ABSTRACT
The factors influencing the development and maintenance of nicotine dependence are numerous and complex. Recent studies indicate that smokers exhibit distinct genetic predispositions to nicotine dependence. We aimed to analyse (1) the association between rs2551038 and cigarette smoking, (2) the association of between the rs3864236-rs2526303-rs2551038 haplotype and cigarette smoking, and (3) the personality traits measured by the NEO Five-Factor Inventory in cigarette users and never-smokers. No significant differences were present in the frequency of rs2551038 genotypes and alleles in the studied cigarette users compared to the control group. Cigarette users, compared to the control group, had higher scores on the NEO-FFI Extraversion scale (p = 0.0011), and lower scores were obtained by the cigarette users for the NEO-FFI Openness (p = 0.0060), Agreeability (p ≤ 0.000), and Conscientiousness (p ≤ 0.000) scales. There was a significant positive Pearson's linear correlation between the age and the Fagestrom test (r = 0.346; p < 0.0001) and the NEO-FFI Openness scale (r = 0.180; p < 0.0001) in the group of cigarette users. We observed significant linkage disequilibrium between rs2526303 and rs3864236 (D' = 0.3581; p < 2.2204 × 10-16) and between rs2526303 and rs2551038 (D' = 0.9993; p < 2.2204 × 10-16) in the tested sample. The sex-stratified haplotype analysis revealed that in the group of male never-smokers, the GTC haplotype was significantly more frequent than in the group of cigarette users (38% vs. 22%; p = 0.0039). The presented study reveals significant differences in personality trait scores between cases and controls. Moreover, the sex-stratified analysis showed significant differences in haplotype distribution. These results underscore the interplay between genetic predisposition, sex, and personality in nicotine-using individuals.
Subject(s)
Nerve Tissue Proteins , Personality , Polymorphism, Single Nucleotide , Smoking , Adult , Female , Humans , Male , Middle Aged , Alleles , Case-Control Studies , Genetic Predisposition to Disease , Genotype , Haplotypes , Linkage Disequilibrium , Nerve Tissue Proteins/genetics , Personality/genetics , Smoking/genetics , Tobacco Use Disorder/genetics , Tobacco Use Disorder/psychologyABSTRACT
BACKGROUND: The health-related quality of life instrument with 8 items (HINT-8) was developed to measure health-related quality of life (HRQoL) in Korea. However, the HINT-8 has not yet been validated among the family caregivers of people with dementia (PwD). DESIGN: A cross-sectional pilot study. OBJECTIVE: The study aimed to examine the convergent and discriminant validity of the HINT-8 among family caregivers of individuals with dementia. SAMPLE: Forty-seven family caregivers of PwD. MEASUREMENTS: HINT-8 was compared with the 5-level EQ-5D (EQ-5D-5L) to assess its convergent and discriminant validity. Additionally, the association between the two instruments assessing HRQoL was examined using the short-form Bédard-Zarit Burden Interview (SZBI). RESULTS: The HINT-8 was a promising and valid HRQoL instrument for family caregivers of PwD. There was a significantly high correlation between the overall HINT-8 and EQ-5D-5L indices (r = 0.85, p < .001). The HINT-8 had acceptable psychometric properties compared to the commonly used EQ-5D-5L, as indicated by the subdomains associated with family caregivers' burden measured by the SZBI. CONCLUSION: Future studies should compare the HINT-8 with existing dementia carer-specific QoL instruments among a larger study sample to enhance its statistical power and confirm its reliability and structural validity.
ABSTRACT
Molecular Dynamics (MD) is a computational technique widely used to evaluate a molecular system's thermodynamic properties and conformational behavior over time. In particular, the energy analysis of a protein conformation ensemble produced though MD simulations plays a crucial role in explaining the relationship between protein dynamics and its mechanism of action. In this research work, the HINT (Hydropathic INTeractions) LogP-based scoring function was first used to handle MD trajectories and investigate the molecular basis behind the intricate PPARγ mechanism of activation. The Peroxisome Proliferator-Activated Receptor γ (PPARγ) is an emblematic example of a highly flexible protein due to the extended ω-loop delimiting the active site, and it is responsible for the receptor's ability to bind chemically different compounds. In this work, we focused on the PPARγ complex with Rosiglitazone, a common anti-diabetic compound and analyzed the molecular basis of the flexible ω-loop stabilization effect produced by the Oleic Acid co-binding. The HINT-based analysis of the produced MD trajectories allowed us to account for all of the energetic contributions involved in interconverting between conformational states and describe the intramolecular interactions between the flexible ω-loop and the helix H3 triggered by the allosteric binding mechanism.
