bluuebunny/crossref_metadata_2025 huggingface dataset:
Polyglutamine Expansion in Huntingtin and Mechanism of DNA Damage Repair Defects in Huntington’s Disease
Authors: Pradhan Subrata , Gao Rui , Bush Keegan , Zhang Nan , Wairkar Yogesh P. , Sarkar Partha S.
Published: April 2022

Emerging evidence suggests that DNA repair deficiency and genome instability may be the impending signs of many neurological diseases. Genome-wide association (GWAS) studies have established a strong correlation between genes that play a role in DNA damage repair and many neurodegenerative diseases, including Huntington’s disease (HD), and several other trinucleotides repeat expansion-related hereditary ataxias. Recently, many reports have documented a significant role played by the DNA repair processes in aging and in modifying many neurodegenerative diseases, early during their progression. Studies from our lab and others have now begun to understand the mechanisms that cause defective DNA repair in HD and surprisingly, many proteins that have a strong link to known neurodegenerative diseases seem to be important players in these cellular pathways. Mutations in huntingtin (HTT) gene that lead to polyglutamine repeat expansion at the N-terminal of HTT protein has been shown to disrupt transcription-coupled DNA repair process, a specialized DNA repair process associated with transcription. Due to the recent progress made in understanding the mechanisms of DNA repair in relation to HD, in this review, we will mainly focus on the mechanisms by which the wild-type huntingtin (HTT) protein helps in DNA repair during transcription, and the how polyglutamine expansions in HTT impedes this process in HD. Further studies that identify new players in DNA repair will help in our understanding of this process in neurons. Furthermore, it should help us understand how various DNA repair mechanism(s) coordinate to maintain the normal physiology of neurons, and provide insights for the development of novel drugs at prodromal stages of these neurodegenerative diseases.
Vestibular Deficits in Deafness: Clinical Presentation, Animal Modeling, and Treatment Solutions
Authors: Maudoux Audrey , Vitry Sandrine , El-Amraoui Aziz
Published: April 2022

The inner ear is responsible for both hearing and balance. These functions are dependent on the correct functioning of mechanosensitive hair cells, which convert sound- and motion-induced stimuli into electrical signals conveyed to the brain. During evolution of the inner ear, the major changes occurred in the hearing organ, whereas the structure of the vestibular organs remained constant in all vertebrates over the same period. Vestibular deficits are highly prevalent in humans, due to multiple intersecting causes: genetics, environmental factors, ototoxic drugs, infections and aging. Studies of deafness genes associated with balance deficits and their corresponding animal models have shed light on the development and function of these two sensory systems. Bilateral vestibular deficits often impair individual postural control, gaze stabilization, locomotion and spatial orientation. The resulting dizziness, vertigo, and/or falls (frequent in elderly populations) greatly affect patient quality of life. In the absence of treatment, prosthetic devices, such as vestibular implants, providing information about the direction, amplitude and velocity of body movements, are being developed and have given promising results in animal models and humans. Novel methods and techniques have led to major progress in gene therapies targeting the inner ear (gene supplementation and gene editing), 3D inner ear organoids and reprograming protocols for generating hair cell-like cells. These rapid advances in multiscale approaches covering basic research, clinical diagnostics and therapies are fostering interdisciplinary research to develop personalized treatments for vestibular disorders.
High Expression of CSF-1R Predicts Poor Prognosis and CSF-1Rhigh Tumor-Associated Macrophages Inhibit Anti-Tumor Immunity in Colon Adenocarcinoma
Authors: Wang Xingchao , Zhang Jianfeng , Hu Baoying , Qian Fei
Published: April 2022

Background

Colony stimulating factor 1 receptor (CSF-1R) is a single channel III transmembrane receptor tyrosine kinase (RTK) and plays an important role in immune regulation and the development of various cancer types. The expression of CSF-1R in colon adenocarcinoma (COAD) and its prognostic value remain incompletely understood. Therefore, we aim to explore the prognostic value of CSF-1R in COAD and its relationship with tumor immunity.

Methods

CSF-1R expression in a COAD cohort containing 103 patients was examined using immunohistochemistry (IHC). The relationship between CSF-1R expression and clinicopathological parameters and prognosis was evaluated. Dual immunofluorescence staining was conducted to determine the localization of CSF-1R in COAD tissues. Univariate and multivariate Cox regression analysis were performed to evaluate independent prognostic factors. Transcriptomic profiles of CSF-1Rhigh and CSF-1Rlow tumor-associated macrophages (TAMs) were investigated. Gene enrichment analysis was used to explore the signal pathways related to CSF-1R. In addition, the relationship between CSF-1R in tumor microenvironment (TME) and tumor immunity was also studied.

Results

IHC analysis showed that CSF-1R was overexpressed in COAD, and higher expression was associated with shorter overall survival (OS). Immunofluorescence staining showed that CSF-1R was co-localized with macrophage marker CD68. Univariate and multivariate Cox regression analysis showed that CSF-1R was an independent prognostic factor for COAD. The results of gene enrichment analysis showed that CSF-1R was involved in tumor immune response and regulation of TME. In addition, CSF-1R was significantly correlated with TME, immune cell infiltration, TMB, MSI, Neoantigen, and immune checkpoint molecules.

