy was 35.51% among lying-in women, and the prevalence rates of basic knowledge and concept, healthy lifestyles and behaviors and basic skills were 47.69%, 83.10% and 38.81%, respectively. Multivariable logistic regression analysis showed that educational level (diploma or undergraduate degree, OR=3.916, 95%CI: 1.250-9.031; master degree and above, OR=4.557, 95%CI: 1.498-11.460), occupation (company employees, OR=2.701, 95%CI: 1.385-5.268; medical staff, OR=2.981, 95%CI: 1.289-6.893), pluripara (OR=5.649, 95%CI: 3.919-8.142), participating in health education activities (OR=2.332, 95%CI: 1.524-3.570), and participating in schools for pregnant women (OR=2.252, 95%CI: 1.541-3.291) were promoting factors for maternal and infant health literacy; while gestational hypertension (OR=0.255, 95%CI: 0.133-0.488) and gestational diabetes (OR=0.318, 95%CI: 0.211-0.478) were inhibiting factors for maternal and infant health literacy. Most participants acquired health knowledge through online media (62.42%), and hoped to participate in health education activities through online media publicity (68.18%).@* Conclusions @#The maternal and infant health literacy level of lying-in women in this survey is associated with education, occupation, parturition frequency, participation in health education activities, participation in schools for pregnant women, gestational hypertension and gestational diabetes.

DA5-CH and Semaglutide Protect against Neurodegeneration and Reduce α-Synuclein Levels in the 6-OHDA Parkinson's Disease Rat Model.

Insulin desensitization has been observed in the brains of patients with Parkinson's disease (PD), which is a progressive neurodegenerative disorder for which there is no cure. Semaglutide is a novel long-actingglucagon-likepeptide-1 (GLP-1) receptor agonist that is on the market as a treatment for type 2 diabetes. It is in a phase II clinical trial in patients with PD. Two previous phase II trials in PD patients showed good effects with the older GLP-1 receptor agonists, exendin-4 and liraglutide. We have developed a dual GLP-1/GIP receptor agonist (DA5-CH) that can cross the blood-brain barrier (BBB) at a higher rate than semaglutide. We tested semaglutide and DA5-CH in the 6-OHDA-lesion rat model of PD. Treatment was semaglutide or DA5-CH (25 nmol/kg, i.p.) daily for 30 days postlesion. Both drugs reduced the apomorphine-induced rotational behavior and alleviated dopamine depletion and the inflammation response in the lesioned striatum as shown in reduced IL-1ß and TNF-α levels, with DA5-CH being more effective. In addition, both drugs protected dopaminergic neurons and increased TH expression in the substantia nigra. Furthermore, the level of monomer and aggregated α-synuclein was reduced by the drugs, and insulin resistance as shown in reduced pIRS-1ser312 phosphorylation was also attenuated after drug treatment, with DA5-CH being more effective. Therefore, while semaglutide showed good effects in this PD model, DA5-CH was superior and may be a better therapeutic drug for neurodegenerative disorders such as PD than GLP-1 receptor agonists that do not easily cross the BBB.

Efficacy of pramipexole on quality of life in patients with Parkinson's disease: a systematic review and meta-analysis.

BACKGROUND: Quality of life (QoL) in patients with Parkinson's disease (PD) is increasingly used as an efficacy outcome in clinical studies of PD to evaluate the impact of treatment from the patient's perspective. Studies demonstrating the treatment effect of pramipexole on QoL remain inconclusive. This study aims to evaluate the effect of pramipexole on QoL in patients with PD by conducting a systematic review and meta-analysis of existing clinical trials. METHODS: A systematic literature search of PubMed, Embase and the Cochrane Library was performed from inception to 30 April 2022 to identify randomised, placebo-controlled trials of patients with idiopathic PD receiving pramipexole, who reported a change from baseline in their QoL as measured by the 39-item Parkinson's Disease Questionnaire (PDQ-39). Risk of bias was independently assessed by two reviewers using the Cochrane Collaboration's tool for bias assessment. RESULTS: Of 80 eligible articles screened, six trials consisting of at least 2000 patients with early or advanced PD were included. From the synthesis of all six selected trials, a significant mean change from baseline in the PDQ-39 total score of -2.49 (95% CI, -3.43 to -1.54; p < 0.0001) was observed with pramipexole compared with placebo. A trend toward improvement in QoL was consistently observed among patients who received optimal doses of pramipexole (≥ 80% of the study population on 1.5 mg dosage), regardless of disease severity (advanced versus early) or baseline QoL levels. CONCLUSION: This meta-analysis provides evidence for the potential treatment benefit of pramipexole in improving QoL in patients with PD.

Parkinson's disease is a chronic, progressive nervous system disorder with no known cure. Patients may experience a number of symptoms including stiffness, slowness, and uncontrollable muscle movements, all of which impact their quality of life. Most clinical studies in Parkinson's disease measure the effect of treatment on improving symptoms, but other aspects such as quality of life are often overlooked. It is important to include quality of life measures in clinical studies of Parkinson's disease, such as the 39-item Parkinson's disease questionnaire (PDQ-39), to understand the impact of treatment from patients' perspectives. Pramipexole is a dopamine agonist that is well-tolerated and effective at treating Parkinson's disease symptoms. However, studies examining its effect on quality of life are inconclusive. This meta-analysis of existing clinical trials therefore aimed to evaluate the effect of pramipexole on quality of life in patients with Parkinson's disease. Six trials consisting of at least 2000 patients with early or advanced Parkinson's disease receiving treatment with pramipexole were included in this meta-analysis. Analysis of these six trials found a significant improvement in PDQ-39 total score with pramipexole compared with placebo. This meta-analysis provides new evidence for the potential treatment benefit of pramipexole in improving quality of life in patients with Parkinson's disease.

