bluuebunny/crossref_metadata_2025 huggingface dataset:
Pharmacogenetic inhibition of TrkB signaling in adult mice attenuates mechanical hypersensitivity and improves locomotor function after spinal cord injury
Authors: Martin Karmarcha K. , Noble Donald J. , Parvin Shangrila , Jang Kyeongran , Garraway Sandra M.
Published: September 2022

Brain-derived neurotrophic factor (BDNF) signals through tropomyosin receptor kinase B (TrkB), to exert various types of plasticity. The exact involvement of BDNF and TrkB in neuropathic pain states after spinal cord injury (SCI) remains unresolved. This study utilized transgenic TrkBF616 mice to examine the effect of pharmacogenetic inhibition of TrkB signaling, induced by treatment with 1NM-PP1 (1NMP) in drinking water for 5 days, on formalin-induced inflammatory pain, pain hypersensitivity, and locomotor dysfunction after thoracic spinal contusion. We also examined TrkB, ERK1/2, and pERK1/2 expression in the lumbar spinal cord and trunk skin. The results showed that formalin-induced pain responses were robustly attenuated in 1NMP-treated mice. Weekly assessment of tactile sensitivity with the von Frey test showed that treatment with 1NMP immediately after SCI blocked the development of mechanical hypersensitivity up to 4 weeks post-SCI. Contrastingly, when treatment started 2 weeks after SCI, 1NMP reversibly and partially attenuated hind-paw hypersensitivity. Locomotor scores were significantly improved in the early-treated 1NMP mice compared to late-treated or vehicle-treated SCI mice. 1NMP treatment attenuated SCI-induced increases in TrkB and pERK1/2 levels in the lumbar cord but failed to exert similar effects in the trunk skin. These results suggest that early onset TrkB signaling after SCI contributes to maladaptive plasticity that leads to spinal pain hypersensitivity and impaired locomotor function.
Positive horizontal-canal head impulse test is not a benign sign for acute vestibular syndrome with hearing loss
Authors: Bery Anand K. , Chang Tzu-Pu
Published: September 2022

Background

Diagnosis of acute vestibular syndrome (AVS) with hearing loss is challenging because the leading vascular cause—AICA territory stroke—can appear benign on head impulse testing. We evaluated the diagnostic utility of various bedside oculomotor tests to discriminate imaging-positive and imaging-negative cases of AVS plus hearing loss.

Method

We reviewed 13 consecutive inpatients with AVS and acute unilateral hearing loss. We compared neurologic findings, bedside and video head impulse testing (bHIT, vHIT), and other vestibular signs (including nystagmus, skew deviation, and positional testing) between MRI+ and MRI– cases.

Results

Five of thirteen patients had a lateral pontine lesion (i.e., MRI+); eight did not (i.e., MRI–). Horizontal-canal head impulse test showed ipsilateral vestibular loss in all five MRI+ patients but only in three MRI– patients. The ipsilesional VOR gains of horizontal-canal vHIT were significantly lower in the MRI+ than the MRI– group (0.56 ± 0.11 vs. 0.87 ± 0.24, p = 0.03). All 5 MRI+ patients had horizontal spontaneous nystagmus beating away from the lesion (5/5). One patient (1/5) had direction-changing nystagmus with gaze. Two had skew deviation (2/5). Among the 8 MRI– patients, one (1/8) presented as unilateral vestibulopathy, four (4/8) had positional nystagmus and three (3/8) had isolated posterior canal hypofunction.

Conclusion

The horizontal-canal head impulse test poorly discriminates central and peripheral lesions when hearing loss accompanies AVS. Paradoxically, a lateral pontine lesion usually mimics unilateral peripheral vestibulopathy. By contrast, patients with peripheral lesions usually present with positional nystagmus or isolated posterior canal impairment, risking misdiagnosis as central vestibulopathy.
Effect and safety of extracorporeal shockwave therapy for postherpetic neuralgia: A randomized single-blind clinical study
Authors: Chen Lu , Qing Ailing , Zhu Tao , Yang Pingliang , Ye Ling
Published: September 2022

Objective

To evaluate the efficacy and safety of extracorporeal shockwave therapy (ESWT) for postherpetic neuralgia.

Design

Randomized single-blind clinical study.

Patients

Patients with postherpetic neuralgia.

Methods

Patients were randomly divided into the control group and the ESWT group. The control group received conventional treatment while the ESWT group received conventional treatment and ESWT. The primary outcome is pain degree as assessed by the numeric rating scale (NRS), and secondary outcomes include brief pain inventory (BPI), Self-rating Anxiety Scale (SAS), Self-rating Depression Scale (SDS), and Pittsburgh Sleep Quality Index (PSQI). Data were collected at baseline and at weeks 1, 4, and 12. Linear mixed-effects models were applied to repeated measurement data.

Results

The scores on the NRS, BPI, SAS, SDS, and PSQI decreased over time in both groups. The NRS and SDS scores of the ESWT group were statistically lower than the control group. There was no time × group interaction in the mixed model analysis. Baseline age was correlated with NRS scores and BPI scores, and invasive treatment was related to PSQI scores, with no interaction effect for baseline confounders observed. No adverse events were observed during the process of this trial.