Subject(s)
Molecular Dynamics Simulation , PPAR gamma , Humans , PPAR gamma/chemistry , PPAR gamma/metabolism , Protein Binding , Protein Conformation , Rosiglitazone/chemistry , Rosiglitazone/pharmacology , ThermodynamicsABSTRACT
Histidine triad nucleotide-binding protein 2 (HINT2) is an enzyme found in mitochondria that functions as a nucleotide hydrolase and transferase. Prior studies have demonstrated that HINT2 plays a crucial role in ischemic heart disease, but its importance in cardiac remodelling remains unknown. Therefore, the current study intends to determine the role of HINT2 in cardiac remodelling. HINT2 expression levels were found to be lower in failing hearts and hypertrophy cardiomyocytes. The mice that overexpressed HINT2 exhibited reduced myocyte hypertrophy and cardiac dysfunction in response to stress. In contrast, the deficiency of HINT2 in the heart of mice resulted in a worsening hypertrophic phenotype. Further analysis indicated that upregulated genes were predominantly associated with the oxidative phosphorylation and mitochondrial complex I pathways in HINT2-overexpressed mice after aortic banding (AB) treatment. This suggests that HINT2 increases the expression of NADH dehydrogenase (ubiquinone) flavoprotein (NDUF) genes. In cellular studies, rotenone was used to disrupt mitochondrial complex I, and the protective effect of HINT2 overexpression was nullified. Lastly, we predicted that thyroid hormone receptor beta might regulate HINT2 transcriptional activity. To conclusion, the current study showcased that HINT2 alleviates pressure overload-induced cardiac remodelling by influencing the activity and assembly of mitochondrial complex I. Thus, targeting HINT2 could be a novel therapeutic strategy for reducing cardiac remodelling.
Subject(s)
Heart , Ventricular Remodeling , Animals , Mice , Ventricular Remodeling/genetics , Mitochondria , Hypertrophy , Electron Transport Complex I/genetics , Nucleotides , Hydrolases , Mitochondrial Proteins/geneticsABSTRACT
Vint proteins have been identified in unicellular metazoans as a novel hedgehog-related gene family, merging the von Willebrand factor type A domain and the Hedgehog/INTein (HINT) domains. We present the first three-dimensional structure of the Vint domain from Tetrahymena thermophila corresponding to the auto-processing domain of hedgehog proteins, shedding light on the unique features, including an adduct recognition region (ARR). Our results suggest a potential binding between the ARR and sulfated glycosaminoglycans like heparin sulfate. Moreover, we uncover a possible regulatory role of the ARR in the auto-processing by Vint domains, expanding our understanding of the HINT domain evolution and their use in biotechnological applications. Vint domains might have played a crucial role in the transition from unicellular to multicellular organisms.
