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It is commonly accepted that exposure to stress may cause overactivity in the orofacial muscles, leading to consistent muscle pain, which is the main symptom of temporomandibular disorders. The central neural mechanism underlying this process, however, remains unclear. The locus coeruleus is considered to play an important role in stress-related behavioral changes. Therefore, the present study was designed to examine the role of locus coeruleus neurons in masseter overactivity induced by stress. C57BL/6 mice were subjected to chronic restraint stress for 14 days to establish an animal model. The behavioral changes and the electromyography of the masseter muscle in mice were measured. The expression of Fos in locus coeruleus was observed by immunofluorescence staining to assess neuronal activation. A chemogenetic test was used to inhibit locus coeruleus neuronal activity, and the behavioral changes and electromyography of the masseter muscle were observed again. The results exhibited that chronic restraint stress could induce anxiety-like behavior, overactivity of the masseter muscle, and significant activation of locus coeruleus neurons in mice. Furthermore, inhibition of noradrenergic neuron activity within the locus coeruleus could alleviate stress-induced anxiety behavior and masseter muscle overactivity. Activation of noradrenergic neurons in locus coeruleus induced by stress may be one of the central regulatory mechanisms for stress-induced anxiety-like behaviors and overactivity of masseter muscles.
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Electromiografía , Locus Coeruleus , Músculo Masetero , Ratones Endogámicos C57BL , Restricción Física , Estrés Psicológico , Animales , Locus Coeruleus/fisiopatología , Músculo Masetero/fisiopatología , Estrés Psicológico/fisiopatología , Masculino , Ratones , Modelos Animales de Enfermedad , Ansiedad/fisiopatología , Ansiedad/etiologíaRESUMEN
OBJECTIVE: This study aims to disclose how loss of fucosyltransferase 2 (Fut2) impacts intestinal inflammation through cGAS-STING pathway that is closely associated with gut microbiota, and which microbial metabolite improves colitis in Fut2 deficiency. METHODS: Chronic colitis was induced in intestinal epithelial Fut2 knock out mice (Fut2â³IEC), whose intestinal inflammation and activity of cGAS-STING pathway were evaluated. 16S rRNA sequencing and metabolomics were performed using intestinal samples. 2-oxindole was used to treat RAW264.7 cells and Fut2â³IEC mice with colitis (Fut2â³IEC-DSS) to investigate the effect of 2-oxindole on cGAS-STING response and intestinal inflammation. RESULTS: Fut2 loss exacerbated chronic colitis in mice, manifested by declined body weight, reduced colon length, increased disease activity index (DAI) and more colon injury in Fut2â³IEC-DSS mice compared with WT-DSS (wild type mice with colitis). Lack of Fut2 promoted activation of cGAS-STING pathway. Fut2 deficiency had a primary impact on colonic microbiota, as shown by alteration of microbial diversity and structure, as well as decreased Lactobacillus. Metabolic structure and tryptophan metabolism in colonic luminal microbiota were also influenced by Fut2 loss. Fut2 deficiency also led to decreased levels of aryl hydrocarbon receptor (AHR) and its ligand 2-oxindole derived from tryptophan metabolism. 2-oxindole compromised cGAS-STING response through activating AHR in macrophages, and protected against intestinal inflammation and overactive cGAS-STING pathway in Fut2â³IEC-DSS mice. CONCLUSION: Fut2 deficiency promotes cGAS-STING pathway through suppressing 2-oxindole-AHR axis, ultimately facilitating the susceptibility to chronic colitis.