Conclusion

Extracorporeal shockwave therapy combined with conventional treatment could relieve pain and improve the psychological state in patients with postherpetic neuralgia without serious adverse effects.
Delirium-related factors and their prognostic value in patients undergoing craniotomy for brain metastasis
Authors: Yoo Jihwan , Joo Bio , Park Juyeong , Park Hun Ho , Park Mina , Ahn Sung Jun , Suh Sang Hyun , Kim Jae-Jin , Oh Jooyoung
Published: September 2022

Background

Delirium is characterized by acute brain dysfunction. Although delirium significantly affects the quality of life of patients with brain metastases, little is known about delirium in patients who undergo craniotomy for brain metastases. This study aimed to identify the factors influencing the occurrence of delirium following craniotomy for brain metastases and determine its impact on patient prognosis.

Method

A total of 153 patients who underwent craniotomy for brain metastases between March 2013 and December 2020 were evaluated for clinical and radiological factors related to the occurrence of delirium. Statistical analysis was conducted by dividing the patients into two groups based on the presence of delirium, and statistical significance was confirmed by adjusting the clinical characteristics of the patients with brain metastases using propensity score matching (PSM). The effect of delirium on patient survival was subsequently evaluated using Kaplan–Meier analysis.

Results

Of 153 patients, 14 (9.2%) had delirium. Age (P = 0.002), sex (P = 0.007), and presence of postoperative hematoma (P = 0.001) were significantly different between the delirium and non-delirium groups. When the matched patients (14 patients in each group) were compared using PSM, postoperative hematoma showed a statistically significant difference (P = 0.036) between the delirium and non-delirium groups. Kaplan–Meier survival analysis revealed that the delirium group had poorer prognosis (log-rank score of 0.0032) than the non-delirium group.

Conclusion

In addition to the previously identified factors, postoperative hematoma was identified as a strong predictor of postoperative delirium. Also, the negative impact of delirium on patient prognosis including low survival rate was confirmed.
Walking speed at the acute and subacute stroke stage: A descriptive meta-analysis
Authors: Tasseel-Ponche Sophie , Delafontaine Arnaud , Godefroy Olivier , Yelnik Alain P. , Doutrellot Pierre-Louis , Duchossoy Charline , Hyra Marie , Sader Thibaud , Diouf Momar
Published: September 2022

Gait disorders are one of the leading patient complaints at the sub-acute stroke stage (SSS) and a main determinant of disability. Walking speed (WS) is a major vital and functional index, and the Ten-Meter Walk Test is considered the gold standard after stroke. Based on a systematic review of the literature, studies published between January 2000 and November 2021 were selected when WS was reported (ten-meter walk test for short distance and/or 6-min walking distance for long distance) within 6 months following a first ischemic and/or hemorrhagic stroke (SSS) in adults prior to receiving specific walking rehabilitation. Following PRISMA guidelines, a meta-analysis was conducted on two kinds of WS: the principal criterion focused on short-distance WS (ten-meter walking test) and the secondary criteria focused on long-distance WS (6-min test) and meta-regressions to study the association of WS with balance, cognitive disorders and autonomy. Nine studies comprising a total of 939 data on post-stroke patients were selected. The weighted average age was 61 years [95% IC [55-67] and males represented 62% ± 2.7 of patients [57-67]. Average short-distance WS was 0.36 ± 0.06 m.s−1[95% CI (0.23–0.49)]. Average long-distance WS was 0.46 ± 0.1 m.s−1[95% CI (0.26–0.66)]. The funnel plot revealed asymmetry of publication bias and high heterogeneity of the nine studies (I2index 98.7% andQ-testp< 0.0001). Meta-regressions of secondary endpoints could not be performed due to a lack of study data. At the SSS, WS would be lower than data in general population published in literature, but above all, lower than the WS required for safe daily autonomy and community ambulation after stroke. WS must be a priority objective of stroke rehabilitation to increase walking function but also for survival, autonomy, social participation and health-related quality of life.
Effect of head-down tilt on clinical outcome and cerebral perfusion in ischemic stroke patients: A case series
Authors: Zhao Zi-Ai , Zhang Nan-Nan , Tao Lin , Cui Yu , Li Meng , Qi Shou-Liang , Chen Hui-Sheng
Published: September 2022

Background

The effect of head position on stroke is not clear. The current study aimed to observe the effect of head-down tilt on acute ischemic stroke (AIS) patients with large vessel occlusion.

Methods

We observed the influence of head-down tilt position on clinical outcomes, myocardial enzymogram and N-terminal pro b-type Natriuretic Peptide in 4 AIS patients who suffered early neurological deterioration (END). Cerebral perfusion imaging was performed in 3 patients using arterial spin labeling.

Results

In series of AIS patients with END, head down tilt (-20°) prevented further neurological deterioration and improved clinical outcomes. An increase in cerebral blood flow was observed by arterial spin labeling after head down tilt treatment. No obvious adverse events occurred.

Conclusion

The case series suggest that head-down tilt may improve clinical outcome in AIS patients through increasing the cerebral perfusion with no obvious adverse events. The finding needs to be confirmed in future clinical trials.
Effectiveness of transcranial direct current stimulation over dorsolateral prefrontal cortex in patients with prolonged disorders of consciousness: A systematic review and meta-analysis
Authors: Liu Siwei , Gao Qiang , Guan Min , Chen Yi , Cheng Shuhai , Yang Lin , Meng Wei , Lu Chunyan , Li Bingqian
Published: September 2022

Background

Transcranial direct current stimulation (tDCS) has been widely studied for treatment of patients with prolonged disorders of consciousness (PDOC). The dorsolateral prefrontal cortex (DLPFC) is a hot target for intervention, but some controversies remain.