Conclusion

CSF-1R can serve as an independent prognostic factor of COAD and promising immunotherapeutic target of COAD.
Case Report: A Lung Adenocarcinoma With Brain Metastasis Harbored Novel MET 14 Skipping Alteration Sensitive to Savolitinib
Authors: Li Jian , Feng Yun , Tan Yuan , Duan Qianqian , Zhang Qin
Published: April 2022

A splice-site mutation that results in a loss of transcription of exon 14 in the oncogenic driver MET occurs in 3 to 4% of patients with non-small-cell lung cancer (NSCLC). Several MET exon 14 skipping alterations have been identified, but different MET exon splice variants tend to have different clinical outcomes which deserve concern. Herein, based on NGS panel analysis, we firstly described a 61-year-old woman with lung adenocarcinoma who harbored a novel MET exon 14 skipping (c.3004_3028+3del) concurrent MET amplification (copy number: 3.91) and benefited from Savolitinib treatment. Moreover, CytoTest MET/CCP7 FISH Probe (c-MET/CCP7 Ratio:1.41 and mean gene copy number:6) and qPCR which based on ABI 7500 also were performed to confirm these two MET alterations. After 2 months of Savolitinib treatment, the clinical evaluation was a partial response (PR). In summary, our finding not only expanded the spectrum of the MET exon14 variant (METex14). Targeted NGS analysis could improve detection of MET alterations in routine practice.
Immunogenic Cell Death-Relevant Damage-Associated Molecular Patterns and Sensing Receptors in Triple-Negative Breast Cancer Molecular Subtypes and Implications for Immunotherapy
Authors: Xu Ming , Lu Jin-hua , Zhong Ya-zhen , Jiang Jing , Shen Yue-zhong , Su Jing-yang , Lin Sheng-you
Published: April 2022

Objectives

Triple-negative breast cancer (TNBC) is defined as a highly aggressive type of breast cancer which lacks specific biomarkers and drug targets. Damage-associated molecular pattern (DAMP)-induced immunogenic cell death (ICD) may influence the outcome of immunotherapy for TNBC patients. This study aims to develop a DAMPs gene signature to classify TNBC patients and to further predict their prognosis and immunotherapy outcome.

Methods

We identified the DAMPs-associated subtypes of 330 TNBCs using K-means analysis. Differences in immune status, genomic alterations, and predicted immunotherapy outcome were compared among each subtype.

Results

A total of 330 TNBCs were divided into three subtypes according to DAMPs gene expression: the nuclear DAMPs subtype, featuring the upregulation of nuclear DAMPs; the inflammatory DAMPs subtype, characterized by the gene set enrichment of the adaptive immune system and cytokine signaling in the immune system; and the DAMPs-suppressed subtype, having the lowest level of ICD-associated DAMPs. Among them, the inflammatory subtype patients had the most favorable survival, while the DAMPs-suppressed subtype was associated with the worst prognosis. The DAMPs subtyping system was successfully validated in the TCGA cohort. Furthermore, we systemically revealed the genomic alterations among the three DAMPs subtypes. The inflammatory DAMPs subtype was predicted to have the highest response rate to immunotherapy, suggesting that the constructed DAMPs clustering had potential for immunotherapy efficacy prediction.

Conclusion

We established a novel ICD-associated DAMPs subtyping system in TNBC, and DAMPs expression might be a valuable biomarker for immunotherapy strategies. Our work could be helpful to the development of new immunomodulators and may contribute to the development of precision immunotherapy for TNBC.
LncRNA ENST869 Targeting Nestin Transcriptional Region to Affect the Pharmacological Effects of Chidamide in Breast Cancer Cells
Authors: Feng Xiuyan , Han Han , Guo Yarui , Feng Xue , Guo Shanchun , Zhou Weiqiang
Published: April 2022

Breast cancer is one of the leading threats to the health of women. It has the highest incidence and mortality in women worldwide. Although progress has been made in the development and application of anti-breast cancer drugs such as Chidamide and others, the occurrence of drug resistance limits the effective application of chemotherapies. The purpose of this study is to explore the role of LncRNA in the pharmacological effect of Chidamide in breast cancer therapy. The human breast cancer MCF-7 or MDA-MB-231 cells were used as the research cell models. The RNA library screening and high-throughput sequencing comparative analysis was conducted. The binding of LncRNA and its downstream target genes in RNA and protein levels was tested. The results showed that the expression of LncRNA ENST869 in cells treated with Chidamide increased significantly, as demonstrated by real-time PCR and cell viability assay. RNAplex analysis showed that LncRNA ENST869 and Nestin mRNA may interact. RNA interference and Western blot analysis indicated that LncRNA ENST869 could target and regulate the expression of Nestin. Luciferase assay and RNA-protein pulldown showed that LncRNA ENST869 affected Nestin transcription. There might be a highly active binding region of LncRNA ENST869 in regulating Nestin transcriptional activity within the site of 250 bp upstream of the transcription starting point of Nestin. In addition, LncRNA ENST869 did not directly interact with Nestin protein to affect its activity. In conclusion, our results demonstrated that LncRNA ENST869 could affect the function of Nestin in breast cancer cells treated with Chidamide. Nestin is a key player in influencing the pharmacological activity of Chidamide and an essential factor in drug resistance of breast cancer cells.
Music-Induced Analgesia in Healthy Participants Is Associated With Expected Pain Levels but Not Opioid or Dopamine-Dependent Mechanisms
Authors: Lunde Sigrid Juhl , Vuust Peter , Garza-Villarreal Eduardo A. , Kirsch Irving , Møller Arne , Vase Lene
Published: April 2022

Music interventions accommodate the profound need for non-pharmacological pain treatment. The analgesic effect of listening to music has been widely demonstrated across studies. Yet, the specific mechanisms of action have still to be elucidated. Although the endogenous opioid and dopamine systems have been suggested to play an important role, a direct link has not been established. In addition, the involvement of placebo mechanisms is likely while largely unexplored. We examined the analgesic effect of music in healthy participants (n = 48) using a 3 × 3 within-subjects design with pharmacological manipulations and a matched, auditory control for music. Participants were exposed to thermal pain stimuli while listening to three auditory excerpts: music (active condition), nature sound (matched, auditory contextual condition), and noise (neutral control condition). The participants rated their expected and perceived pain levels in relation to each of the auditory excerpts. To investigate the involvement of the endogenous opioid and dopamine systems, the test session was performed three times on separate days featuring a double-blind randomized oral administration of naltrexone (opioid antagonist), haloperidol (dopamine antagonist), and an inactive agent (control). Our results support an analgesic effect of music. Contrary to current hypotheses, neither of the antagonists attenuated the effect of music. Yet, the participants' expectations for pain relief predicted their perceived pain levels during the auditory excerpts—even when controlling for a gradual learning effect. In conclusion, we demonstrate that the analgesic effect of music is at least partially mediated by expectations of an analgesic effect—a core mechanism in placebo effects—but not by opioid and dopamine-dependent mechanisms.