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Colitis , Fucosiltransferasas , Microbioma Gastrointestinal , Proteínas de la Membrana , Ratones Noqueados , Nucleotidiltransferasas , Oxindoles , Transducción de Señal , Animales , Humanos , Masculino , Ratones , Enfermedad Crónica , Colitis/inducido químicamente , Colitis/inmunología , Colon/patología , Colon/inmunología , Colon/metabolismo , Sulfato de Dextran , Modelos Animales de Enfermedad , Fucosiltransferasas/genética , Fucosiltransferasas/metabolismo , Fucosiltransferasas/deficiencia , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Ratones Endogámicos C57BL , Nucleotidiltransferasas/genética , Nucleotidiltransferasas/metabolismo , Células RAW 264.7 , Receptores de Hidrocarburo de Aril/metabolismo , Receptores de Hidrocarburo de Aril/genéticaRESUMEN
Enhance performance in manufacturing carbon emission (MCE) reduction has become a widespread consensus and a necessary part, which cannot be achieved without the joint participation of manufacturing enterprises and supervisory departments. Accordingly, how to coordinate the interests of both sides and design a reasonable incentive-compatible mechanism becomes an urgent task at present. Considering the two subsidy funding channels of peer funds and government finance, this study applies the evolutionary game model to analyze feasible schemes for designing incentive-compatible mechanism of MCE supervision, discusses and simulates the realistic scenarios and influencing factors of incentive-compatible mechanism under the non-subsidized and subsidized schemes. The results show that MCE supervision is in an incentive-incompatible state under the non-subsidized incentive scheme, while in a constrained incentive-compatible state under the subsidized incentive scheme. With the increase of peer funds and penalty coefficient or the decrease of subsidy coefficient, the period of MCE supervision to reach an incentive-compatible state becomes shorter. However, a lower peer fund and penalty coefficient or a higher subsidy coefficient will contribute to a state of incentive-incompatible or a periodic cycle state of "incentive-compatible â incentive-incompatible âincentive-compatibleâ " in the MCE supervision.
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Carbono , China , MotivaciónRESUMEN
Metal-organic framework compounds are extensively utilized in various fields, such as electrode materials, owing to their distinctive porous structure and significant specific surface area. In this study, NiCoAl-MOF metal-organic framework precursors were synthesized by a solvothermal method, and NiAl2O4/NiCo2O4 electrode materials were prepared by the subsequent calcination of the precursor. These materials were characterized by XRD, XPS, BET tests, and SEM, and the electrochemical properties of the electrode materials were tested by CV and GCD methods. BET tests showed that NiAl2O4/NiCo2O4 has an abundant porous structure and a large specific surface area of up to 105 m2 g-1. The specific capacitance of NiAl2O4/NiCo2O4 measured by the GCD method reaches up to 2870.83 F g-1 at a current density of 1 A g-1. The asymmetric supercapacitor NiAl2O4/NiCo2O4//AC assembled with activated carbon electrodes has a maximum energy density of 166.98 W h kg-1 and a power density of 750.00 W kg-1 within a voltage window of 1.5 V. In addition, NiAl2O4/NiCo2O4 materials have good cycling stability. These advantages make it a good candidate for the application of high-performance supercapacitors.
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Supercapacitor is an important energy storage device widely used in the automobile industry, military production, and communication equipment because of its fast charge-discharge rate, and high power density. Herein, carbon quantum dots modified and Y3+ doped Ni3(NO3)2(OH)4 (NiY@CQDs) nanospheres are prepared by a solvothermal method and used as an electrode material. The electrochemical properties of NiY@CQDs were measured in a three-electrode system. An asymmetric supercapacitor (ASC) cell was assembled with activated carbon (AC) as the anode and NiY@CQDs as the cathode. The electrochemical properties of the ASC device were measured in a two-electrode system. Experimental results show the shape of NiY@CQDs is petal-shaped and the introducing carbon quantum dots and doping Y3+ significantly increases the specific surface area, conductivity, and specific capacitance of Ni3(NO3)2(OH)4. The mass-specific capacitance of NiY@CQDs reaches up to 2944â F g-1 at a current density of 1â A g-1. The asymmetric supercapacitor of NiY@CQDs//AC has a high energy density of 138.65â Wh kg-1 at a power density of 1500â W kg-1, displaying a wide range of application prospects in the energy storage area.