Purpose

This review aimed to systematically investigate the therapeutic effects of DLPFC-anodal-tDCS for patients with PDOC through a meta-analysis approach.

Data sources

Searches for relevant articles available in English were conducted using EMBASE, Medline, Web of Science, EBSCO, and Cochrane Central Register of Controlled Trials from inception until March 26, 2022.

Study selection

All randomized parallel or cross-over controlled trials comparing the effect of intervention with active-tDCS and Sham-tDCS on Coma Recovery Scale Revised (CRS-R) score in individuals with PDOC were included.

Data extraction

Two authors independently extracted data, assessed the methodological quality, and rated each study.

Data synthesis

Ten randomized parallel or cross-over controlled trials were eligible for systematic review, and eight of the studies involving 165 individuals were identified as eligible for meta-analysis. Compared with Sham-tDCS, the use of anode-tDCS over DLPFC improved the CRS-R score (SMD = 0.71; 95% CI: 0.47–0.95, I2 = 10%). Patients with PDOC classified as MCS and clinically diagnosed as CVA or TBI may benefit from anode-tDCS.

Limitations

Failure to evaluate the long-term effects and lack of quantitative analysis of neurological examination are the main limitations for the application of anode-tDCS.

Conclusions

Anodal-tDCS over the left DLPFC may be advantageous to the recovery of patients with MCS and clinically diagnosed with CVA or TBI. There is a lack of evidence to support the duration of the disease course will limit the performance of the treatment. Further studies are needed to explore the diversity of stimulation targets and help to improve the mesocircuit model.

Systematic review registration

https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=279391, identifier: CRD42022279391.
How shifting visual perspective during autobiographical memory retrieval influences emotion: A change in retrieval orientation
Authors: Küçüktaş Selen , St Jacques Peggy L.
Published: September 2022

Visual perspective during autobiographical memory (AM) retrieval influences how people remember the emotional aspects of memories. Prior research in emotion regulation has also shown that shifting from an own eyes to an observer-like perspective is an efficient way of regulating the affect elicited by emotional AMs. However, the impact of shifting visual perspective is also dependent on the nature of the emotion associated with the event. The current review synthesizes behavioral and functional neuroimaging findings from the event memory and emotion regulation literature that examine how adopting particular visual perspectives and actively shifting across them during retrieval alters emotional experience, by primarily focusing on emotional intensity. We review current theories explaining why shifts in perspectives may or may not change the emotional characteristics of memories, then propose a new theory, suggesting that the own eyes and observer-like perspectives are two different retrieval orientations supported by differential neural activations that lead episodic details to be reconstructed in specific ways.
The EBRAINS Hodgkin-Huxley Neuron Builder: An online resource for building data-driven neuron models
Authors: Bologna Luca Leonardo , Smiriglia Roberto , Lupascu Carmen Alina , Appukuttan Shailesh , Davison Andrew P. , Ivaska Genrich , Courcol Jean-Denis , Migliore Michele
Published: September 2022

In the last decades, brain modeling has been established as a fundamental tool for understanding neural mechanisms and information processing in individual cells and circuits at different scales of observation. Building data-driven brain models requires the availability of experimental data and analysis tools as well as neural simulation environments and, often, large scale computing facilities. All these components are rarely found in a comprehensive framework and usually require ad hoc programming. To address this, we developed the EBRAINS Hodgkin-Huxley Neuron Builder (HHNB), a web resource for building single cell neural models via the extraction of activity features from electrophysiological traces, the optimization of the model parameters via a genetic algorithm executed on high performance computing facilities and the simulation of the optimized model in an interactive framework. Thanks to its inherent characteristics, the HHNB facilitates the data-driven model building workflow and its reproducibility, hence fostering a collaborative approach to brain modeling.
Distinct histological alterations of cortical interneuron types in mouse models of Huntington’s disease
Authors: Voelkl Kerstin , Schulz-Trieglaff Elena Katharina , Klein Rüdiger , Dudanova Irina
Published: September 2022

Huntington’s disease (HD) is a debilitating hereditary motor disorder caused by an expansion of the CAG triplet repeat in the Huntingtin gene. HD causes neurodegeneration particularly in the basal ganglia and neocortex. In the cortex, glutamatergic pyramidal neurons are known to be severely affected by the disease, but the involvement of GABAergic interneurons remains unclear. Here, we use a combination of immunostaining and genetic tracing to investigate histological changes in three major cortical interneuron types — parvalbumin (PV), somatostatin (SST), and vasoactive intestinal peptide (VIP) interneurons — in the R6/2 and zQ175DN mouse models of HD. In R6/2 mice, we find a selective reduction in SST and VIP, but not PV-positive cells. However, genetic labeling reveals unchanged cell numbers for all the interneuron types, pointing to molecular marker loss in the absence of cell death. We also observe a reduction in cell body size for all three interneuron populations. Furthermore, we demonstrate progressive accumulation of mutant Huntingtin (mHTT) inclusion bodies in interneurons, which occurs faster in SST and VIP compared to PV cells. In contrast to the R6/2 model, heterozygous zQ175DN knock-in HD mice do not show any significant histological changes in cortical cell types at the age of 12 months, apart from the presence of mHTT inclusions, which are abundant in pyramidal neurons and rare in interneurons. Taken together, our findings point to differential molecular changes in cortical interneuron types of HD mice.
Non-invasive diagnosis and monitoring tool of children’s mental health: A point-of-care immunosensor for IL-6 quantification in saliva samples
Authors: Cruz Andrea , Vieira Maria , Mesquita Ana R. , Sampaio Adriana , Mendes-Pinto Inês , Soares Isabel , Freitas Paulo P.
Published: September 2022