Clinical Trial Registration

www.clinicaltrials.gov, identifier: NCT03410563.
Chorioamnionitis Causes Kidney Inflammation, Podocyte Damage, and Pro-fibrotic Changes in Fetal Lambs
Authors: Hoogenboom Lieke A. , Lely A. Titia , Kemp Matthew W. , Saito Masatoshi , Jobe Alan H. , Wolfs Tim G. A. M. , Schreuder Michiel F.
Published: April 2022

Background

Perinatal complications, such as prematurity and intrauterine growth restriction, are associated with increased risk of chronic kidney disease. Although often associated with reduced nephron endowment, there is also evidence of increased susceptibility for sclerotic changes and podocyte alterations. Preterm birth is frequently associated with chorioamnionitis, though studies regarding the effect of chorioamnionitis on the kidney are scarce. In this study, we aim to unravel the consequences of premature birth and/or perinatal inflammation on kidney development using an ovine model.

Methods

In a preterm sheep model, chorioamnionitis was induced by intra-amniotic injection of lipopolysaccharide (LPS) at either 2, 8, or 15 days prior to delivery. Control animals received intra-amniotic injections of sterile saline. All lambs were surgically delivered at 125 days’ gestation (full term is 150 days) and immediately euthanized for necropsy. Kidneys were harvested and processed for staining with myeloperoxidase (MPO), Wilms tumor-1 (WT1) and alpha-smooth muscle actine (aSMA). mRNA expression of tumor necrosis factor alpha (TNFA), Interleukin 10 (IL10), desmin (DES), Platelet derived growth factor beta (PDGFB), Platelet derived growth factor receptor beta (PDGFRB), synaptopodin (SYNPO), and transforming growth factor beta (TGFB) was measured using quantitative PCR.

Results

Animals with extended (but not acute) LPS exposure had an inflammatory response in the kidney. MPO staining was significantly increased after 8 and 15 days (p = 0.003 and p = 0.008, respectively). Expression of TNFA (p = 0.016) and IL10 (p = 0.026) transcripts was increased, peaking on day 8 after LPS exposure. Glomerular aSMA and expression of TGFB was increased on day 8, suggesting pro-fibrotic mesangial activation, however, this was not confirmed with PDFGB or PDGFRB. The number of WT1 positive nuclei in the glomerulus, as well as expression of synaptopodin, decreased, indicating podocyte injury.

Conclusion

We report that, in an ovine model of prematurity, LPS-induced chorioamnionitis leads to inflammation of the immature kidney. In addition, this process was associated with podocyte injury and there are markers to support pro-fibrotic changes to the glomerular mesangium. These data suggest a potential important role for antenatal inflammation in the development of preterm-associated kidney disease, which is frequent.
Stratification by Non-invasive Biomarkers of Non-alcoholic Fatty Liver Disease in Children
Authors: Kwon Yiyoung , Kim Eun Sil , Choe Yon Ho , Kim Mi Jin
Published: April 2022

Background

The spectrum of non-alcoholic fatty liver disease (NAFLD) ranges from isolated hepatic steatosis to non-alcoholic steatohepatitis to fibrosis. We aimed to introduce useful biomarkers released during liver inflammation and fibrogenesis that are easy to use in outpatient clinic and adjust to children to evaluate each NAFLD stage without biopsy.

Methods

This prospective study included 60 patients aged under 19 years whose alanine aminotransferase (ALT) levels were elevated from March 2021. All patients were proven to have NAFLD by ultrasonography and laboratory work-up to exclude other causes of hepatitis. Fibroscan and additional laboratory tests for biomarkers [procollagen type1 amino-terminal propeptide (P1NP), osteocalcin, interleukin-6 (IL-6), and Mac-2 binding protein glycosylated isomer (M2BPGi)] were performed. Fibroscan-AST (FAST) score was used for the comparison of steatohepatitis and liver stiffness measurement (kPa) was used for the comparison of advanced fibrosis.

Results

The biomarker that showed a significant difference between the FAST-positive and negative groups was the P1NP/osteocalcin ratio with a p-value of 0.008. The area under receiver operating characteristic (AUROC) of P1NP/osteocalcin ratio*ALT values (values obtained through multivariate analysis) was 0.939 with the cut-off value of 305.38. The biomarkers that showed a significant difference between the LSM-positive and negative groups were IL-6 and M2BPGi with a p-values of 0.005 and <0.001. AUROC of IL-6 *AST values (values obtained through multivariate analysis) was 0.821 with the cut-off value of 228.15. M2BPGi showed a significant linear relationship with LSM in Pearson correlation analysis (Pearson correlation coefficient = 0.382; p = 0.003). The diagnostic capability of M2BPGi to evaluate advanced fibrosis showed an acceptable result (AUROC = 0.742; p = 0.022).

