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1.
Chem Sci ; 2024 Sep 16.
Article in English | MEDLINE | ID: mdl-39360013

ABSTRACT

The century-old inverted Keggin ion has been revisited in an effort to unleash its potential in the structural engineering and functional development of polyoxomolybdates (POMos). Over the past hundred years, attempts to program the metal-oxo scaffold of inverted Keggins have been conducted continually but without any success. In this work, a structurally inert, inverted Keggin-type POMo could finally be altered by means of a binary heterogroup-templated approach, resulting in the successful isolation of two lacunary species. The local structure and charge distribution of these species are adjustable, and hence they serve as available building blocks for the subsequent controlled assembly of a CeIII-incorporated derivative. From the plenary to the lacunary, the enclosed structure of the inverted Keggin has been opened up significantly, resulting in less steric hindrance, along with a transition from an electron neutral species to a negatively charged species. Owing to these beneficial properties, the emerging defect-containing polyanions demonstrated outstanding Lewis acid-base catalytic activity in the high efficiency production of pyrazoles.

2.
Int J Surg ; 2024 Sep 12.
Article in English | MEDLINE | ID: mdl-39264581

ABSTRACT

BACKGROUND: Oncoplastic breast-conserving surgery (OBCS) improves satisfaction in patients who would fare otherwise sub-optimal cosmetic outcome, while brings challenge in tumor-bed identification during adjuvant radiotherapy. The ultra-hypofractionated breast radiotherapy further shortens treatment sessions from moderately hypofractionated regimens. To circumscribe the difficulty in tumor-bed contouring and the additional toxicity from larger boost volumes, we propose to move forward the boost session preoperatively from the adjuvant radiation part. Thus, the present study aims to evaluate the feasibility of a new treatment paradigm of preoperative primary-tumor boost before breast-conserving surgery (BCS) or OBCS followed by adjuvant ultra-hypofractionated whole-breast irradiation (u-WBRT) for patients with early-stage breast cancer. METHODS: There was a phase II study. Patients younger than 55 years old, with a biopsy confirmed mono-centric breast cancer, without lymph node involvement were enrolled. Preoperative primary-tumor boost was given by a single 10 Gy in 1 fraction, and BCS or OBCS was conducted within two weeks afterwards. Adjuvant u-WBRT (26 Gy/5.2 Gy/5 f) was given in 6 weeks postoperatively without any boost, after the full recovery from surgery. Surgical complications and patient-reported outcomes, as assessed via Breast-Q questionnaires, were documented. A propensity score matching approach was employed to identify a control group at a 1:1 ratio for BREAST-Q outcomes comparison. RESULTS: From May 2022 to September 2023, 36 patients were prospectively enrolled. Surgical complications were observed in 7 cases (19.4%), including 3 cases with Clavien-Dindo (CD) grade 1-2 and 4 cases with CD grade 3 complications. All but four patients (11.1%) started the planned u-WBRT within one week after the pre-defined due dates postoperatively (≤49 d). Four patients (11.1%) developed grade 2 radiodermatitis after chemotherapy initiation. Compared to the study group, the control patients reported higher scores in chest physical well-being (P=0.045) and in their attitudes towards arm swelling (P=0.01). No significant difference was detected in the other of domains (Satisfaction with Breasts, Sexual and Psychosocial Well-Being, and Adverse Effects of Radiation). With a median follow-up period of 9.8 months (2.4-18.9 mo), none had any sign of relapse. CONCLUSION: This Phase II clinical trial confirmed the technical and safety feasibility of novel radiation schedule in patients undergoing BCS or OBCS. According to the BREAST-Q questionnaire, patients who underwent novel radiation schedules reported lower satisfaction in chest physical well-being. A randomized controlled trial is necessary to further investigate these findings. Additionally, long-term follow-up is required to assess oncological outcomes.