Mental disorders are commonly featured as chronic conditions with often onset during childhood. In this context, inflammation has been associated with a higher risk of developing physical and mental health problems. Interleukin (IL)-6 is a key mediator of inflammatory responses and plays a pivotal role in immune and nervous system interaction. High levels of IL-6 during childhood are associated with mental problems, indicating that the IL-6 molecular pathway may represent a new target for monitoring and treating these conditions. Here, we report the detection of IL-6 in saliva samples from children (N = 118, mean age 4.4 years old) with behavioral problems using an immunosensor based on electrochemical impedance spectroscopy. This work demonstrates that the proposed immunosensor requires smaller sample volumes and is significantly faster and more sensitive than conventional ELISA while maintaining comparable levels of specificity and reproducibility. The point-of care immunosensor for detection of IL-6 in saliva samples presented herewith is, therefore, an attractive solution to the clinical practice as a rapid non-invasive, high-sensitive monitoring tool of mental health problems, especially in vulnerable patient populations such as children.
Psoriasis and neurodegenerative diseases—a review
Authors: Nowowiejska Julia , Baran Anna , Flisiak Iwona
Published: September 2022

Psoriasis is a chronic skin disease with underlying genetic, inflammatory and immunological background, which is a great medical problem, currently regarded as a systemic condition. Neurodegenerative diseases (NDs) are characterized by a progressive loss of nervous tissue, which affects elderly people more frequently; therefore, it is suspected that, due to society's aging, morbidity is going to increase. We performed a thorough review in order to investigate for the first time whether psoriasis may predispose to different particular neurodegenerative diseases—Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS). PubMed search resulted in the retrieval of 833 records, of which 77 eligible were included in the review. Our thorough analysis revealed there are some potential links between psoriasis and NDs (inflammation, oxidative stress, genetics, cardiometabolic disorders), but there is no strong evidence that psoriasis may predispose to NDs. Based on the evidence, it seems that the risk of PD in psoriatics is not increased, and the evidence for increased risk of AD slightly prevails the data that state the opposite. ALS risk does not seem to be increased in psoriatics. The paucity of original studies does not allow for the formulation of definitive conclusions but encourages to perform further investigations.
Thymus, undernutrition, and infection: Approaching cellular and molecular interactions
Authors: Savino Wilson , Durães Jonathan , Maldonado-Galdeano Carolina , Perdigon Gabriela , Mendes-da-Cruz Daniella Arêas , Cuervo Patricia
Published: September 2022

Undernutrition remains a major issue in global health. Low protein-energy consumption, results in stunting, wasting and/or underweight, three deleterious forms of malnutrition that affect roughly 200 million children under the age of five years. Undernutrition compromises the immune system with the generation of various degrees of immunodeficiency, which in turn, renders undernourished individuals more sensitive to acute infections. The severity of various infectious diseases including visceral leishmaniasis (VL), influenza, and tuberculosis is associated with undernutrition. Immunosuppression resulting from protein-energy undernutrition severely impacts primary and secondary lymphoid organs involved in the response to related pathogens. The thymus—a primary lymphoid organ responsible for the generation of T lymphocytes—is particularly compromised by both undernutrition and infectious diseases. In this respect, we will discuss herein various intrathymic cellular and molecular interactions seen in undernutrition alone or in combination with acute infections. Many examples illustrated in studies on humans and experimental animals clearly revealed that protein-related undernutrition causes thymic atrophy, with cortical thymocyte depletion. Moreover, the non-lymphoid microenvironmental compartment of the organ undergoes important changes in thymic epithelial cells, including their secretory products such as hormones and extracellular matrix proteins. Of note, deficiencies in vitamins and trace elements also induce thymic atrophy. Interestingly, among the molecular interactions involved in the control of undernutrition-induced thymic atrophy is a hormonal imbalance with a rise in glucocorticoids and a decrease in leptin serum levels. Undernutrition also yields a negative impact of acute infections upon the thymus, frequently with the intrathymic detection of pathogens or their antigens. For instance, undernourished mice infected withLeishmania infantum(that causes VL) undergo drastic thymic atrophy, with significant reduction in thymocyte numbers, and decreased levels of intrathymic chemokines and cytokines, indicating that both lymphoid and microenvironmental compartments of the organ are affected. Lastly, recent data revealed that some probiotic bacteria or probiotic fermented milks improve the thymus status in a model of malnutrition, thus raising a new field for investigation, namely the thymus-gut connection, indicating that probiotics can be envisioned as a further adjuvant therapy in the control of thymic changes in undernutrition accompanied or not by infection.
Sucralose consumption ameliorates high-fat diet-induced glucose intolerance and liver weight gain in mice
Authors: Pino-Seguel Pamela , Moya Omara , Borquez Juan Carlos , Pino-de la Fuente Francisco , Díaz-Castro Francisco , Donoso-Barraza Camila , Llanos Miguel , Troncoso Rodrigo , Bravo-Sagua Roberto
Published: September 2022