Conclusions

Non-invasive biomarkers can be used to predict each stage of NAFLD in children. The measurements of P1NP, IL-6 or M2BPGi along with the basic chemistry tests would help determine the stage of NAFLD they correspond to at the time of initial diagnosis and predict responsiveness after the treatment.
Mesenchymal Stem Cell-Derived Extracellular Vesicles for the Treatment of Bronchopulmonary Dysplasia
Authors: Xi Yufeng , Ju Rong , Wang Yujia
Published: April 2022

Bronchopulmonary dysplasia (BPD) is the most common chronic respiratory disease in premature infants. However, there is a lack of effective treatment. Mesenchymal stromal cells derived extracellular vesicles (MSC-EVs), as nano- and micron-sized heterogeneous vesicles secreted by MSCs, are the main medium for information exchange between MSCs and injured tissue and organ, playing an important role in repairing tissue and organ injury. EVs include exosomes, microvesicles and so on. They are rich with various proteins, nucleic acids, and lipids. Now, EVs are considered as a new way of cell-to-cell communication. EVs mainly induce regeneration and therapeutic effects in different tissues and organs through the biomolecules they carry. The surface membrane protein or loaded protein and nucleic acid molecules carried by EVs, can activate the signal transduction of target cells and regulate the biological behavior of target cells after binding and cell internalization. MSC-EVs can promote the development of pulmonary vessels and alveoli and reduce pulmonary hypertension (PH) and inflammation and play an important role in the repair of lung injury in BPD. The regeneration potential of MSC-EVs is mainly due to the regulation of cell proliferation, survival, migration, differentiation, angiogenesis, immunoregulation, anti-inflammatory, mitochondrial activity and oxidative stress. As a new type of cell-free therapy, MSC-EVs have non-immunogenic, and are small in size and go deep into most tissues. What’s more, it has good biological stability and can be modified and loaded with drugs of interest. Obviously, MSC-EVs have a good application prospect in the treatment of lung injury and BPD. However, there are still many challenges to make MSC-EVs really enter clinical application.
In vitro Anticancer Activity of the Polar Fraction From the Lophocereus schottii Ethanolic Extract
Authors: Orozco-Barocio Arturo , Robles-Rodríguez Blanca Susana , Camacho-Corona María del Rayo , Méndez-López Luis Fernando , Godínez-Rubí Marisol , Peregrina-Sandoval Jorge , Rivera Gildardo , Rojas Mayorquín Argelia E. , Ortuno-Sahagun Daniel
Published: April 2022

Cancer is an increasingly common disease and is considered one of the main causes of death in the world. Lophocereus schottii (L. schottii) is a cactus used in Mexico in traditional medicine for cancer treatment. This study aimed to determine the effect of the ethanolic extract and the polar and nonpolar fractions of L. schottii in murine L5178Y lymphoma cells in vitro, analyzing their effect on the proliferative activity of splenocytes, and establishing the effective concentration 50 (EC50) of the polar fraction. In addition, the secondary metabolites present in the extracts were determined by ultra-performance liquid chromatography-mass spectrometry (UPLC-MS). The study establishes that the three extracts of L. schottii have a cytotoxic effect on L5178Y cells and on the splenocytes stimulated with ConA. Additionally, the polar fraction has a significantly greater effect being three times more effective than cyclophosphamide on inhibiting the viability of L5178Y cells. Secondary metabolites present are mainly flavonoids and alkaloids, but there are also some terpenoids and sterols. Ultimately, polar fraction can be considered an anticancer substance, since its EC50 of 15 μg/mL is within the parameters established by the National Cancer Institute.
Setanaxib (GKT137831) Ameliorates Doxorubicin-Induced Cardiotoxicity by Inhibiting the NOX1/NOX4/Reactive Oxygen Species/MAPK Pathway
Authors: Zheng Hui , Xu Nannan , Zhang Zihao , Wang Fen , Xiao Jie , Ji Xiaoping
Published: April 2022

Background: Doxorubicin (DOX)-induced cardiotoxicity is a highly concerning issue, and the mechanism by which DOX induces cardiotoxicity is likely to be multifactorial. NADPH oxidase (NOX) is associated with DOX-induced cardiotoxicity. Setanaxib (GKT137831), a preferential direct inhibitor of NOX1 and NOX4, can delay or prevent the progression of many cardiovascular disorders by inhibiting reactive oxygen species (ROS) generation. In this study, we investigated the role of GKT137831 in ameliorating DOX-induced cardiotoxicity and the potential mechanisms of its action.

Methods and Results: The mice model of cardiotoxicity induced by DOX was established, and GKT137831 treatment was performed at the same time. Neonatal rat cardiomyocytes (NRCMs) were treated with DOX or GKT137831 for in vitro experiments. We found that DOX administration impaired cardiac function in vivo, reflected by decreased left ventricular ejection fraction (LVEF) and fractional shortening (FS%). DOX also impaired the viability of NRCMs in vitro. In addition, DOX increased the levels of NOX1 and NOX4 expression and ROS production and the cardiomyocyte apoptosis rate, both in vivo and in vitro. GKT137831 improved cardiac function, as indicated by the increased LVEF and FS%. In vitro, GKT137831 improved NRCM viability. It also decreased ROS production and the cardiomyocyte apoptosis rate. Apoptotic indices, such as cleaved PARP (c-PARP), cleaved caspase 3 (CC3) and BAX expression levels, were decreased, and the antiapoptotic index of Bcl-2 expression was increased. DOX markedly activated phosphorylated JNK, ERK and p38 proteins in NRCMs. Specific inhibitors of JNK (SP600125), ERK (PD98059) or p38 (SB203580) inhibited DOX-induced apoptosis of NRCMs. GKT137831 pretreatment inhibited excessive DOX-induced MAPK pathway activation.