Subject(s)
Protein Domains , Protozoan Proteins , Tetrahymena thermophila , Tetrahymena thermophila/metabolism , Tetrahymena thermophila/genetics , Protozoan Proteins/chemistry , Protozoan Proteins/metabolism , Protozoan Proteins/genetics , Ligands , Models, Molecular , Hedgehog Proteins/metabolism , Hedgehog Proteins/chemistry , Hedgehog Proteins/genetics , Amino Acid Sequence , Protein FoldingABSTRACT
The development of a substance use disorder (SUD) is a multifaceted process influenced by both genetic and environmental factors. Recent research has suggested the potential involvement of the HINT1 gene in various aspects of plasticity, mood regulation, anxiety-like behaviour, and stress-coping mechanisms. Moreover, personality traits are also recognised to be instrumental in developing substance dependency. Given these considerations, our study investigated the associations among cigarette smoking, personality traits, and the rs2526303 polymorphism. Additionally, we investigated the interactions between personality traits and rs2526303 in the HINT1 gene. The study group comprised 531 volunteers: 375 cigarette users (mean age = 29.42 ± 10.72; F = 49%, M = 51%) and 156 never-smokers (mean age = 26.93 ± 10.09; F = 79%, M = 21%). Genotyping was conducted using the real-time PCR method, and the NEO Five-Factor Personality Inventory and State-Trait Anxiety Inventory were administered. There were no statistically significant differences in the frequency of rs2526303 genotypes and alleles in the cigarette user group compared to the control group. Compared to the control group, the cigarette users obtained higher scores in the assessment of the NEO-FFI Extraversion scale and lower results for the NEO-FFI Openness, Agreeableness, and Conscientiousness scales. Additionally, there was a statistically significant effect of rs2526303 genotype interaction and cigarette-using status on the conscientiousness scale. These outcomes collectively suggest a notable association between cigarette smoking and specific dimensions of personality, particularly highlighting differences in extraversion, openness, agreeableness, and conscientiousness. Furthermore, the detected interaction effect involving rs2526303 concerning conscientiousness signifies a complex interplay between genetic factors and smoking behaviour.
Subject(s)
Substance-Related Disorders , Tobacco Products , Humans , Adolescent , Young Adult , Adult , Smokers , Polymorphism, Genetic , Personality Inventory , Personality/genetics , Substance-Related Disorders/genetics , Nerve Tissue Proteins/geneticsABSTRACT
(1) Background: For successful hearing aid (HA) use during daily life, an objective parameter reflecting the subjective satisfaction is required. We explored the aided hearing status, hearing in noise test (HINT) scores, and subjective outcomes to predict performance improvements in everyday living. (2) Methods: A total of 406 patients with hearing loss (HL) who were prescribed HAs were included and were divided into two groups according to the symmetricity of HL. The relationship between audiometric data and subjective questionnaires under unaided and aided (3 months) conditions were investigated. (3) Results: Patients with symmetric HL showed a significant HINT signal-to-noise ratio (SNR) change and significant increase in their subjective satisfaction questionnaire score under the bilateral HA condition. On the other hand, the HINT SNR change and subjective questionnaire score showed various significances according to the side of HA (better or worse hearing) in asymmetric HL HINT SNR and was significantly correlated with the subjective questionnaire score in symmetric HL patients and AHL patients with unilateral HA in their better ear. (4) Conclusions: The HINT SNR improvement after long-term HA use could be an effective tool for predicting the subjective satisfaction of HA use and HA validation.
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Objective:To summarize the characteristics of autosomal recessive axonal neuropathy with neuromyotonia (ARAN-NM) caused by HINT1 gene mutation. Methods:Retrospective case summary.Clinical data of 2 Tibetan siblings diagnosed with ARAN-NM in the Department of Pediatrics of Peking University First Hospital in August 2023 were retrospectively analyzed.A review of literature reporting relevant Chinese patients was conducted.Results:The proband and her elder brother were aged 13 and 19, respectively.Both developed abnormal gait at the age of 11, followed by varus, claudication, and weak thumb strength.The proband also had neuromyotonia.Physical examinations showed that the proband and her elder brother had decreased muscle strength of the extremities, mainly in the thumbs and distal ends of lower limbs.The distal muscles of the proband′s lower extremities and the muscles of both hands of the proband′s elder brother were atrophied.Both feet showed talipes equinovarus in the proband and her elder brother.The proband′s electromyography (EMG) showed peripheral nerve injuries (motor and sensory axonal involvement, especially in distal ends) and myotonic potentials.The trio-whole exon sequencing detected homozygous pathogenic variation in HINT1 gene in both the proband and her elder brother, who were diagnosed as ARAN-NM based on c. 169A>G (p.K57E). After the Carbamazepine treatment, the proband′s neuromyotonia, numbness and weakness were relieved.Both the proband and her elder brother underwent orthopaedic surgery and rehabilitation.Their foot deformities and gait were significantly improved.Two Chinese literatures (2 patients) and four English literatures (8 patients) were retrieved.Including the proband and her elder brother in this study, there were 12 ARAN-NM patients, 10 of whom had clinical data.The ages of onset and diagnosis were 2-16 (1 case unknown) and 13-33 years old, respectively.Myasthenia was present in 9 patients, especially in distal ends.Eight patients were complicated with neuromyotonia, nine patients with muscle atrophy, seven patients with foot deformity, and two patients with sensory disturbance.Creatine kinase(CK) was elevated in all 9 patients tested or CK.EMG showed neurogenic injuries in all patients and neuromyotonia discharge in six patients.Three patients were treated with Carbamazepine, and some symptoms were relieved.Missense/nonsense mutations were found in the 12 patients, and the high-frequency variation was c. 112T>C (p.C38R). Conclusions:ARAN-NM is a rare autosomal recessive neuromuscular disease caused by HINT1 gene mutation.There is no ethnic difference in clinical manifestations, mainly distal limb weakness with neuromyotonia.Carbamazepine can alleviate some symptoms, and orthopaedic surgery can improve foot deformity and gait.