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Herein, a CuNiFe LDHs/BiO2-x composite photocatalyst was successfully synthesized using a hydrothermal method and applied to activate peroxymonosulfate to degrade ciprofloxacin under visible light irradiation. Owing to the synergistic effect of photocatalysis and PMS activation, a high removal efficiency of CIP up to 88.3% was achieved. The prepared photocatalysts were characterized using XRD, FT-IR, SEM, XPS, UV-Vis DRS, and other methods. The optimal loading amount of CuNiFe LDHs was determined, and the effects of PMS dosage, initial pH value, and inorganic anions (Cl-, CO32-, and NO3-) on the degradation were investigated. Electron paramagnetic resonance and free radical trapping experiments demonstrated that·OH and h+ were the main active species for degrading CIP, and the possible degradation mechanism of the system was proposed.
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Type H vessels couple angiogenesis with osteogenesis, while sympathetic cues regulate vascular and skeletal function. The crosstalk between sympathetic nerves and type H vessels in bone remains unclear. Here, we first identify close spatial connections between sympathetic nerves and type H vessels in bone, particularly in metaphysis. Sympathoexcitation, mimicked by isoproterenol (ISO) injection, reduces type H vessels and bone mass. Conversely, beta-2-adrenergic receptor (ADRB2) deficiency maintains type H vessels and bone mass in the physiological condition. In vitro experiments reveal indirect sympathetic modulation of angiogenesis via paracrine effects of mesenchymal stem cells (MSCs), which alter the transcription of multiple angiogenic genes in endothelial cells (ECs). Furthermore, Notch signaling in ECs underlies sympathoexcitation-regulated type H vessel formation, impacting osteogenesis and bone mass. Finally, propranolol (PRO) inhibits beta-adrenergic activity and protects type H vessels and bone mass against estrogen deficiency. These findings unravel the specialized neurovascular coupling in bone homeostasis and regeneration.
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Molybdenum disulfide (MoS2) has been deemed as one of the promising noble-metal-free electrocatalysts for hydrogen evolution reaction (HER), but it suffers from the inert basal plane and low electronic conductivity. Regulating the morphology of MoS2during the synthesis on conductive substrates is a synergistic strategy for enhancing the HER performance. In this work, vertical MoS2nanosheets were fabricated on carbon cloth (CC) using an atmospheric pressure chemical vapor deposition method. The growth process could be effectively tuned through introducing hydrogen gas during vapor deposition process, resulting in nanosheets with increased edge density. The mechanism for edge-enriching through controlling the growth atmosphere is systematically studied. The as-prepared MoS2exhibits excellent HER activity due to the combination of optimized microstructures and coupling with CC. Our findings provide new insights to design advanced MoS2-based electrocatalysts for HER.
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Central nervous system (CNS) disorders exhibit complex neurophysiological and pathological mechanisms, which seriously affect the quality of life in patients. Acupuncture, widely accepted as complementary and alternative medicine, has been proven to exert significant therapeutic effects on CNS diseases. As a part of the innate immune system, NLRP3 inflammasome contributes to the pathogenesis of CNS diseases via regulating neuroinflammation. To further explore the mechanisms of acupuncture regulating NLRP3 inflammasome in CNS diseases, our study focused on the effects of acupuncture on neuroinflammation and the NLRP3 inflammasome in vascular dementia, Alzheimer's disease, stroke, depression, and spinal cord injury. This study confirmed that the activation of NLRP3 inflammasome promotes the development of CNS diseases, and inhibiting the activation of NLRP3 inflammasome is a potential key target for the treatment of CNS diseases. In addition, it is concluded that acupuncture alleviates neuroinflammation by inhibiting the activation of the NLRP3 inflammasome pathway, thereby improving the progression of CNS diseases, which provides a theoretical basis for acupuncture to attenuate neuroinflammation and improve CNS diseases.