3.
Adv Radiat Oncol ; 9(10): 101589, 2024 Oct.
Article in English | MEDLINE | ID: mdl-39309703

ABSTRACT

Purpose: The Audiovisual-Assisted Therapeutic Ambience in Radiotherapy (AVATAR) trial was a prospective multicenter study (NCT03991156) examining the combination of video immersion with radiation therapy and was successfully conducted through the collaboration of pediatric radiation oncology teams at 10 institutions independent of any pre-existing consortium. We sought to analyze and report the methodology of trial conception and development, process map, and cost. Methods and Materials: The study enrolled patients aged 3 to 10 years preparing to undergo radiation therapy, integrated the combination of AVATAR-based video immersion with radiation therapy at each institution, and offered AVATAR use as an alternative to anesthesia, with rates of anesthesia use and outcomes of serial standardized anxiety and quality-of-life assessments assessed among the 81 children enrolled. A process map was created based on the trial timeline with the following components: study development time (time from conception of the trial to the accrual of the first patient, including design phase, agreement and approval phase, and site preparation phase), and accrual duration time (time from the first to last accrual). Costs and institutional success rates were calculated. Results: Time from inception of study to last accrual was 3.6 years (1313 days). The study development time was 417 days (31.7%), and accrual duration time was 896 days (68.3%), with the final 50% of accrual occurring in <6 months. Equipment cost was approximately $550 per institution and was covered by funding from the lead study institution. All 10 centers were successful with AVATAR implementation, defined as ≥50% of patients able to avoid anesthesia with the use of AVATAR, including centers with both photon and proton therapy. Conclusions: This report elaborates on the methodology and timeline of trial conception and development using data from a previously published supportive care study combining video immersion with radiation therapy among 10 cooperating pediatric oncology institutions. It highlights the potential for multicenter collaborations on prospective trials integrating supportive care therapies with radiation therapy.

4.
Biomed Pharmacother ; 180: 117471, 2024 Sep 24.
Article in English | MEDLINE | ID: mdl-39321515

ABSTRACT

BACKGROUND: Evasion of pyroptosis is an effective survival strategy employed by cancer cells to evade immune cell attacks and drug-induced cytotoxicity. Exploring potent molecules capable of inducing pyroptosis in cancer cells has significant clinical implications for the control of cancer progression. Unexpectedly, we found that the local anesthetic tetracaine hydrochloride (TTC) induced pyroptosis, specifically in uveal melanoma but not in acral or cutaneous melanoma. METHODS: We investigated the effects of TTC on various melanoma cell lines and performed transcriptome sequencing of TTC-treated uveal melanoma cells. The role of gasdermin E (GSDME), an executive protein responsible for pyroptosis, was explored using CRISPR-Cas13d knockdown, caspase-3 inhibitor treatment, and western blot analysis. Differential gene expression and pathway enrichment analyses were performed. Furthermore, we used tissue microarrays to assess GSDME expression levels in melanoma tissues from different anatomical sites. RESULTS: TTC significantly induced pyroptosis specifically in uveal melanoma cells with high GSDME expression levels. TTC treatment could lead to GSDME cleavage by the caspase-3 in uveal melanoma C918 cells. GSDME knockdown or caspase-3 inhibition suppressed TTC-induced pyroptosis. Transcriptome analysis revealed differentially expressed genes enriched in signaling pathways related to pyroptosis, immunity, and cytokines. CONCLUSIONS: This study showed that the local anesthetic TTC effectively induces pyroptosis in uveal melanoma through the caspase-3/GSDME pathway, highlighting its potential application in immunotherapy. Notably, the use of TTC has potential as an agent for inducing pyroptosis and as an adjuvant anticancer therapy in uveal melanoma.

5.
Aging Dis ; 2024 Sep 25.
Article in English | MEDLINE | ID: mdl-39325938

ABSTRACT

Fibronectin (FN) can bind to certain integrin receptors on the cell surface through short peptide sequences, thereby transmitting extracellular stimuli to intracellular effector molecules. FNDC4 plays a similar role due to the constitution of a type III FN domain, which is a binding site for DNA, heparin, or cell surface. It mainly functions as a signal transmitter after being cleaved and secreted as the extracellular N-terminal fibronectin type III domain (sFNDC4). Emerging studies have shown that FNDC4 plays crucial roles in numerous diseases and holds significant implications for guiding clinical treatment. This review aims to summarize the different roles and the latest advances of FNDC4 in the development of various diseases, in order to provide new ideas for clinical treatment.