ABSTRACT
The biological target identification process, a pivotal phase in the drug discovery workflow, becomes particularly challenging when mutations affect proteins' mechanisms of action. COVID-19 Spike glycoprotein mutations are known to modify the affinity toward the human angiotensin-converting enzyme ACE2 and several antibodies, compromising their neutralizing effect. Predicting new possible mutations would be an efficient way to develop specific and efficacious drugs, vaccines, and antibodies. In this work, we developed and applied a computational procedure, combining constrained logic programming and careful structural analysis based on the Structural Activity Relationship (SAR) approach, to predict and determine the structure and behavior of new future mutants. "Mutations rules" that would track statistical and functional types of substitutions for each residue or combination of residues were extracted from the GISAID database and used to define constraints for our software, having control of the process step by step. A careful molecular dynamics analysis of the predicted mutated structures was carried out after an energy evaluation of the intermolecular and intramolecular interactions using the HINT (Hydrophatic INTeraction) force field. Our approach successfully predicted, among others, known Spike mutants.
Subject(s)
COVID-19 , SARS-CoV-2 , Humans , SARS-CoV-2/metabolism , Workflow , Mutation , Glycoproteins/genetics , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/metabolism , Protein BindingABSTRACT
A long-lasting goal of computational biochemists, medicinal chemists, and structural biologists has been the development of tools capable of deciphering the molecule-molecule interaction code that produces a rich variety of complex biomolecular assemblies comprised of the many different simple and biological molecules of life: water, small metabolites, cofactors, substrates, proteins, DNAs, and RNAs. Software applications that can mimic the interactions amongst all of these species, taking account of the laws of thermodynamics, would help gain information for understanding qualitatively and quantitatively key determinants contributing to the energetics of the bimolecular recognition process. This, in turn, would allow the design of novel compounds that might bind at the intermolecular interface by either preventing or reinforcing the recognition. HINT, hydropathic interaction, was a model and software code developed from a deceptively simple idea of Donald Abraham with the close collaboration with Glen Kellogg at Virginia Commonwealth University. HINT is based on a function that scores atom-atom interaction using LogP, the partition coefficient of any molecule between two phases; here, the solvents are water that mimics the cytoplasm milieu and octanol that mimics the protein internal hydropathic environment. This review summarizes the results of the extensive and successful collaboration between Abraham and Kellogg at VCU and the group at the University of Parma for testing HINT in a variety of different biomolecular interactions, from proteins with ligands to proteins with DNA.