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Macrocyclic retinoic acid receptor-related orphan receptor C2 (RORC2) inverse agonists have been designed with favorable properties for topical administration. Inspired by the unanticipated bound conformation of an acyclic sulfonamide-based RORC2 ligand from cocrystal structure analysis, macrocyclic linker connections between the halves of the molecule were explored. Further optimization of analogues was accomplished to maximize potency and refine physiochemical properties (MW, lipophilicity) best suited for topical application. Compound 14 demonstrated potent inhibition of interleukin-17A (IL-17A) production by human Th17 cells and in vitro permeation through healthy human skin achieving high total compound concentration in both skin epidermis and dermis layers.
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With the soaring number of multidrug-resistant bacteria, it is imperative to develop novel efficient antibacterial agents and discovery new antibacterial pathways. Herein, we designed and synthesized a series of structurally novel glycyrrhetinic acid (GA) derivatives against multidrug-resistant Staphylococcus aureus (MRSA). The in vitro antibacterial activity of these compounds was evaluated using the microbroth dilution method, agar plate coating experiments and real-time growth curves, respectively. Most of the target derivatives showed moderate antibacterial activity against Staphylococcus aureus (S. aureus) and MRSA (MIC = 3.125-25 µM), but inactivity against Escherichia coli (E. Coli) and Pseudomonas aeruginosa (P. aeruginosa) (MIC > 200 µM). Among them, compound 11 had the strongest antibacterial activity against MRSA, with an MIC value of 3.125 µM, which was 32 times and 64 times than the first-line antibiotics penicillin and norfloxacin, respectively. Additionally, transcriptomic (RNA-seq) and quantitative polymerase chain reaction (qPCR) analysis revealed that the antibacterial mechanism of compound 11 was through blocking the arginine biosynthesis and metabolic and the H2S biogenesis. Importantly, compound 11 was confirmed to have good biocompatibility through the in vitro hemolysis tests, cytotoxicity assays and the in vivo quail chicken chorioallantoic membrane (qCAM) experiments. Current study provided new potential antibacterial candidates from glycyrrhetinic acid derivatives for clinical treatment of MRSA infections.
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Antibacterianos , Arginina , Diseño de Fármacos , Ácido Glicirretínico , Staphylococcus aureus Resistente a Meticilina , Infecciones Estafilocócicas , Humanos , Antibacterianos/farmacología , Arginina/biosíntesis , Escherichia coli/efectos de los fármacos , Ácido Glicirretínico/análogos & derivados , Ácido Glicirretínico/farmacología , Staphylococcus aureus Resistente a Meticilina/efectos de los fármacos , Pruebas de Sensibilidad Microbiana , Staphylococcus aureus/efectos de los fármacos , Sulfuro de Hidrógeno/metabolismoRESUMEN
To understand the potential role of microglia in synaptic pruning following status epilepticus (SE), we examined the time course of expression of Iba-1, and immune and neuroinflammatory regulators, including CD86, CD206, and CX3CR1, and TLR4/NF-κB after SE induced by pilocarpine in rats. Behavioral tests, TUNEL (terminal deoxynucleotidyl transferase dUTP nick end labeling) staining, immunohistochemical staining, Western blotting, PCR, and fluorescence double staining assessments were performed. The expression of Iba-1 protein was lowest in the control group, and peaked after 2 days (p < 0.001). CD86 and CD206 mRNA levels increased gradually in the microglia of the epilepsy group after 12 hours, 1 day, 2 days, and 3 days; peak expression was on the second day. The expression of the chemokine receptor CX3CR1 in microglia increased to varying degrees after SE, and expression of the presynaptic protein synapsin decreased. The expression of TLR4/NF-κB in microglia positively correlated with Iba-1 protein expression. These findings indicate that the TLR4/NF-κB signaling pathway may be involved in the activation and polarization of microglia in epilepsy and in excess synaptic pruning, which could lead to an increase in brain injury.