6.
Cell Biol Toxicol ; 40(1): 81, 2024 Sep 19.
Article in English | MEDLINE | ID: mdl-39297891

ABSTRACT

Tetracaine, a local anesthetic, exhibits potent cytotoxic effects on multiple cancer; however, the precise underlying mechanisms of its anti-cancer activity remain uncertain. The anti-cancer activity of tetracaine was found to be the most effective among commonly used local anesthetics in this study. After tetracaine treatment, the differentially expressed genes in melanoma cells were identified by the RNAseq technique and enriched in the lysosome signaling pathway, cullin family protein binding, and proteasome signaling pathway through Kyoto Encyclopedia of Genes and Genomes. Additionally, the ubiquitin-like neddylation signaling pathway, which is hyperactivated in melanoma, could be abrogated due to decreased NAE2 expression after tetracaine treatment. The neddylation of the pro-oncogenic Survivin, which enhances its stability, was significantly reduced following treatment with tetracaine. The activation of neddylation signaling by NEDD8 overexpression could reduce the antitumor efficacy of tetracaine in vivo and in vitro. Furthermore, vemurafenib-resistant melanoma cells showed higher level of neddylation, and potential substrate proteins undergoing neddylation modification were identified through immunoprecipitation and mass spectrometry. The tetracaine treatment could reduce drug resistance via neddylation signaling pathway inactivation in melanoma cells. These findings demonstrate that tetracaine effectively inhibits cell proliferation and alleviates vemurafenib resistance in melanoma by suppressing the neddylation signaling pathway, providing a promising avenue for controlling cancer progression.


Subject(s)
Cell Proliferation , Drug Resistance, Neoplasm , Melanoma , Signal Transduction , Tetracaine , Vemurafenib , Melanoma/drug therapy , Melanoma/metabolism , Melanoma/pathology , Melanoma/genetics , Humans , Cell Proliferation/drug effects , Cell Line, Tumor , Signal Transduction/drug effects , Vemurafenib/pharmacology , Drug Resistance, Neoplasm/drug effects , Animals , Tetracaine/pharmacology , NEDD8 Protein/metabolism , NEDD8 Protein/genetics , Mice , Mice, Nude , Antineoplastic Agents/pharmacology
7.
Cell Commun Signal ; 22(1): 389, 2024 Aug 05.
Article in English | MEDLINE | ID: mdl-39103830

ABSTRACT

Modern human society is burdened with the pandemic of cardiovascular and metabolic diseases. Metrnl is a widely distributed secreted protein in the body, involved in regulating glucose and lipid metabolism and maintaining cardiovascular system homeostasis. In this review, we present the predictive and therapeutic roles of Metrnl in various cardiovascular and metabolic diseases, including atherosclerosis, ischemic heart disease, cardiac remodeling, heart failure, hypertension, chemotherapy-induced myocardial injury, diabetes mellitus, and obesity.


Subject(s)
Biomarkers , Cardiovascular Diseases , Metabolic Diseases , Humans , Metabolic Diseases/metabolism , Metabolic Diseases/drug therapy , Cardiovascular Diseases/metabolism , Biomarkers/metabolism , Animals
8.
Proc Inst Mech Eng H ; 238(8-9): 897-908, 2024.
Article in English | MEDLINE | ID: mdl-39180409

ABSTRACT

The selection of internal fixation as the primary fixation modality for the patient is one of the challenges for the surgeon treating the patient in question. A model of the lateral tibial plateau fracture was established. Three different configurations of internal fixators namely L bone plate, T bone plate, and screw-washer were analyzed. Three stages after surgery were simulated to assess the displacement of bone plates, screws, washers, and the stress shielding ratio in the fracture area.At three stages after surgery, the T bone plate showed better stability for patients during rehabilitation compared with the remaining two schemes, and the screw-washer scheme was the least stable due to the larger internal fixation displacement and stress shielding ratio in the fracture area. In contrast, the L bone plate scheme showed better stability in the early stages after surgery but was second only to the screw-washer scheme in the middle and late stages after surgery. The T bone plate showed better stability and became a new selection for surgeons to treat related patients. At three stages after surgery, the T bone plate has better biomechanical stability compared to the L bone plate and screw-washer schemes.