ABSTRACT
Nicotine is the major reinforcing component of tobacco and it is believed that the pharmacological effects of nicotine motivate the initiation and maintenance of a smoking habit. HINT1 appears to play a role in the modulation of the effects of drug abuse. Hence, the aim of this study was the analysis of the association between the rs3864283 polymorphism of the HINT1 gene and cigarette use; the analysis of personality traits assessed by the means of the NEO-FFI Inventory; the analysis of anxiety measured by the STAI questionnaire; and the analysis of the interactions between the rs3864283 and both personality traits and anxiety. The study group consisted of 522 volunteers. Of these, 371 were cigarette users and 151 were never-smokers. The genomic DNA was isolated from venous blood using standard procedures. The results of both inventories, i.e., NEO-FFI and STAI., were reported as the sten scores. Genotyping was conducted with the real-time PCR method. Statistically significant differences were found in the frequency of rs3864283 genotypes and alleles in the tested sample of Cigarette Users when compared to the control group. The Cigarette Users compared to the control group obtained higher scores in the assessment of NEO-FFI extraversion scale, and significantly lower results were obtained for the NEO-FFI openness scale, the agreeableness scale, and the conscientiousness scale. There was a statistically significant effect of rs3864283 genotype interaction and Cigarette Use or not using (control group) on the extraversion scale. There was also a statistically significant effect of Cigarette Users or the control group on the extraversion scale score. The results obtained in the presented study indicated a significant association between the HINT1 rs3864283 variant and smoking status. Moreover, this is the first study incorporating genetic association of above-mentioned polymorphic site with interaction analysis of personality traits and anxiety. Overall, the results of this study suggest that HINT1 is an important genetic component associated with nicotine usage mechanisms.
Subject(s)
Nicotine , Tobacco Products , Humans , Personality/genetics , Polymorphism, Genetic , Anxiety/genetics , Personality Inventory , Nerve Tissue Proteins/geneticsABSTRACT
Histidine triad nucleotide-binding protein 2 (HINT2) is a dimeric protein that belongs to the histidine triad protein superfamily, predominantly expressed in the liver, pancreas, and adrenal gland, and localised to the mitochondrion. HINT2 binds nucleotides and catalyses the hydrolysis of nucleotidyl substrates. Moreover, HINT2 has been identified as a key regulator of multiple biological processes, including mitochondria-dependent apoptosis, mitochondrial protein acetylation, and steroidogenesis. Genetic manipulation has provided new insights into the physiological roles of HINT2 in several processes, such as inhibition of cancer progression, regulation of hepatic lipid metabolism, and protective effects on the cardiovascular system. The current review outlines the background and functions of HINT2. In addition, it summarises research progress on the correlation between HINT2 and human malignancies, hepatic metabolic diseases, and cardiovascular diseases, with an attempt to provide new research directions emerging in this field and to unveil the therapeutic value of HINT2 as a target in the combat of human diseases.
Subject(s)
Histidine , Liver , Humans , Histidine/metabolism , Liver/metabolism , Mitochondria/metabolism , Mitochondrial Proteins/metabolism , Nucleotides/metabolismABSTRACT
Objectives: The aim of this study is to develop the Turkish version of hearing in noise test for children (HINT-C) by providing norms and correction factors for the children in different age groups.Methods: A total of 77 individuals with normal hearing - 62 children (6-12 years old) and 15 adults (18-30 years old) - were included. Twelve phonemically balanced 10-sentence lists were created from the adult version of the Turkish HINT (Study 1). Age-specific norms, correction factors and maturation effects were examined using the Turkish HINT-C (Study 2).Results: Mean performances under different listening conditions and Spatial Release from Masking (SRM) advantage values were obtained for the 6-, 8-, 10-, and 12-year-old and estimated for the 7-, 9-, and 11-year-old age groups, and correction factors were calculated for all children age groups. Turkish-speaking children did not achieve adult-like hearing in noise performance, until they were 12 years old.Conclusions: Twelve phonemically balanced 10-sentence lists of Turkish HINT-C were created, and the mean performances of children in different age groups were measured. In addition to the age-specific HINT-C norms and correction factors for the 6-, 8-, 10-, and 12-year-old age groups, the maturation effects were determined.Highlights The assessment of speech-in-noise perception is highly critical for children.To evaluate the speech-in-noise perception ability, 12 phonemically balanced 10-sentence lists of Turkish HINT-C were created.Speech-in-noise perception ability improves with age.Turkish-speaking children do not achieve adult-like hearing in noise performance, until they were 12 years old.