Conclusion: This study revealed that GKT137831 can alleviate DOX-induced cardiomyocyte apoptosis by inhibiting NOX1/4-driven ROS production. The upregulation of MAPK pathway induced by NOX1/4-derived ROS production may be the potential mechanism of GKT137831 action. GKT137831 may be a potential drug candidate to ameliorate DOX-induced cardiotoxicity.
Rifaximin Ameliorates Non-alcoholic Steatohepatitis in Mice Through Regulating gut Microbiome-Related Bile Acids
Authors: Jian Jie , Nie Mei-Tong , Xiang Baoyu , Qian Hui , Yin Chuan , Zhang Xin , Zhang Menghui , Zhu Xuan , Xie Wei-Fen
Published: April 2022

Non-alcoholic steatohepatitis (NASH) is the progressive stage of non-alcoholic fatty liver disease (NAFLD). The non-absorbable antibiotic rifaximin has been used for treatment of irritable bowel syndrome, traveling diarrhea, and hepatic encephalopathy, but the efficacy of rifaximin in NASH patients remains controversial. This study investigated the effects and underlying mechanisms of rifaximin treatment in mice with methionine and choline deficient (MCD) diet-induced NASH. We found that rifaximin greatly ameliorated hepatic steatosis, lobular inflammation, and fibrogenesis in MCD-fed mice. Bacterial 16S rRNA sequencing revealed that the gut microbiome was significantly altered in MCD-fed mice. Rifaximin treatment enriched 13 amplicon sequence variants (ASVs) belonging to the groups Muribaculaceae, Parabacteroides, Coriobacteriaceae_UCG-002, uncultured Oscillospiraceae, Dubosiella, Rikenellaceae_RC9_gut_group, Mucispirillum, and uncultured Desulfovibrionaceae. However, rifaximin treatment also reduced seven ASVs in the groups Aerococcus, Oscillospiraceae, uncultured Ruminococcaceae, Bilophila, Muribaculaceae, Helicobacter, and Alistipes in MCD-fed mice. Bile acid-targeted metabolomic analysis indicated that the MCD diet resulted in accumulation of primary bile acids and deoxycholic acid (DCA) in the ileum. Rifaximin delivery reduced DCA levels in MCD-fed mice. Correlation analysis further showed that DCA levels were associated with differentially abundant ASVs modulated by rifaximin. In conclusion, rifaximin may ameliorate NASH by decreasing ileal DCA through alteration of the gut microbiome in MCD-fed mice. Rifaximin treatment may therefore be a promising approach for NASH therapy in humans.
Evidence for Bell-Shaped Dose-Response Emetic Effects of Temsirolimus and Analogs: The Broad-Spectrum Antiemetic Efficacy of a Large Dose of Temsirolimus Against Diverse Emetogens in the Least Shrew (Cryptotis parva)
Authors: Belkacemi Louiza , Sun Yina , Darmani Nissar A.
Published: April 2022

Temsirolimus is a prodrug form of sirolimus (rapamycin). With its analogs (everolimus, ridaforolimus, and rapamycin), it forms a group of anticancer agents that block the activity of one of the two mammalian targets of rapamycin (mTOR) complexes, mTORC1. We investigated the emetic potential of varying doses (0, 0.5, 1, 2.5, 5, 10, 20, and 40 mg/kg, i.p.) of temsirolimus in the least shrew. Temsirolimus caused a bell-shaped and dose-dependent increase in both the mean vomit frequency and the number of shrews vomiting with maximal efficacy at 10 mg/kg (p < 0.05 and p < 0.02, respectively). Its larger doses (20 or 40 mg/kg) had no significant emetic effect. We also evaluated the emetic potential of its analogs (5, 10, and 20 mg/kg, i.p.), all of which exhibited a similar emetic profile. Our observational studies indicated that temsirolimus can reduce the shrew motor activity at 40 mg/kg, and subsequently, we examined the motor effects of its lower doses. At 10 and 20 mg/kg, it did not affect the spontaneous locomotor activity (distance moved) but attenuated the mean rearing frequency in a U-shaped manner at 10 mg/kg (p < 0.05). We then determined the broad-spectrum antiemetic potential of a 20 mg/kg (i.p.) dose of temsirolimus against diverse emetogens, including selective and nonselective agonists of 1) dopaminergic D2/3 receptors (apomorphine and quinpirole); 2) serotonergic 5-HT3 receptors [5-HT (serotonin) and 2-methyl-5-HT]; 3) cholinergic M1 receptors (pilocarpine and McN-A-343); 4) substance P neurokinin NK1 receptors (GR73632); 5) the L-type calcium (Ca2+) channel (LTCC) (FPL64176); 6) the sarcoplasmic endoplasmic reticulum Ca2+ ATPase inhibitor, thapsigargin; 7) the CB1 receptor inverse agonist/antagonist, SR141716A; and 8) the chemotherapeutic cisplatin. Temsirolimus prevented vomiting evoked by the aforementioned emetogens with varying degrees. The mechanisms underlying the pro- and antiemetic effects of temsirolimus evaluated by immunochemistry for c-fos expression demonstrated a c-fos induction in the AP and NTS, but not DMNX with the 10 mg/kg emetic dose of temsirolimus, whereas its larger antiemetic dose (20 mg/kg) had no significant effect. Our study is the first to provide preclinical evidence demonstrating the promising antiemetic potential of high doses of temsirolimus and possibly its analogs in least shrews.
Engineered Exosomes-Mediated Transfer of hsa-miR-320a Overcomes Chemoresistance in Cervical Cancer Cells via Targeting MCL1
Authors: Zhou Jinling , Wang Yuanhe , Zhang Lizhu , Chen Qin , Zhu Xiaojun , Jiang Peiyue , Jiang Nan , Zhao Wei , Li Baohua
Published: April 2022