Sucralose is one of the most widely used artificial sweeteners used by the food industry to reduce the calorie density of their products. Although broadly regarded as innocuous, studies show contrasting results depending on whether the research subjects are lean or overweight. In this study, we studied the effect of sucralose consumption on glucose homeostasis in a model of obesity. Male C57BL/6J mice were fed ad libitum with control or a high-fat diet (HFD) and drank either water or sucralose (0.1 mg/mL) for 8 weeks. To characterize the ensuing metabolic changes, we evaluated weight gain, glucose and pyruvate tolerance, and physical performance. Also, we assessed markers of steatosis and mitochondrial mass and function in the liver. Our results show that sucralose reduced weight gain, glucose, and pyruvate intolerance, and prevented the decrease in physical performance of HFD-fed mice. In the liver, sucralose also had a positive effect, preventing the decrease in mitochondrial mass exerted by HFD. Altogether, our results indicate that in the context of an obesogenic diet, sucralose has a beneficial effect at the organismal and hepatic levels.
In silico characterization of aryl benzoyl hydrazide derivatives as potential inhibitors of RdRp enzyme of H5N1 influenza virus
Authors: Ghosh Abhishek , Panda Parthasarathi , Halder Amit Kumar , Cordeiro Maria Natalia D. S.
Published: September 2022

RNA-dependent RNA polymerase (RdRp) is a potential therapeutic target for the discovery of novel antiviral agents for the treatment of life-threatening infections caused by newly emerged strains of the influenza virus. Being one of the most conserved enzymes among RNA viruses, RdRp and its inhibitors require further investigations to design novel antiviral agents. In this work, we systematically investigated the structural requirements for antiviral properties of some recently reported aryl benzoyl hydrazide derivatives through a range of in silico tools such as 2D-quantitative structure-activity relationship (2D-QSAR), 3D-QSAR, structure-based pharmacophore modeling, molecular docking and molecular dynamics simulations. The 2D-QSAR models developed in the current work achieved high statistical reliability and simultaneously afforded in-depth mechanistic interpretability towards structural requirements. The structure-based pharmacophore model developed with the docked conformation of one of the most potent compounds with the RdRp protein of H5N1 influenza strain was utilized for developing a 3D-QSAR model with satisfactory statistical quality validating both the docking and the pharmacophore modeling methodologies performed in this work. However, it is the atom-based alignment of the compounds that afforded the most statistically reliable 3D-QSAR model, the results of which provided mechanistic interpretations consistent with the 2D-QSAR results. Additionally, molecular dynamics simulations performed with the apoprotein as well as the docked complex of RdRp revealed the dynamic stability of the ligand at the proposed binding site of the receptor. At the same time, it also supported the mechanistic interpretations drawn from 2D-, 3D-QSAR and pharmacophore modeling. The present study, performed mostly with open-source tools and webservers, returns important guidelines for research aimed at the future design and development of novel anti-viral agents against various RNA viruses like influenza virus, human immunodeficiency virus-1, hepatitis C virus, corona virus, and so forth.
The effect of montelukast, a leukotriene receptor antagonist, on the acetic acid-induced model of colitis in rats: Involvement of NO-cGMP-KATP channels pathway
Authors: Ghorbanzadeh Behnam , Behmanesh Mohammad Amin , Mahmoudinejad Roya , Zamaniyan Mehdi , Ekhtiar Shadi , Paridar Yousef
Published: September 2022

Inflammatory bowel disease is a chronic autoimmune disorder that may involve entire gastrointestinal tract. The leukotrienes have a role as mediators in the pathophysiology of colitis. Here, we investigated the effect of a leukotriene receptor antagonist, montelukast, and also the role of the NO-cGMP-KATP channel pathway in acetic acid-induced colitis. Rectal administration of acetic acid (4%) was used for induction of colitis in rats. To investigate our hypothesis, the rats were intraperitoneally pre-treated with L-NAME (NOS inhibitor), L-arginine, sildenafil, methylene blue, glibenclamide, or diazoxide 15 min before treatment with montelukast (5–20 mg/kg, i. p.), for three consecutive days. Then, microscopic, macroscopic, and inflammatory parameters were evaluated. Montelukast reduced the microscopic and macroscopic damage induced by acetic acid. Montelukast also reduced the level of IL-1β and TNF-α. We also showed that the effects of montelukast were significantly attenuated by L-NAME, methylene blue (guanylate cyclase inhibitor), and an ATP-sensitive potassium channel blocker (glibenclamide). Also, the administration of L-arginine, sildenafil, and diazoxide before montelukast produced protective effect. In conclusion, the pathway of the NO-cGMP-KATP channel is involved in the protective effect of montelukast in acetic acid-induced colonic tissue damage.
Upregulation of TLR4/MyD88 pathway in alcohol-induced Wernicke’s encephalopathy: Findings in preclinical models and in a postmortem human case
Authors: Moya Marta , Escudero Berta , Gómez-Blázquez Elena , Rebolledo-Poves Ana Belen , López-Gallardo Meritxell , Guerrero Carmen , Marco Eva M. , Orio Laura
Published: September 2022