Subject(s)
Bone Plates , Fracture Fixation, Internal , Tibial Fractures , Fracture Fixation, Internal/instrumentation , Fracture Fixation, Internal/methods , Tibial Fractures/surgery , Tibial Fractures/physiopathology , Biomechanical Phenomena , Humans , Mechanical Phenomena , Bone Screws , Finite Element Analysis , Stress, Mechanical , Mechanical Tests , Tibial Plateau Fractures
9.
Zhongguo Gu Shang ; 37(7): 649-54, 2024 Jul 25.
Article in Chinese | MEDLINE | ID: mdl-39104064

ABSTRACT

OBJECTIVE: To explore the clinical efficacy of double beam double tunnel enhanced reconstruction technique in the treatment of knee anterior cruciate ligament(ACL) training injuries. METHODS: Twenty-nine cases of ACL injury of knee joint from January 2021 to December 2021 were retrospectively analyzed. All the cases were underwent ligament reconstruction surgery. Cases were grouped by surgical technique:there were 14 patients in conventional reconstruction group, including 13 males and 1 female, aged from 22 to 31 years old with an average of (27.07±7.28) years old, autogenous hamstring tendon was used for ligament reconstruction. There were 15 patients in the enhanced reconstruction group, including 13 males and 2 females, aged from 25 to 34 years old with an average of (29.06±4.23) years old, double tunnel ligament reconstruction, the autogenous hamstring muscle was used as the anteromedial bundle, and the posterolateral bundle was replaced by a high-strength line. The difference between knee tibial anterior distance, Lysholm score, International Knee Literature Committee (IKDC) subjective score, Tegner motor level score and visual analog scale (VAS) at 6th and 12th months after the surgery, limb symmetry index (LSI) were recorded at the last follow-up and surgery-related adverse effects during follow-up. RESULTS: All patients were followed up, ranged from 13 to 15 months with an average of (13.7±0.8) months. There were no serious adverse reactions related to surgery during the period. There was no statistical difference between the preoperative general data and the observation index of the two groups (P>0.05). The difference in tibial anterior distance at 6 and 12 months in the enhanced reconstruction group (1.45±0.62) mm and (1.74±0.78) mm which were lower those that in the conventional reconstruction group (2.42±0.60) mm and (2.51±0.63) mm(P<0.05). There was no significant difference in postoperative Lysholm score, Tegner motor level score, IKDC score, VAS, and limb symmetry index at the last follow-up(P>0.05). CONCLUSION: The enhanced reconstruction technique can more effectively maintain the stability of the knee joint and has no significant effect on the postoperative knee joint function compared with the traditional ligament reconstruction technique. The short-term curative effect is satisfactory, and it is suitable for the group with high sports demand.


Subject(s)
Anterior Cruciate Ligament Injuries , Anterior Cruciate Ligament Reconstruction , Humans , Male , Female , Adult , Anterior Cruciate Ligament Reconstruction/methods , Anterior Cruciate Ligament Injuries/surgery , Young Adult , Retrospective Studies , Treatment Outcome
10.
Article in English | MEDLINE | ID: mdl-39207296

ABSTRACT

Solar-driven interface desalination has emerged as a promising strategy to address the global freshwater shortage crisis. However, the separation and recovery of multicomponent oil-contaminated seawater remain a key challenge. This study reports a novel high-strength Janus photothermal membrane with a unique reverse wettability design. On one side, the membrane has hydrophilic and oleophobic properties, while on the other, it has hydrophobic and oleophilic characteristics. The Janus membrane demonstrates dual functionality: solar desalination and oil-water separation. This dual functionality enables efficient separation and recovery of four components from contaminated seawater: purified water, salt crystals, light oil, and heavy oil. As a result, the Janus membrane achieves an evaporation rate of 2.06 kg m-2 h-1 under 1.0 sun. The ion (Na+, K+, Ca2+, and Mg2+) removal rate approaches 100% with nearly complete recovery of salt crystals. Furthermore, various types of oils can be accurately separated, with separation efficiency approaching 100%. An integrated separation device successfully separates and recovers the four components. This research presents significant potential for efficient separation and recovery of complex components in oil-contaminated seawater.