In cervical cancer (CC), cisplatin resistance greatly restricts the application in clinical. Here, we report that engineered exosomes-mediated transfer of hsa-miR-320a overcomes chemoresistance in cervical cancer cells via targeting Myeloid Cell Leukemia Sequence 1 (MCL1). In DDP resistant CC tissues, as well as cell lines, it was found that miR-320a expression is lower, engineered miR-320a exosomes were used to attenuate DDP resistance in Hela/DDP and Caski/DDP cells. Mechanistically, we find that MCL1, which is a target of miR-320a, overcomes DDP resistance in Hela/DDP cells and in mice. In conclusion, we report that the engineered miR-320a exosomes is proved to be effective and safe.
Contractile State Dependent Sarcomere Length Variability in Isolated Guinea-Pig Cardiomyocytes
Authors: Lookin Oleg , Khokhlova Anastasia , Myachina Tatiana , Butova Xenia , Cazorla Olivier , de Tombe Pieter
Published: April 2022

Cardiomyocytes contract keeping their sarcomere length (SL) close to optimal values for force generation. Transmural heterogeneity in SL across the ventricular wall coordinates the contractility of the whole-ventricle. SL heterogeneity (variability) exists not only at the tissue (macroscale) level, but also presents at the level of a single cardiomyocyte (microscale level). However, transmural differences in intracellular SL variability and its possible dependence on the state of contraction (e.g. end-diastole or end-systole) have not been previously reported. In the present study, we studied three aspects of sarcomere-to-sarcomere variability in intact cardiomyocytes isolated from the left ventricle of healthy guinea-pig: 1) transmural differences in SL distribution between subepi- (EPI) and subendocardial (ENDO) cardiomyocytes; 2) the dependence of intracellular variability in SL upon the state of contraction; 3) local differences in SL variability, comparing SL distributions between central and peripheral regions within the cardiomyocyte. To characterize the intracellular variability of SL, we used different normality tests for the assessment of SL distributions, as well as nonparametric coefficients to quantify the variability. We found that individual SL values in the end-systolic state of contraction followed a normal distribution to a lesser extent as compared to the end-diastolic state of contraction (∼1.3-fold and ∼1.6-fold in ENDO and EPI, respectively). The relative and absolute coefficients of sarcomere-to-sarcomere variability in end-systolic SL were significantly greater (∼1.3-fold) as compared to end-diastolic SL. This was independent of both the transmural region across the left ventricle and the intracellular region within the cardiomyocyte. We conclude that the intracellular variability in SL, which exists in normal intact guinea-pig cardiomyocytes, is affected by the contractile state of the myocyte. This phenomenon may play a role in inter-sarcomere communication in the beating heart.
Metformin Inhibits Na+/H+ Exchanger NHE3 Resulting in Intestinal Water Loss
Authors: Han Yiran , Yun C. Chris
Published: April 2022

Glycemic control is the key to the management of type 2 diabetes. Metformin is an effective, widely used drug for controlling plasma glucose levels in diabetes, but it is often the culprit of gastrointestinal adverse effects such as abdominal pain, nausea, indigestion, vomiting, and diarrhea. Diarrhea is a complex disease and altered intestinal transport of electrolytes and fluid is a common cause of diarrhea. Na+/H+ exchanger 3 (NHE3, SLC9A3) is the major Na+ absorptive mechanism in the intestine and our previous study has demonstrated that decreased NHE3 contributes to diarrhea associated with type 1 diabetes. The goal of this study is to investigate whether metformin regulates NHE3 and inhibition of NHE3 contributes to metformin-induced diarrhea. We first determined whether metformin alters intestinal water loss, the hallmark of diarrhea, in type 2 diabetic db/db mice. We found that metformin decreased intestinal water absorption mediated by NHE3. Metformin increased fecal water content although mice did not develop watery diarrhea. To determine the mechanism of metformin-mediated regulation of NHE3, we used intestinal epithelial cells. Metformin inhibited NHE3 activity and the effect of metformin on NHE3 was mimicked by a 5′-AMP-activated protein kinase (AMPK) activator and blocked by pharmacological inhibition of AMPK. Metformin increased phosphorylation and ubiquitination of NHE3, resulting in retrieval of NHE3 from the plasma membrane. Previous studies have demonstrated the role of neural precursor cell expressed, developmentally down-regulated 4-2 (Nedd4-2) in regulation of human NHE3. Silencing of Nedd4-2 mitigated NHE3 inhibition and ubiquitination by metformin. Our findings suggest that metformin-induced diarrhea in type 2 diabetes is in part caused by reduced Na+ and water absorption that is associated with NHE3 inhibition, probably by AMPK.
Thriving in Oxygen While Preventing ROS Overproduction: No Two Systems Are Created Equal
Authors: Mendez-Romero O. , Ricardez-García C. , Castañeda-Tamez P. , Chiquete-Félix N. , Uribe-Carvajal S.
Published: April 2022

From 2.5 to 2.0 billion years ago, atmospheric oxygen concentration [O2] rose thousands of times, leading to the first mass extinction. Reactive Oxygen Species (ROS) produced by the non-catalyzed partial reduction of O2 were highly toxic eliminating many species. Survivors developed different strategies to cope with ROS toxicity. At the same time, using O2 as the final acceptor in respiratory chains increased ATP production manifold. Thus, both O2 and ROS were strong drivers of evolution, as species optimized aerobic metabolism while developing ROS-neutralizing mechanisms. The first line of defense is preventing ROS overproduction and two mechanisms were developed in parallel: 1) Physiological uncoupling systems (PUS), which increase the rate of electron fluxes in respiratory systems. 2) Avoidance of excess [O2]. However, it seems that as avoidance efficiency improved, PUSs became less efficient. PUS includes branched respiratory chains and proton sinks, which may be proton specific, the mitochondrial uncoupling proteins (UCPs) or unspecific, the mitochondrial permeability transition pore (PTP). High [O2] avoidance also involved different strategies: 1) Cell association, as in biofilms or in multi-cellularity allowed gas-permeable organisms (oxyconformers) from bacterial to arthropods to exclude O2. 2) Motility, to migrate from hypoxic niches. 3) Oxyregulator organisms: as early as in fish, and O2-impermeable epithelium excluded all gases and only exact amounts entered through specialized respiratory systems. Here we follow the parallel evolution of PUS and O2-avoidance, PUS became less critical and lost efficiency. In regard, to proton sinks, there is fewer evidence on their evolution, although UCPs have indeed drifted in function while in some species it is not clear whether PTPs exist.
Sharing or Not: Psychological Motivations of Brand Rumors Spread and the Stop Solutions
Authors: Zhang Xu , Zhu Hong , Huang Yu , Xiao Chunqu
Published: April 2022