Wernicke’s encephalopathy (WE) is a neurologic disease caused by vitamin B1 or thiamine deficiency (TD), being the alcohol use disorder its main risk factor. WE patients present limiting motor, cognitive, and emotional alterations related to a selective cerebral vulnerability. Neuroinflammation has been proposed to be one of the phenomena that contribute to brain damage. Our previous studies provide evidence for the involvement of the innate immune receptor Toll-like (TLR)4 in the inflammatory response induced in the frontal cortex and cerebellum in TD animal models (animals fed with TD diet [TDD] and receiving pyrithiamine). Nevertheless, the effects of the combination of chronic alcohol consumption and TD on TLR4 and their specific contribution to the pathogenesis of WE are currently unknown. In addition, no studies on TLR4 have been conducted on WE patients since brains from these patients are difficult to achieve. Here, we used rat models of chronic alcohol (CA; 9 months of forced consumption of 20% (w/v) alcohol), TD hit (TDD + daily 0.25 mg/kg i.p. pyrithiamine during 12 days), or combined treatment (CA + TDD) to check the activation of the proinflammatory TLR4/MyD88 pathway and related markers in the frontal cortex and the cerebellum. In addition, we characterized for the first time the TLR4 and its coreceptor MyD88 signature, along with other markers of this proinflammatory signaling such as phospo-NFκB p65 and IκBα, in the postmortem human frontal cortex and cerebellum (gray and white matter) of an alcohol-induced WE patient, comparing it with negative (no disease) and positive (aged brain with Alzheimer’s disease) control subjects for neuroinflammation. We found an increase in the cortical TLR4 and its adaptor molecule MyD88, together with an upregulation of the proinflammatory signaling molecules p-NF-ĸB and IĸBα in the CA + TDD animal model. In the patient diagnosed with alcohol-induced WE, we observed cortical and cerebellar upregulation of the TLR4/MyD88 pathway. Hence, our findings provide evidence, both in the animal model and the human postmortem brain, of the upregulation of the TLR4/MyD88 proinflammatory pathway in alcohol consumption–related WE.
Association between antibiotics and dementia risk: A retrospective cohort study
Authors: Kim Minseo , Park Sun Jae , Choi Seulggie , Chang Jooyoung , Kim Sung Min , Jeong Seogsong , Park Young Jun , Lee Gyeongsil , Son Joung Sik , Ahn Joseph C. , Park Sang Min
Published: September 2022

Background: The possible relation between antibiotic exposure and the alteration of gut microbiota, which may affect dementia risk, has been revealed. However, the association between antibiotics and dementia incidence has rarely been studied. We aimed to determine the association between antibiotic exposure and the risk of dementia.

Methods: This population-based retrospective cohort study used data from the National Health Insurance Service-Health Screening Cohort (NHIS-HEALS) in South Korea. Exposure was the cumulative days of antibiotic prescription from 2002 to 2005. Newly diagnosed overall dementia, Alzheimer’s disease (AD), and vascular dementia (VD) were identified based on diagnostic codes and prescriptions for dementia-related drugs. The follow-up investigation was carried out from 1 January 2006 to 31 December 2013. The Cox proportional hazards regression was used to assess the association between cumulative antibiotic prescription days and dementia incidence.

Results: A total of 313,161 participants were analyzed in this study. Compared to antibiotic non-users, the participants who used antibiotics for 91 or more days had an increased risk of overall dementia [adjusted hazard ratio (aHR), 1.44; 95% confidence interval (CI), 1.19–1.74], AD (aHR, 1.46; 95% CI, 1.17–1.81), and VD (aHR, 1.38; 95% CI, 0.83–2.30). Those who used five or more antibiotic classes had higher risks of overall dementia (aHR, 1.28; 95% CI, 1.00–1.66) and AD (aHR, 1.34; 95% CI, 1.00–1.78) than antibiotic non-users.

Conclusion: Antibiotic exposure may increase the risk of dementia in a cumulative duration-dependent manner among adult participants. Future studies are needed to assess the causality between the long-term prescription of antibiotics and dementia risk.
GSK3β-dependent lysosome biogenesis: An effective pathway to mitigate renal fibrosis with LM49
Authors: Ren Jinhong , Wei Huizhi , Sun Jian , Feng Xiue , Zhang Yuanlin , Yuan Hongxia , Miao Junqiu , Qi Xiaoming , Qiao Yuanbiao , Xiao Baoguo , Li Qingshan
Published: September 2022

Renal fibrosis is an incurable disorder characterised by an imbalance of the extracellular matrix (ECM) favouring excess production over degradation. The identification of actionable pathways and agents that promote ECM degradation to restore ECM homeostasis may help mitigate renal fibrosis. In this study, we identified 5,2′-dibromo-2,4′,5′-trihydroxydiphenylmethanone (LM49), a compound we previously synthesised, as a small-molecule inducer of ECM degradation. LM49 administration efficiently reduced ECM deposition in renal tissue of diabetic nephropathy rats and in transforming growth factor β-treated renal fibroblast cells. LM49 promoted the cytosol-to-nucleus translocation of transcription factor EB (TFEB) to increase lysosome biogenesis, leading to lysosome-based degradation of the ECM. TFEB-mediated lysosome biogenesis was induced by LM49 directly inhibiting the activity of glycogen synthase kinase 3β (GSK3β) rather than mammalian target of rapamycin complex 1. LM49 inhibited GSK3β kinase activity concentration-dependently via competing with ATP. Direct binding between LM49 and GSK3β was confirmed by the bio-layer interferometry assay, cellular thermal shift assay, and drug affinity responsive target stability. A molecular docking and molecular dynamic simulation revealed that LM49 occupied the ATP pocket of GSK3β, which was consistent with the kinase activity assay. In summary, LM49 enhances TFEB-mediated lysosome biogenesis by directly inhibiting GSK3β, leading to the degradation of the ECM by lysosomes. The enhancement of GSK3β-dependent lysosome biogenesis to rebalance the ECM may be a novel strategy to counteract renal fibrosis, and LM49 may be a viable clinical candidate for treating this disorder.
NOX1 promotes myocardial fibrosis and cardiac dysfunction via activating the TLR2/NF-κB pathway in diabetic cardiomyopathy
Authors: Zhang Dandan , Li Yilan , Wang Weijie , Lang Xueyan , Zhang Yanxiu , Zhao Qianqian , Yan Jingru , Zhang Yao
Published: September 2022