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Epilepsia , Estado Epiléptico , Ratas , Animales , FN-kappa B/metabolismo , Microglía/metabolismo , Receptor Toll-Like 4/genética , Receptor Toll-Like 4/metabolismo , Epilepsia/inducido químicamente , Epilepsia/metabolismo , Transducción de Señal , Estado Epiléptico/inducido químicamente , Estado Epiléptico/metabolismoRESUMEN
Objective @#To investigate the histological damage recovery of temporomandibular joint condylar cartilage caused by chronic unpredictable moderate stress, aiming to provide an experimental basis for the prevention and treatment of temporomandibular disorder.@*Methods @#This animal experiment was approved by the Laboratory Animal Ethical Inspection, School of Stomatology, The Fourth Military Medical University (No. 2020081). 60 male SD rats were randomly divided into control group, stress group, and 2-, 4- and 8-week post-stress recovery groups. Rats were subjected to chronic unpredictable moderate stress (CUMS) for 8 weeks including damp sawdust for 24 hours, tilted cage for 12 hours, noise for 4 hours, light/dark cycle reversal, water immersion, tail clamp, and restraint stress. The serum assessment, behavioral tests, histological and ultrastructural observation were performed 2-, 4- and 8-weeks after stress factors were removed. Serum levels of adrenocorticotropic hormone (ACTH) and corticosterone (CORT) were determined with ELISA. The sucrose preference test (SPT) and the forced swim test (FST) were used to assess the depressive-like behavior. The expression level of interleukin-1α (IL-1α) and matrix metalloproteinases-3 (MMP-3) were determined by Immunohistochemistry and Western blot.@*Results @#At the end of 8 weeks of CUMS, the serum levels of CORT and ACTH were significantly higher in stress group compared with control group (P<0.01). The sucrose preference decreased significantly and the immobility time increased significantly in the stressed rats compared with those in the control group, indicating a successful establishment of CUMS. The condylar cartilage showed significant degenerative changes, with disorganized collagen fibers and reduced proteoglycan synthesis on the cartilage surface. IL-1α and MMP-3 were expressed in the intracellular and extracellular matrix of the condylar cartilage, and their expression levels were increased (P<0.01). After 2 weeks of stress removal, the serum levels of CORT and ACTH were decreased but higher than control group (P<0.01), and behavioral changes were still different from the control group (P<0.01); the loosened collagen fibers could still be seen on the surface of condylar cartilage, and some free cell areas were visible within the proliferative layer; additionally, IL-1α and MMP-3 expression in the condyle was reduced in all layers of cartilage when compared with the stress group, but was still higher than in the control group (P<0.01). After 4 weeks of stress removal, the serum levels of CORT and ACTH changes returned to normal levels and behavioral changes were still different from control group (P<0.05); a few collagen fibers could be seen on the surface of the condylar cartilage and the expressions of IL-1α and MMP-3 decreased significantly compared with the stress group (P<0.01), with the similar level of IL-1α (P>0.05) and higher expression of MMP-3 comparing with the control group (P<0.01). After 8 weeks of stress removal, behavioral changes returned to normal levels, with no statistically significant differences compared with the control group (P>0.05). The condylar collagen fibers increased and showed a corrugated pattern, and no serious subchondral bone damage as well as irreversible damage occurred. Both of the expression levels of IL-1α and MMP-3 approached those of the control group after 8 weeks of stress removal (P>0.05). @*Conclusion@# The behavioral changes and condylar cartilage damage caused by CUMS could be self-repaired. The decline in IL-1α and MMP-3 expression may be one of the intrinsic mechanisms of this self-repair process.
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Chronic rhinosinusitis (CRS) is a highly heterogeneous disease characterized by inflammation in the nasal and sinus mucosa. The CRS phenotypes, based on the presence or absence of nasal polyps, are known as CRS with nasal polyps (CRSwNP) and CRS without nasal polyps (CRSsNP). However, this classification has limitations in fully capturing the mechanisms and clinical manifestations of CRS. To address the heterogeneity of CRS, there has been a growing focus on classifying the condition into distinct endotypes. Endotype classification involves grouping patients based on specific molecular, immunological, and clinical characteristics, allowing for more personalized and targeted treatment approaches.This review delves into the current state of endotype classifications for CRS. It explores the role of geographic factors, microbiome, and subphenotype in shaping different endotypes. Additionally, the review examines how various clinical features are associated with specific endotypes, providing valuable insights into tailoring treatment options for better outcomes and transitions between different endotypes.Overall, this review offers a comprehensive and up-to-date perspective on the intricate realm of CRS endotype classifications. By unraveling the molecular and clinical intricacies, this review lays the foundation for more precise, effective, and individualized treatment strategies in the management of CRS.