Brand rumors can harm brands’ image and bring significant impacts on customers’ decision-making and sharing behavior. Finding practical strategies for preventing the spread of brand rumors continues to be a challenge. Building on the social contagion theory, the current research enriches the discussion on understanding why people spread rumors and how to deal with the spreading of rumors. Sharing brand rumors is motivated by a variety of complex psychological reasons, but prior research didn’t adequately analyze the problem from a complexity perspective. Therefore, using a sample of 416 interviewers within eight types of brand rumors, this study employs fuzzy-set qualitative comparative analysis (fsQCA) to investigate the combination of rumor psychological communication motivations in brand activities and solutions to prevent the spread of brand rumors. The current study discoveries three and two first-level configurational solutions, respectively, that can promote positive and negative rumor spreading. To summarize, emotional stimulation is a key component in the spread of rumors; altruism and relationship management motivation can coexist at times; and untrusted rumors are disseminated through other motivation factors. Solutions to prevent rumors from spreading are also provided. Furthermore, the findings help to understand the psychology of configurational motivation and how it can help brands reduce the spread of brand rumors. Finally, these discoveries’ theoretical contributions and practical implications are presented.
New Life Transition of Former Caregivers: Positive Mental Health Approach
Authors: Mora-Lopez Gerard , Berenguer-Poblet Marta , Berbis-Morelló Carme , Albacar-Rioboo Nuria , Montesó-Curto Pilar , Aguaron-García María Jesús , Ferré-Grau Carme
Published: April 2022

After the end of their time as a caregiver, former caregivers have needs and feelings that have been subject to little study to date. The aim of the study is to determine and analyse the feelings, perceptions and practices of former caregivers in the reconstruction of their daily lives. This is a qualitative study based on the Grounded Theory developed by Charmaz. The study involved 14 former caregivers who had cared for their relative for more than 2 years and who had stopped caring for them more than 2 years previously. Fourteen in-depth interviews were conducted and data were collected over 13 months between 2015 and 2017. Data were analysed using the Grounded Theory Method. In addition, this study was approved by the ethics committee of the Institut Universitari d’Investigació en Atenció Primària Jordi Gol. The former caregiver experiences a transition, which begins in the days before the death of their relative and may continue for more than 3 years. Three critical moments in the post-caring transition were found: (1) the post-caring emptiness; (2) the end of the period as a caregiver; and (3) the movement towards a new life. Family and professional support is needed during this transition. Former caregivers experience a transition in the rebuilding of their daily lives; furthermore, former caregivers may be a source of support for other caregivers, which is linked to positive mental health factors. Healthcare organisations need to acknowledge the emotional, psychosocial and psychological health of former caregivers.
Safety Learning in Anxiety, Pavlovian Conditioned Inhibition and COVID Concerns
Authors: Thurston Meghan D. , Cassaday Helen J.
Published: April 2022

Experimental studies of fear conditioning have identified the effectiveness of safety signals in inhibiting fear and maintaining fear-motivated behaviors. In fear conditioning procedures, the presence of safety signals means that the otherwise expected feared outcome will not now occur. Differences in the inhibitory learning processes needed to learn safety are being identified in various psychological and psychiatric conditions. However, despite early theoretical interest, the role of conditioned inhibitors as safety signals in anxiety has been under-investigated to date, in part because of the stringent test procedures required to confirm the demonstration of conditioned inhibition as such. Nonetheless, the theoretical implications of an inhibitory learning perspective continue to influence clinical practice. Moreover, our understanding of safety signals is of additional importance in the context of the increased health anxiety and safety behaviors generated by the COVID-19 pandemic.
Transcranial Electrical Stimulation for Relief of Peripartum Mental Health Disorders in Women Undergoing Cesarean Section With Combined Spinal–Epidural Anesthesia: A Pilot Randomized Clinical Trial
Authors: Zhao Qiu , Han Yuan , Hu Xiao-Yi , Zhang Song , Zhang Long , Wang Jun , Zhang Qian-Qian , Tao Ming-Shu , Fang Jia-xing , Yang Jie , Liu Rong-Guang , Sun Xun , Zhou Jian , Li Xiang , Mannan-Abdul  , Zhang Hongxing , Liu He , Cao Jun-Li
Published: April 2022

Objective

This study aimed to explore transcranial electrical stimulation (tES) to relieve peripartum anxiety and depressive symptoms in women undergoing cesarean section with combined spinal–epidural anesthesia.