11.
Angew Chem Int Ed Engl ; 63(41): e202407928, 2024 Oct 07.
Article in English | MEDLINE | ID: mdl-39022842

ABSTRACT

Although highly appealing for rapid access of molecular complexity, multi-functionalization of alkenes that allows incorporation of more than two functional groups remains a prominent challenge. Herein, we report a novel strategy that merges dipolar cycloaddition with photoredox promoted radical ring-opening remote C(sp3)-H functionalization, thus enabling a smooth 1,2,5-trifunctionalization of unactivated alkenes. A highly regioselective [3+2] cycloaddition anchors a reaction trigger onto alkene substrates. The subsequent halogen atom transfer (XAT) selectively initiates ring-opening process, which is followed by a series of 1,5-hydrogen atom transfer (1,5-HAT) and intermolecular fluorine atom transfer (FAT) events. With this method, site-selective introduction of three different functional groups is accomplished and a broad spectrum of valuable ß-hydroxyl-ϵ-fluoro-nitrile products are synthesized from readily available terminal alkenes.

12.
Adv Mater ; 36(36): e2404763, 2024 Sep.
Article in English | MEDLINE | ID: mdl-39051514

ABSTRACT

Collaborative perception between a vehicle and the road has the potential to enhance the limited perception capability of autonomous driving technologies. With this background, self-powered vehicle-road integrated electronics (SVRIE) with a multilevel fractal structure is designed to play a dual role, including a SVRIE device integrated into vehicle tires and a SVRIE array embedded into a road surface. The pressure sensing capability and anti-crosstalk performance of the SVRIE array are characterized separately to validate the feasibility of applying the SVRIE in a cooperative vehicle-infrastructure system. It is demonstrated that the SVRIE based on the multi-layered fractal structure exhibits maximum performance in collaborative sensing and interaction between vehicles and road information, such as vehicle motion, road surface condition, and tire life cycle health monitoring. Traditional data analysis methods are often of questionable accuracy. Therefore, a convolutional neural network is used to classify the vehicle and road conditions with accuracy of at least 88.3%. The transfer learning model is constructed to enhance the road surface identification capabilities with 100% accuracy. The accuracies of the vehicle tire motion recognition and tire health monitoring are 97% and 99%, respectively. This work provides new ideas for collaborative perception between vehicles and roadsides.

13.
Prog Neurobiol ; 240: 102656, 2024 Sep.
Article in English | MEDLINE | ID: mdl-39009108

ABSTRACT

The orientation map is one of the most well-studied functional maps of the visual cortex. However, results from the literature are of different qualities. Clear boundaries among different orientation domains and blurred uncertain distinctions were shown in different studies. These unclear imaging results will lead to an inaccuracy in depicting cortical structures, and the lack of consideration in experimental design will also lead to biased depictions of the cortical features. How we accurately define orientation domains will impact the entire field of research. In this study, we test how spatial frequency (SF), stimulus size, location, chromatic, and data processing methods affect the orientation functional maps (including a large area of dorsal V4, and parts of dorsal V1) acquired by intrinsic signal optical imaging. Our results indicate that, for large imaging fields, large grating stimuli with mixed SF components should be considered to acquire the orientation map. A diffusion model image enhancement based on the difference map could further improve the map quality. In addition, the similar outcomes of achromatic and chromatic gratings indicate two alternative types of afferents from LGN, pooling in V1 to generate cue-invariant orientation selectivity.


Subject(s)
Brain Mapping , Visual Cortex , Visual Cortex/physiology , Visual Cortex/diagnostic imaging , Brain Mapping/methods , Animals , Photic Stimulation/methods , Orientation/physiology , Humans , Visual Pathways/physiology , Visual Pathways/diagnostic imaging , Male
14.
Small ; : e2400569, 2024 Jul 24.
Article in English | MEDLINE | ID: mdl-39046127

ABSTRACT

Solar thermal utilization has broad applications in a variety of fields. Currently, maximizing the photo-thermal conversion efficiency remains a research hotspot in this field. The exquisite plant structures in nature have greatly inspired human structural design across many domains. In this work, inspired by the photosynthesis of helical grass, a HM type solar absorber made in graphene-based composite sheets is used for solar thermal conversion. The unique design promoted more effective solar energy into thermal energy through multiple reflections and scattering of solar photons. Notably, the Helical Micropillar (HM) is fabricated using a one-step projection 3D printing process based on a special 3D helical beam. As a result, the solar absorber's absorbance value can reach 0.83 in the 400-2500 nm range, and the surface temperature increased by ≈128.3% relative to the original temperature. The temperature rise rate of the solar absorber reached 22.4 °C min-1, demonstrating the significant potential of the HM in practical applications of solar thermal energy collection and utilization.