Subject(s)
Cochlear Implantation , Speech Perception , Adult , Humans , Child , Adolescent , Young Adult , Speech Reception Threshold Test , Language , Noise , Hearing TestsABSTRACT
HINT1 is an ubiquitous homodimeric purine phosphoramidase belonging to the histidine-triad superfamily. In neurons, HINT1 stabilizes the interaction of different receptors and regulates the effects of their signaling disturbances. Changes in HINT1 gene are associated with autosomal recessive axonal neuropathy with neuromyotonia. Aim of the study was detailed description of patients' phenotype with HINT1 homozygous NM_005340.7: c.110G>C (p.Arg37Pro) variant. Seven homozygous and three compound heterozygous patients were recruited and evaluated using standardized tests for CMT patients, in four patients' nerve ultrasonography was performed. The median age of symptom onset was 10 years (range 1-20), with initial complaints being distal lower limb weakness with gait impairment, combined with muscle stiffness, more pronounced in the hands than in the legs and worsened by cold. Arm muscles became involved later, presenting with distal weakness and hypotrophy. Neuromyotonia was present in all reported patients and is thus a diagnostic hallmark. Electrophysiological studies demonstrated axonal polyneuropathy. Impaired mental performance was observed in six out of ten cases. In all patients with HINT1 neuropathy, ultrasound examination showed significantly reduced muscle volume as well as spontaneous fasciculations and fibrillations. The nerve cross-sectional areas of the median and ulnar nerves were closer to the lower limits of the normal values. None of the investigated nerves had structural changes. Our findings broaden the phenotype of HINT1-neuropathy and have implications for diagnostics and ultrasonographic evaluation of HINT1-neuropathy patients.
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AIMS: Myocardial infarction (MI) is one of the serious diseases with great mortality over the world. Myocardial mitochondrial oxidative stress has been implicated as a key player in MI. The histidine triad nucleotide-binding protein 2 (HINT2) is a nucleotide hydrolase and transferase located in mitochondria. HINT2 has multiple functions such as regulating mitochondrial lipid metabolism and respiration and glucose homeostasis. Although HINT2 has been shown to protect against MI, the underlying mechanisms were not fully elucidated. In this study, the effects of HINT2 on oxidative stress during MI were explored. METHODS AND RESULTS: MI mouse models in both wild-type and HINT2-deficient mice were established. The expression of HINT2 in HINT2-deficient mice was determined by quantitative real-time PCR and western blot. The levels of oxidative stress were measured, including the levels of malondialdehyde (MDA), nitric oxide (NO), superoxide dismutase (SOD), and glutathione (GSH). The myocardial functions, as indicated by left ventricular end-diastolic diameter (LVEDD), left ventricular end-systolic diameter (LVESD), left ventricular ejection fraction (LVEF), and left ventricular fractional shortening (LVFS), were monitored. Both mRNA and protein expressions of HINT2 in the myocardial tissues were significantly down-regulated in MI mice starting at 6 h post-MI. MI induced oxidative stress 6 h post-MI in myocardial tissues of wild-type mice, as suggested by the enhanced MDA and NO levels and decreased SOD and GSH levels. The expression of HINT2 was negatively correlated to the MDA and NO levels and positively correlated to the SOD and GSH levels. HINT2-deficient MI mice had significantly elevated levels of MDA and NO and significantly decreased levels of SOD and GSH when compared with wild-type MI mice. HINT2-deficient MI mice had higher LVEDD and LVESD and lower LVEF and LVFS compared with wild-type MI mice, indicating that HINT2 deficiency exacerbated myocardial dysfunction. CONCLUSIONS: HINT2 deficiency causes deteriorative oxidative stress in MI mice, leading to exacerbated myocardial dysfunction.