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Pólipos Nasales , Rinitis , Rinosinusitis , Sinusitis , Humanos , Rinitis/terapia , Sinusitis/terapia , Inflamación , Enfermedad CrónicaRESUMEN
A quantum gas microscope plays an important role in cold-atom experiments, which provides a high-resolution imaging of the spatial distributions of cold atoms. Here we design, build and calibrate an integrated microscope for quantum gases with all the optical components fixed outside the vacuum chamber. It provides large numerical aperture (NA) of 0.75, as well as good optical access from side for atom loading in cold-atom experiments due to long working distance (7 mm fused silica+6 mm vacuum) of the microscope objective. We make a special design of the vacuum viewport with a T-shape window, to suppress the window flatness distortion introduced by the metal-glass binding process, and protect the high-resolution imaging from distortions due to unflattened window. The achieved Strehl ratio is 0.9204 using scanning-near-field microscopy (SNOM) fiber coupling incoherent light as point light source.
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Background: Controlled hypotension technique was usually used to reduce intraoperative bleeding, and it could improve visualization of the surgical field during total knee arthroplasty (TKA). However, inappropriate controlled hypotension, through reducing cerebral blood flow or cerebral perfusion pressure, may cause postoperative cognitive dysfunction (POCD), so it is important to identify the appropriate level of controlled hypotension. Objective: To investigate the effects of different levels of controlled hypotension on regional cerebral oxygen saturation and postoperative cognitive function in patients undergoing TKA. Methods: Patients meeting inclusion criteria were enrolled through preoperative visits and basic information was obtained. The patients were randomly divided into three groups: Group A, MAP was maintained at 90-100% of the baseline; Group B, MAP was maintained at 80-90% of the baseline; Group C, MAP was maintained at 70-80% of the baseline. The MAP, HR, and rSO2 were observed and recorded during the operation. The C-reactive protein (CRP), hemoglobin (Hb) and MMSE score at 1, 3, and 7 days after operation were recorded. SPSS25.0 was used for data analysis. Result: When the MAP had a decrease among the three groups, rSO2 did not decrease significantly, and none of the patients experienced POCD which was measured by MMSE. And there was no correlation between the decline in rSO2 and that in MAP. Conclusion: No POCD was experienced in the three groups, and we recommend that the controlled hypotensive target indicated by MAP was maintained at 70-80% of the baseline which not only decreases intraoperative bleeding and improve the quality of the surgical field, but also is still within safe levels.
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Developing low-cost, environmentally friendly and efficient non-precious metal electrocatalysts as alternatives to noble metals for the hydrogen evolution reaction (HER) is highly essential for the sustainable advancement of green hydrogen energy. Herein, a novel heterostructured Ni3P/Ni nanoparticle anchored in nitrogen-doped mesoporous carbon nanofibers (Ni3P/Ni@N-CNFs) is prepared by a facile solid-phase calcination protocol. The results demonstrated that benefiting from the intensive electronic coupling effect at the interface of the Ni3P/Ni heterostructure, the electron configuration of the Ni active site is optimized and thus the favorable HER activity. Furthermore, the N-doped carbon nanofiber scaffold with an extensive mesoporous structure endows Ni3P/Ni@N-CNFs with abundant electrochemically active sites together with excellent conductivity and stability, contributing to fast electron/mass transport. As expected, the resultant Ni3P/Ni@N-CNF electrocatalyst exhibited exceptional HER catalytic properties under universal pH conditions, driving a current density of 10 mA cm-2 at pretty low overpotentials of 121 mV, 145 mV and 187 mV in acidic, basic and neutral solutions, respectively, and retaining the catalytic stability for over 60 h. This intriguing work represents a fresh perspective for designing and exploiting highly advanced phosphide electrocatalysts for green hydrogen fuel production.