Diabetic cardiomyopathy (DCM) is a prevalent complication in patients with diabetes, resulting in high morbidity and mortality. However, the molecular mechanisms of diabetic cardiomyopathy have yet to be fully elucidated. In this study, we investigated a novel target, NOX1, an isoform of superoxide-producing NADPH oxidase with key functional involvement in the pathophysiology of DCM. The DCM rat model was established by a high-fat diet combined with streptozotocin injections. DCM rats elicited myocardial fibrosis exacerbation, which was accompanied by a marked elevation of NOX1 expression in cardiac tissue. In particular, a specific NOX1 inhibitor, ML171, effectively decreased myocardial fibrosis and protected against cardiac dysfunction in DCM rats. Rat neonatal cardiac fibroblasts were incubated with high glucose (HG, 33 mM) as an in vitro model of DCM. We also observed that the expression of NOX1 was upregulated in HG-cultured cardiac fibroblasts. Silencing of NOX1 was found to attenuate myocardial fibrosis and oxidative stress in HG-induced cardiac fibroblasts. Furthermore, the upregulation of NOX1 by hyperglycemia induced activation of the TLR2/NF-κB pathway both in vitro and in vivo, whereas these effects were significantly attenuated with NOX1 gene silencing and further enhanced with NOX1 gene overexpression. In summary, we demonstrated that NOX1 induced activation of the TLR2/NF-κB pathway and increased reactive oxygen species production accumulation, which ultimately increased myocardial fibrosis and deteriorated cardiac function in diabetic cardiomyopathy. Our study revealed that NOX1 was a potential therapeutic target for DCM.
A model-informed approach to assess the risk of immune checkpoint inhibitor-induced autoimmune myocarditis
Authors: van der Vegt Solveig A. , Wang Ying-Jie , Polonchuk Liudmila , Wang Ken , Waters Sarah L. , Baker Ruth E.
Published: September 2022

Immune checkpoint inhibitors (ICIs), as a novel immunotherapy, are designed to modulate the immune system to attack malignancies. Despite their promising benefits, immune-related adverse events (IRAEs) may occur, and incidences are bound to increase with surging demand of this class of drugs in treating cancer. Myocarditis, although rare compared to other IRAEs, has a significantly higher fatal frequency. Due to the overwhelming complexity of the immune system, this condition is not well understood, despite the significant research efforts devoted to it. To better understand the development and progression of autoimmune myocarditis and the roles of ICIs therein, we suggest a new approach: mathematical modelling. Mathematical modelling of myocarditis has enormous potential to determine which parts of the immune system are critical to the development and progression of the disease, and therefore warrant further investigation. We provide the immunological background needed to develop a mathematical model of this disease and review relevant existing models of immunology that serve as the mathematical inspiration needed to develop this field.
Macrophage malfunction in Triptolide-induced indirect hepatotoxicity
Authors: Qin Tingting , Hasnat Muhammad , Zhou Yang , Yuan Ziqiao , Zhang Wenzhou
Published: September 2022

Background and Objective: Indirect hepatotoxicity is a new type of drug-induced hepatotoxicity in which the character of a drug that may induce its occurrence and the underlying mechanism remains elusive. Previously, we proved that Triptolide (TP) induced indirect hepatotoxicity upon LPS stimulation resulting from the deficiency of cytoprotective protein of hepatocyte. However, whether immune cells participated in TP-induced indirect hepatotoxicity and the way immune cells change the liver hypersensitivity to LPS still need to be deeply investigated. In this study, we tried to explore whether and how macrophages are involved in TP-induced indirect hepatotoxicity.

Method: Firstly, TP (500 μg/kg) and LPS (0.1 mg/kg) were administrated into female C57BL/6 mice as previously reported. Serum biochemical indicators, morphological changes, hepatic macrophage markers, as well as macrophage M1/M2 markers were detected. Secondly, macrophage scavenger clodronate liposomes were injected to prove whether macrophages participated in TP-induced indirect hepatotoxicity. Also, the ability of macrophages to secrete inflammatory factors and macrophage phagocytosis were detected. Lastly, reverse docking was used to find the target of TP on macrophage and the possible target was verified in vivo and in RAW264.7 cells.

Results: TP pretreatment increased the liver hypersensitization to LPS accompanied by the recruitment of macrophages to the liver and promoted the transformation of macrophages to M1 type. Depletion of hepatic macrophages almost completely alleviated the liver injury induced by TP/LPS. TP pretreatment increased the secretion of pro-inflammatory factors and weakened the phagocytic function of macrophages upon LPS exposure. Reverse docking results revealed that MerTK might be the real target of TP.