Subject(s)
Myocardial Infarction , Ventricular Function, Left , Mice , Animals , Stroke Volume , Myocardial Infarction/genetics , Myocardial Infarction/metabolism , Oxidative Stress , Disease Models, Animal , Superoxide Dismutase/metabolism , Nucleotides/metabolism , Hydrolases/metabolism , Mitochondrial Proteins/metabolismABSTRACT
Background: Histidine triad nucleotide binding protein 1 (HINT1) is a haplo-insufficient tumor suppressor gene that plays a significant role in cell proliferation and survival. However, to date, no systematic pan-cancer analysis has been conducted to explore its function in prognosis, and its oncogenic and immunological roles. We also analyzed the role of HINT1 in breast cancer (BC) progression in vitro. Methods: An analysis of the HINT1 expression pattern was performed using the TIMER database. The infiltration of immune cells into several cancer types was also studied using the Xena Shiny tool. To determine the relationship between stemness and the expression of HINT1 mRNA, the Spearman correlation test was used with the SangerBox tool. The correlation between HINT1 and functional states in various cancers was determined from the CancerSEA database. The potential role of HINT1 in BC oncogenesis was also investigated by Western blot and Annexin V/PI assays. Results: The Cancer Genome Atlas pan-cancer data analysis suggested that HINT1 was extensively altered in most tumor tissues but not in most adjacent normal tissues. A high expression of HINT1 was associated with the decreased infiltration of cluster of differentiation (CD)4+ T cells. Importantly, increased HINT1 expression was also associated with a large majority of tumors with high stemness and lower stromal, immune, and estimate scores. Further, the expression of HINT1 was significantly associated with the tumor mutational burden (TMB) and microsatellite instability (MSI) in certain tumor types. Finally, HINT1 overexpression was found to impair BC progression by promoting cell apoptosis. HINT1 upregulation also reduced the expression of microphthalmia transcription factor (MITF) and ß-catenin in BC Michigan Cancer Foundation-7 (MCF-7) cells, and the phosphorylation of protein kinase B (p-Akt). Conclusions: The present study showed that HINT1 plays an oncogenic role in various cancers and could also be used as a biomarker for BC.
ABSTRACT
Introduction: Recessive mutations in the gene encoding the histidine triad nucleotide-binding protein 1 (HINT1) are associated with axonal motor-predominant Charcot-Marie-Tooth (CMT) disease with neuromyotonia. A total of 24 HINT1 gene mutations have been reported so far. Some of these cases had mild to moderate elevations of creatinine kinase with no earlier reports of muscle biopsy findings in these cases. In this study, we describe a patient with axonal motor-predominant neuropathy and myopathy with rimmed vacuoles, likely due to a novel HINT1 gene mutation. Case report: A 35-year-old African American man presented with insidious onset and progressive symmetric distal leg weakness followed by hand muscle atrophy and weakness since the age of 25. He had no muscle cramps or sensory complaints. His 38-year-old brother developed similar symptoms beginning in his early 30 s. On neurologic examination, the patient had distal weakness and atrophy in all limbs, claw hands, pes cavus, absent Achilles reflexes, and normal sensory examination. Electrodiagnostic studies revealed absent/reduced compound motor action potential amplitudes distally with normal sensory responses with no neuromyotonia. His sural nerve biopsy showed a chronic non-specific axonal neuropathy, and a biopsy of the tibialis anterior muscle demonstrated myopathic features and several muscle fibers harboring rimmed vacuoles without inflammation in addition to chronic denervation changes. A homozygous variant, p.I63N (c.188T > A), in the HINT1 gene was found in both brothers. Conclusion: We describe a novel, likely pathogenic, HINT1 pI63N (c.188T > A) homozygous variant associated with hereditary axonal motor-predominant neuropathy without neuromyotonia in two African American brothers. The presence of rimmed vacuoles on muscle biopsy raises the possibility that mutations in the HINT1 gene may also cause myopathy.
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PURPOSE: The aim of the study was to develop the German Hearing in Noise Test (HINT) with female speaker by fulfilling the recommendations by International Collegium of Rehabilitative Audiology (ICRA) for using a female speaker to create new multilingual speech tests and to determine norms and to compare these norms with German male speech tests-the male speakers HINT and the Oldenburg Sentence Test (OLSA). METHODS: The HINT with a female speaker consists of the same speech material as the male speaking HINT. After recording the speech material, 10 normal hearing subjects were included to determine the performance-intensity function (PI function). 24 subjects were part of the measurements to determine the norms and compare them with the norms of male HINT and OLSA. Comparably, adaptive, open-set methods under headphones (HINT) and sound field (OLSA) were used. RESULTS: Acoustic phonetic analysis demonstrated significant difference in mean fundamental frequency, its range and mean speaking rate between both HINT speakers. The calculated norms by three of the tested four conditions of the HINT with a female speaker are not significantly different from the norms with a male speaker. No significant effect of the speaker's gender of the first HINT measurement and no significant correlation between the threshold results of the HINT and the OLSA were determined. CONCLUSIONS: The Norms for German HINT with a female speaker are comparable to the norms of the HINT with a male speaker. The speech intelligibility score of the HINT does not depend on the speakers' gender despite significant difference of acoustic-phonetic parameters between the female and male HINT speaker's voice. Instead, the speech intelligibility rating must be seen as a function of the used speech material.