15.
Front Immunol ; 15: 1403752, 2024.
Article in English | MEDLINE | ID: mdl-38975343

ABSTRACT

Type 1 diabetes (T1D) arises from autoimmune-mediated destruction of insulin-producing pancreatic beta cells. Recent advancements in the technology of generating pancreatic beta cells from human pluripotent stem cells (SC-beta cells) have facilitated the exploration of cell replacement therapies for treating T1D. However, the persistent threat of autoimmunity poses a significant challenge to the survival of transplanted SC-beta cells. Genetic engineering is a promising approach to enhance immune resistance of beta cells as we previously showed by inactivating the Renalase (Rnls) gene. Here, we demonstrate that Rnls loss of function in beta cells shapes autoimmunity by mediating a regulatory natural killer (NK) cell phenotype important for the induction of tolerogenic antigen-presenting cells. Rnls-deficient beta cells mediate cell-cell contact-independent induction of hallmark anti-inflammatory cytokine Tgfß1 in NK cells. In addition, surface expression of regulatory NK immune checkpoints CD47 and Ceacam1 is markedly elevated on beta cells deficient for Rnls. Altered glucose metabolism in Rnls mutant beta cells is involved in the upregulation of CD47 surface expression. These findings are crucial to better understand how genetically engineered beta cells shape autoimmunity, giving valuable insights for future therapeutic advancements to treat and cure T1D.


Subject(s)
Autoimmunity , Diabetes Mellitus, Type 1 , Insulin-Secreting Cells , Killer Cells, Natural , Killer Cells, Natural/immunology , Killer Cells, Natural/metabolism , Animals , Insulin-Secreting Cells/immunology , Insulin-Secreting Cells/metabolism , Mice , Diabetes Mellitus, Type 1/immunology , Humans , CD47 Antigen/metabolism , CD47 Antigen/genetics , CD47 Antigen/immunology , Transforming Growth Factor beta1/metabolism , Mice, Inbred NOD , Monoamine Oxidase
16.
Nat Commun ; 15(1): 6102, 2024 Jul 19.
Article in English | MEDLINE | ID: mdl-39030211

ABSTRACT

Visible-light photocatalysis has evolved as a powerful technique to enable controllable radical reactions. Exploring unique photocatalytic mode for obtaining new chemoselectivity and product diversity is of great significance. Herein, we present a photo-induced chemoselective 1,2-diheteroarylation of unactivated alkenes utilizing halopyridines and quinolines. The ring-fused azaarenes serve as not only substrate, but also potential precursors for halogen-atom abstraction for pyridyl radical generation in this photocatalysis. As a complement to metal catalysis, this photo-induced radical process with mild and redox neutral conditions assembles two different heteroaryl groups into alkenes regioselectively and contribute to broad substrates scope. The obtained products containing aza-arene units permit various further diversifications, demonstrating the synthetic utility of this protocol. We anticipate that this protocol will trigger the further advancement of photo-induced alkyl/aryl halides activation.

17.
Phys Eng Sci Med ; 2024 Jul 15.
Article in English | MEDLINE | ID: mdl-39008261

ABSTRACT

An improved Finite Element Model(FEM) is applied to compare the biomechanical stability of plates with three different options in the treatment of distal fibula fractures in this study. The Computed Tomography(CT) scan of the knee to ankle segment of a volunteer was performed. A 3D fibula FEM was reconstructed based on the CT data. Three different loads (uni-pedal standing, torsion, and twisting) were applied, the same as in the experiments in the literature. The stresses and strains of the three options were compared under the same loads, using a 4-hole locking plate (Option A), a 5-hole locking plate (Option B), and a 6-hole locking plate (Option C) in a standard plate for lateral internal fixation. The simulation results show that all three options showed a stress masking effect. Option C had the best overall biomechanical performance and could effectively distribute the transferred weight. This is because option C has greater torsional stiffness and better biomechanical stability than options A and B, and therefore, option C is the recommended internal fixation method for distal fibula fractures. The Finite Element Analysis(FEA) method developed in this work applies to the stress analysis of fracture treatment options in other body parts.