Conclusion: TP disrupts inflammatory cytokines profile and phagocytic function of hepatic macrophages, resulting in the production of massive inflammatory factors and the accumulation of endotoxin in the liver, ultimately leading to the indirect hepatotoxicity of TP. MerTK might be the target of TP on the macrophage, while the binding of TP to MerTK should be investigated in vivo and in vitro.
Toxicity evaluation induced by single and 28-days repeated exposure of withametelin and daturaolone in Sprague Dawley rats
Authors: Baig Muhammad Waleed , Majid Muhammad , Nasir Bakht , Hassan Syed Shams ul , Bungau Simona , Haq Ihsan-ul
Published: September 2022

Safe preclinical dose determination is predictive of human toxicity and can have a profound impact on the overall progress of the compound in early drug discovery process. In this respect, current study sought to investigate for the first time the acute and subacute oral toxicity of two pharmacologically active natural compounds i.e., withametelin and daturaolone in Sprague Dawley rats following OECD guideline 420 and 407, respectively. As per acute toxicity studies, withametelin and daturaolone were characterized as Globally Harmonized System (GHS) category 4 and 5 compounds, respectively. Sub-acute daily dose of withametelin was 5, 2.5, and 1.25 mg/kg but, for daturaolone, it was 10, 5, and 2.5 mg/kg. High dose (5 and 2.5 mg/kg) withametelin groups showed dose dependent changes in the general, hematological, biochemical and histopathological parameters in both sexes, the most prominent being hyperthyroidism while no toxicity was observed at lower doses (1.25 and 0.75 mg/kg), No Observable Adverse Effect Level (NOAEL) being 1.25 mg/kg. Daturaolone was comparatively safer and showed dose dependent significant changes in hepatic enzyme (Alanine Transaminase), bilirubin, creatinine, and glucose levels while histological changes in testes were also observed. Lower doses (5, 2.5, and 1.25 mg/kg) of daturaolone showed no significant toxic effects and 5 mg/kg was declared as its NOAEL. Depending upon our findings, starting effective oral dose levels of 1.25 mg/kg/day for withametelin and 5 mg/kg/day for daturaolone are proposed for repeated dose (up to 28 days) preclinical pharmacological evaluation models. Long term studies with more behavioral, biochemical, histopathological and hormonal parameters are proposed to strengthen the findings.
The effect of regular aerobic exercise on renal function in patients with CKD: A systematic review and meta-analysis
Authors: Ma Qirui , Gao Ye , Lu Jiandong , Liu Xinhong , Wang Ruolin , Shi Yajun , Liu Jingqi , Su Hao
Published: September 2022

Objective: To evaluate the effect of regular aerobic exercise on the improvement of renal function in patients with chronic kidney disease through meta-analysis and to provide targeted exercise recommendations for patients with CKD.

Methods: PubMed, Web of Science, EBSCO, China National Knowledge Infrastructure (CNKI), and other databases were searched, and randomized controlled trials on the effects of regular aerobic exercise on renal function-related indexes in patients with CKD were collected according to the inclusion and exclusion criteria. The methodological quality of the included literature was evaluated using the Cochrane evaluation tool second generation, and statistical analysis was performed using R analysis software.

Results: A total of 12 randomized controlled trials (RCTs) with a total of patients with CKD were included, and the results of the meta-analysis showed that regular aerobic exercise significantly improved the estimated glomerular filtration rate SMD = 0.65, 95% CI [0.30, 1.00], serum creatinine SMD = -0.63, 95% CI [-0.86, -0.40], 24-h urine protein volume in patients with CKD SMD = -0.41, 95% CI [-0.70, -0.11], and serum urea nitrogen SMD = -0.66, 95% CI [-1.20, -0.12]. Single exercise session longer than 30 min significantly improved the estimated glomerular filtration rate in CKD patients (p < 0.01), and walking and running as exercise modalities significantly improved CKD patients’ SCr levels were significantly improved by walking and running as exercise modalities (p < 0.05), and the improvement effect was not significant when cycling was selected as an exercise modality.

Conclusion: Regular aerobic exercise has a significant effect on the estimated glomerular filtration rate, serum creatinine, 24-h urine protein amount, and blood urea nitrogen in CKD patients. Aerobic exercise with a single exercise duration longer than 30 min has a more significant effect on the estimated glomerular filtration rate, and aerobic exercise by walking or running can more effectively improve the serum creatinine in CKD patients.
Association between interindividual variability in training volume and strength gain
Authors: Ema Ryoichi , Saito Itaru , Akagi Ryota
Published: September 2022

This study aimed to examine the association between interindividual variability in strength changes and in training volume. A total of 26 untrained men completed 4-weeks of isometric knee extension (KE group, n = 12) and hip flexion (HF group, n = 14) training. Each training session comprised four sets of ten isometric contractions, 3-s contractions every 20 s. Training volume, which was defined as impulse during contractions, and maximal voluntary contraction (MVC) torque during KE and HF were evaluated. Based on the magnitude of MVC torque changes, the participants were divided into the high and low responders (n = 13; KE = 6 and HF = 7 per responders). The MVC torque changes (KE, 20.8%; HF, 22.4%) and total training volume did not significantly differ between the two groups. A higher training volume was demonstrated in the low responders than the high responders. The total training volume was positively associated with the MVC torque changes in low responders (r = 0.869%, 95% confidence interval [0.610, 0.960], p < 0.001), but not in high responders [r = 0.229, 95% confidence interval (−0.368, 0.693), p = 0.451], KE or HF group. Results showed that training volume was an important factor in determining the magnitude of strength gains in low responders, and MVC torque could improve by approximately 20% with the use of the study protocol regardless of joint actions involved during training.