Methods

This double-blind, randomized, sham-controlled trial was conducted in the Affiliated Hospital of Xuzhou Medical University from March 2021 and May 2021. One hundred and forty-eight full-term parturients giving birth by elective cesarean section were selected, and 126 were included in the intent-to-treat analysis. Parturients were provided standardized anesthesia and randomized to the active-tES (a-tES) group and sham-tES group. Parturients and outcome assessors were blinded to treatment allocation. The primary outcome was the changes in peripartum mental health disorders, including anxiety, assessed by the Pregnancy-Related Anxiety Questionnaire-Revised 2 (PRAQ-R2). Secondary outcomes included peripartum depressive symptoms, assessed by the Edinburgh Postnatal Depression Scale (EPDS), maternal satisfaction, fatigue level, sleep quality index, and pain score during and after operation. Data were collected before entering the operating room (T0), between post-anesthesia and pre-surgery (T1), before leaving the operating room (T2), and at 24 h post-surgery (T3).

Results

One hundred and twenty-six eligible parturients were enrolled in the two groups: a-tES group (N = 62) and sham-tES group (N = 64). Treatment with tES resulted in significantly lower scores of anxiety compared with sham-tES (T2: P < 0.001; T3: P = 0.001). Moreover, the a-tES groups showed a significant reduction in depression scores (T2: P = 0.003; T3: P = 0.032).

Conclusion

In this randomized pilot study, tES treatment is efficacious in alleviating peripartum anxiety and depressive symptoms in women undergoing cesarean section and has been demonstrated to be a novel strategy for improving peripartum mental health disorders.

Clinical Trial Registration

[www.chictr.org.cn], identifier [ChiCTR2000040963].
Perceptions of Telemental Health Care Delivery During COVID-19: A Cross-Sectional Study With Providers, February-March 2021
Authors: Wilczewski Hattie , Paige Samantha R. , Ong Triton , Barrera Janelle F. , Soni Hiral , Welch Brandon M. , Bunnell Brian E.
Published: April 2022

The COVID-19 pandemic accelerated adoption of telemental health (TMH). Providers with limited TMH experience faced challenges during the rapid switch to remote patient care. We investigated TMH providers’ perceptions about remote care one year into the pandemic according to when providers adopted telemedicine (i.e., before vs. after March 2020) and how much of their caseloads were served remotely (i.e., < 50% vs. ≥ 50%). Between February–March 2021, 472 TMH providers completed a cross-sectional, web-based survey that measured perceived benefits and satisfaction with telemedicine, therapeutic alliance, patient-centered communication, eHealth literacy, multicultural counseling self-efficacy, and facilitating factors of using telemedicine. Providers who began using telemedicine before the pandemic reported having better training, task-related therapeutic alliance with patients, and ability to conduct multicultural interventions, assessments, and session management. Providers who served ≥ 50% of their caseload remotely reported greater satisfaction with their practice, stronger beliefs about the benefits of telemedicine, and greater perceived effects of telemedicine on alleviating the impact of COVID-19. There were no differences in reports of patient-centered communication nor eHealth literacy. In conclusion, providers who adopted TMH more recently may require additional training and support to successfully establish a working alliance with their patients, especially with multicultural aspects of care.
Nightmare Rescripting: Using Imagery Techniques to Treat Sleep Disturbances in Post-traumatic Stress Disorder
Authors: Albanese Marzia , Liotti Marianna , Cornacchia Lucia , Mancini Francesco
Published: April 2022

Besides affecting 8% of the general population, nightmares are one of the most frequent symptoms of traumatized individuals. This can be a significant factor in the treatment of post-traumatic disorders; indeed, several studies demonstrated its strong predictive and prognostic value. Sleep disorders, nightmares in particular, could be very distressing for individuals and need targeted interventions, especially if they are associated with a PTSD diagnosis. To date, the best technique for the treatment of traumatic sleep disturbances seems to be Imagery Rehearsal Therapy (IRT), an empirically supported method. Through a review of the literature on this matter, this article aims to outline the incidence and consequences of nightmares in PTSD, illustrate how IRT could prove useful in their treatment, and investigate its clinical applications.
Increased Prefrontal Activation During Verbal Fluency Task After Repetitive Transcranial Magnetic Stimulation Treatment in Depression: A Functional Near-Infrared Spectroscopy Study
Authors: Huang Jiaxi , Zhang Jiaqi , Zhang Tingyu , Wang Pu , Zheng Zhong
Published: April 2022

Background

Previous studies have shown the clinical effect of 2 Hz repetitive transcranial magnetic stimulation (rTMS) for depression; however, its underlying neural mechanisms are poorly understood. The aim of this study was to examine the effects of rTMS on the activity of the prefrontal cortex in patients with depression, using functional near-infrared spectroscopy (fNIRS).

Methods

Forty patients with major depressive disorder (MDD) and 40 healthy controls were enrolled in this study. Patients underwent 4 weeks of 2 Hz TMS delivered to the right dorsolateral prefrontal cortex (DLPFC). fNIRS was used to measure the changes in the concentration of oxygenated hemoglobin ([oxy-Hb]) in the prefrontal cortex during a verbal fluency task (VFT) in depressed patients before and after rTMS treatment. The severity of depression was assessed using the Hamilton Rating Scale for Depression-24 item (HAMD-24).

Results

Prior to rTMS, depressed patients exhibited significantly smaller [oxy-Hb] values in the bilateral prefrontal cortex during the VFT compared with the healthy controls. After 4 weeks of 2 Hz right DLPFC rTMS treatment, increased [oxy-Hb] values in the bilateral frontopolar prefrontal cortex (FPPFC), ventrolateral prefrontal cortex (VLPFC) and left DLPFC during the VFT were observed in depressed patients. The increased [oxy-Hb] values from baseline to post-treatment in the right VLPFC in depressed patients were positively related to the reduction of HAMD score following rTMS.

Conclusion

These findings suggest that the function of the prefrontal cortex in depressed patients was impaired and could be recovered by 2 Hz rTMS. The fNIRS-measured prefrontal activation during a cognitive task is a potential biomarker for monitoring depressed patients’ treatment response to rTMS.