Pan-tropomyosin receptor kinase immunohistochemistry is a feasible routine screening strategy for NTRK fusions in mismatch repair-deficient colorectal carcinomas.

We have previously revealed the high enrichment of NTRK fusion in mismatch repair deficient (dMMR) CRCs. Optimized diagnostic approaches are urgently needed to identify dMMR CRCs that could benefit from TRK inhibitor therapy. A consecutive cohort of 240 surgically resected dMMR CRCs from 2015 to 2021 was collected for pan-TRK immunohistochemistry (IHC) using pan-TRK clone EPR17341 (VENTANA). We analyzed the sensitivity and specificity of pan-TRK IHC with sequential DNA/RNA-based Next Generation Sequencing (NGS) as the reference method and further explored IHC staining patterns and their correlation with fusion variants in dMMR CRCs. Of 240 dMMR CRCs, 15 (6.2%) were stained positive for pan-TRK IHC, and the sensitivity and specificity were both 100%. Five staining patterns were revealed, which correlated with fusion variants. Diffuse and strong positivity in membrane and cytoplasm were detected in all 6 cases with TPM3-NTRK1 fusions (6/15, 40%). Weak granular cytoplasmic staining, including diffuse or focal positivity, was found in 6 NTRK3 fusions (3 ETV6-NTRK3 and 3 EML4-NTRK3) (6/15, 40%). Diffuse and strong nuclear positivity was noticed in 2 LMNA-NTRK1 fusions (2/15, 13.3%). Intense granular cytoplasmic staining was observed in the only case with PLEKHA6-NTRK1 fusion (1/15, 6.7%). Interestingly, pan-TRK positivity was observed in one case with precursor lesions in both precancerous and cancerous regions, whereas MLH1 loss was restricted to the cancerous region. In summary, an optimized multi-step algorithm using pan-TRK IHC as a screening method was proposed to identify CRC patients harboring NTRK fusions.

Cholecystokinin and glucagon-like peptide-1 analogues regulate intestinal tight junction, inflammation, dopaminergic neurons and α-synuclein accumulation in the colon of two Parkinson's disease mouse models.

Parkinson's disease (PD) is the second most common neurodegenerative disease, and no treatment is available to stop its progression. Studies have shown that the colonic pathology of PD precedes that of the brain. The 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD mouse model and the human A53T α-synuclein (α-syn) transgenic PD mouse model show colonic pathology and intestinal dopaminergic neuronal damage, which is comparable to the intestinal pathology of PD. Cholecystokinin (CCK) and glucagon-like peptide-1 (GLP-1), which are brain-gut peptides, have neurotrophic and anti-inflammatory properties. Two GLP-1R agonists have already shown robust effects in phase II trials in PD patients. However, whether they have beneficial effects on colonic pathology in PD remains unclear. In this study, MPTP-treated mice and human A53T α-syn transgenic mice were intraperitoneally injected with a CCK analogue or Liraglutide, a GLP-1 analogue, once a day for 5 weeks. Levels of colonic epithelial tight junction proteins including occludin and zonula occludens-1 (ZO-1), inflammatory biomarkers including inducible nitric oxide synthase (iNOS) and tumor necrosis factor-alpha (TNF-α), brain-derived neurotrophic factor (BDNF), tyrosine hydroxylase (TH) and α-syn were analyzed. The results show that the CCK analogue and Liraglutide both restored the disruption of intestinal tight junction, reduced colonic inflammation, inhibited colonic dopaminergic neurons reduction and the accumulation of α-syn oligomers in the colon of both PD mice models. This study suggested that CCK or GLP-1 analogues could be beneficial to the improvement of leaky gut barrier, inflammation, dopaminergic neuron impairment and accumulation of α-syn in the colon of PD patients.

Electroacupuncture Attenuates Learning and Memory Impairment via PI3K/Akt Pathway in an Amyloid ß 25-35-Induced Alzheimer's Disease Mouse Model.

The main characteristic of Alzheimer's disease (AD) is the progressive decline of learning and memory ability. Electroacupuncture (EA) may improve AD-related learning and memory ability. However, the underlying molecular mechanism of action remains unclear. The objective of the present study was to assess the effects and the molecular mechanism of EA on learning and memory in an amyloid ß 25-35 (Aß 25-35) induced AD mouse model. The AD model was established by intracerebroventricular (ICV) administration of Aß 25-35 oligomers. AD mice were electroacupunctured with wisdom three-needle combined with Baihui (GV20) five times per week for three consecutive weeks. The Morris water maze (MWM) and Y maze tests were applied to evaluate spatial learning and memory ability. A transmission electron microscope (TEM) was used to measure mitochondria and autophagy of hippocampal neurons, and western blot was applied to observe molecular changes in the mice hippocampus. The results suggested that EA treatment significantly alleviated learning and memory impairment related to AD, reduced mitochondria damage, improved autophagy, increased mitochondrial protein 2 (Mfn2), Beclin 1, and LC3B, and decreased the expressions of fission protein 1 (Fis1) level. Furthermore, EA further upregulated the protein expression of phosphatidylinositol 3-kinase (PI3K) and the ratio of p-Akt/Akt in the hippocampus of AD mice. This study demonstrates that EA treatment attenuates cognitive deficits, modulates mitochondrial fusion and fission, and enhances autophagy via the PI3K/Akt pathway in a mouse AD model.