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Lipotoxicity and unresolved oxidative stress are key drivers of metabolic inflammation in nonalcoholic steatohepatitis (NASH). cAMP-response element binding protein H(CREBH) is a liver-specific transcription factor and regulates the glucose and lipid metabolism of NASH. However, its role in mitochondrial oxidative stress and its association with sirtuin 3 (SIRT3), a master regulator of deacetylation for mitochondrial proteins, remains elusive. In this study, AML-12 cells were treated with palmitic acid to imitate the pathological changes of NASH in vitro and 8-week-old male C57BL/6J mice were fed with a high-fat (HF) diet or a methionine-choline-deficient (MCD) diet to build the widely accepted in vivo model of NASH. We found that lipid overload induced mitochondrial oxidative stress and stimulated the expression of CREBH and SIRT3. CREBH overexpression alleviated the mitochondrial oxidative stress. Moreover, CREBH promoted SIRT3 expression, which regulated the deacetylation of manganese superoxide dismutase (MnSOD) and inhibited NOD-Like Receptor Pyrin Domain Containing 3 (Nlrp3) inflammasome activation whereas suppression of SIRT3 damaged the protecting ability of CREBH in mitochondrial oxidative stress. CREBH knockout mice were highly susceptible to HF and MCD diet-induced NASH with more severe oxidative stress. Collectively, our results firstly provided the support that CREBH could serve as a protective factor in the progression of NASH by regulating the acetylation of MnSOD and the activation of Nlrp3 inflammasome through SIRT3. These results suggest that CREBH might be a valuable therapeutic candidate for NASH.
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Proteína de Unión a Elemento de Respuesta al AMP Cíclico/metabolismo , Enfermedad del Hígado Graso no Alcohólico , Sirtuina 3 , Animales , Inflamasomas/genética , Inflamasomas/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Proteína con Dominio Pirina 3 de la Familia NLR/genética , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Enfermedad del Hígado Graso no Alcohólico/genética , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Estrés Oxidativo , Sirtuina 3/genética , Sirtuina 3/metabolismo , Superóxido Dismutasa/genética , Superóxido Dismutasa/metabolismoRESUMEN
Background: Hereditary hypomagnesemia with secondary hypocalcemia (HSH) is a rare autosomal recessive disease due to biallelic TRPM6 mutations. Although the reports of HSH caused by TRPM6 mutations are not very rare, the age of onset in previously reported HSH cases were <1 year. Methods: We collected and analyzed the clinical data of twin brothers with onset age over 1 year old and performed whole exome sequencing in the patients and their parents. Confirmed by Sanger sequencing, missense mutation was analyzed in silico. We also searched Pubmed, and extracted clinical data from case reports and case series with full text in English, reporting original data of patients with TRPM6 mutations. Results: The twin patients had canonical HSH phenotype with compound novel TRPM6 mutations, p.T87K and c.705dupT, inherited from their father and mother, respectively. T87 is a highly conserved site and T87K is predicted to cause hydrogen bond disruption. We identified 26 articles published between May 28, 2002 to December 31, 2021 which reported a total of 88 patients with TRPM6 mutation. We found that the most common clinical phenotypes were hypomagnesemia, hypocalcemia, and convulsions. However, the age of onset in HSH patients almost always occurred under 12 months old, the twin patients of our study were 18 and 26 months old at onset. Conclusion: We identified two novel TRPM6 mutations in a Chinses family with HSH, and showed that the age of onset with c.704c-c.705(exon7)insT and c.260(exon4)C>A mutation in TRPM6 was much later than other mutations and would be much less serious.