Subject(s)
Noise , Speech Perception , Humans , Male , Female , Auditory Threshold , Perceptual Masking , Hearing Tests , Speech Intelligibility , Speech Reception Threshold Test/methodsABSTRACT
AIMS: Colorectal cancer (CRC) is one of the most common malignant tumors worldwide. This study aimed to explore the effects of Polysaccharide of Lactobacillus casei SB27 in colon cancer and its possible mechanisms. METHODS: Colon cancer was induced by giving dextran sulfate sodium and Azoxymethane. Uman Colon Cancer Cell Line (HCT)-116 cells were used to vitro model in this experiment. RESULTS: Polysaccharide of L. casei SB27 reduced colon cancer in azoxymethane-dextran sulfate sodium (AOM+DSS)-induced mice. Polysaccharide of L. casei SB27 reduced colon cancer prognosis in vitro model. Polysaccharide of L. casei SB27 reduced short chain fatty acids by Bacillus coli. Polysaccharide of L. casei promoted mitochondrial damage by Calcium ion entry. Polysaccharide of L. casei induced histidine nucleotide binding protein 2/mitochondrial calcium uniporter (HINT2/MCU) signaling pathway. Immunocoprecipitation (IP) showed that HINT2 protein interlinked MCU protein. Polysaccharide of L. casei suppressed HINT2 ubiquitination. The regulation of HINT2 affected the effects of L. casei polysaccharide on colon cancer prognosis and mitochondrial damage by Calcium ion entry in vitro model. CONCLUSION: In conclusion, the present report demonstrated that polysaccharide of L. casei SB27 reduced colon cancer cell prognosis through mitochondrial damage by upregulation of HINT2. Polysaccharide of L. casei SB27 might be used for colon cancer treatment and could be helpful for personalized treatment.
Subject(s)
Colonic Neoplasms , Lacticaseibacillus casei , Humans , Mice , Animals , Up-Regulation , Dextran Sulfate , Calcium/metabolism , Colonic Neoplasms/drug therapy , Colonic Neoplasms/genetics , Prognosis , Azoxymethane , Hydrolases/genetics , Hydrolases/metabolism , Mitochondrial Proteins/geneticsABSTRACT
Year-round virological characterization of circulating epidemic influenza viruses is conducted worldwide to detect the emergence of viruses that may escape pre-existing immunity or acquire resistance to antivirals. High throughput phenotypic assays are needed to complement the sequence-based analysis of circulating viruses and improve pandemic preparedness. The recent entry of a polymerase inhibitor, baloxavir, into the global market further highlighted this need. Here, we optimized a cell-based assay that considerably streamlines antiviral and antigenic testing by replacing lengthy immunostaining and imaging procedures used in current assay with measuring the enzymatic activity of nascent neuraminidase (NA) molecules expressed on the surface of virus-infected cells. For convenience, this new assay was named IRINA (Influenza Replication Inhibition Neuraminidase-based Assay). IRINA was successfully validated to assess inhibitory activity of baloxavir on virus replication by testing a large set (>150) of influenza A and B viruses, including drug resistant strains and viruses collected during 2017-2022. To test its versatility, IRINA was utilized to evaluate neutralization activity of a broadly reactive human anti-HA monoclonal antibody, FI6, and post-infection ferret antisera, as well as the inhibition of NA enzyme activity by NA inhibitors. Performance of IRINA was tested in parallel using respective conventional assays. IRINA offers an attractive alternative to current phenotypic assays, while maintaining reproducibility and high throughput capacity. Additionally, the improved turnaround time may prove to be advantageous when conducting time sensitive studies, such as investigating a new virus outbreak. This assay can meet the needs of surveillance laboratories by providing a streamlined and cost-effective approach for virus characterization.