18.
bioRxiv ; 2024 Jun 13.
Article in English | MEDLINE | ID: mdl-38915698

ABSTRACT

Renalase (Rnls), annotated as an oxidase enzyme, is a GWAS gene associated with Type 1 Diabetes (T1D) risk. We previously discovered that Rnls inhibition delays diabetes onset in mouse models of T1D in vivo , and protects pancreatic ß cells against autoimmune killing, ER and oxidative stress in vitro . The molecular biochemistry and functions of Rnls are entirely uncharted. Here we find that Rnls inhibition defends against loss of ß cell mass and islet dysfunction in chronically stressed Akita mice in vivo . We used RNA sequencing, untargeted and targeted metabolomics and metabolic function experiments in mouse and human ß cells and discovered a robust and conserved metabolic shift towards glycolysis, amino acid abundance and GSH synthesis to counter protein misfolding stress, in vitro . Our work illustrates a function for Rnls in mammalian cells, and suggests an axis by which manipulating intrinsic properties of ß cells can rewire metabolism to protect against diabetogenic stress.

19.
Biochem Biophys Res Commun ; 723: 150220, 2024 Sep 03.
Article in English | MEDLINE | ID: mdl-38850811

ABSTRACT

Aging is characterized as the process of functional decline in an organism from adulthood, often marked by a progressive loss of cellular function and systemic deterioration of multiple tissues. Among the numerous molecular, cellular, and systemic hallmarks associated with aging, mitochondrial dysfunction is considered one of the pivotal factors that initiates the aging process. During aging, mitochondria undergo varying degrees of damage, resulting in impaired energy production and disruption of the homeostatic regulation of mitochondrial quality control systems, which in turn affects cellular energy metabolism and results in cellular dysfunction, accelerating the aging process. AMP-activated protein kinase (AMPK) and the mechanistic target of rapamycin complex 1 (mTORC1) are two central kinase complexes responsible for sensing intracellular nutrient levels, regulating metabolic homeostasis, modulating aging and play a crucial role in maintaining the homeostatic balance of mitochondria. Our previous studies found that the novel compound tetramethylpyrazine nitrone (TBN) can protect mitochondria via the AMPK/mTOR pathway in many animal models, extending healthy lifespan through the Nrf2 signaling pathway in nematodes. Building upon this foundation, we have posited a reasonable hypothesis, TBN can improve mitochondrial function to delay aging by regulating the AMPK/mTORC1 signaling pathway. This study focuses on the C. elegans, exploring the impact and underlying mechanisms of TBN on aging and mitochondrial function (especially the mitochondrial quality control system) during the aging process. The present studies demonstrated that TBN extends lifespan of wild-type nematodes and is associated with the AMPK/mTORC1 signaling pathway. TBN elevated ATP and NAD+ levels in aging nematodes while orchestrating mitochondrial biogenesis and mitophagy. Moreover, TBN was observed to significantly enhance normal activities during aging in C. elegans, such as mobility and pharyngeal pumping, concurrently impeding lipofuscin accumulation that were closely associated with AMPK and mTORC1. This study not only highlights the delayed effects of TBN on aging but also underscores its potential application in strategies aimed at improving mitochondrial function via the AMPK/mTOR pathway in C. elegans.


Subject(s)
AMP-Activated Protein Kinases , Aging , Caenorhabditis elegans , Mechanistic Target of Rapamycin Complex 1 , Mitochondria , Pyrazines , Signal Transduction , Animals , Caenorhabditis elegans/metabolism , Caenorhabditis elegans/drug effects , Mechanistic Target of Rapamycin Complex 1/metabolism , Pyrazines/pharmacology , Mitochondria/metabolism , Mitochondria/drug effects , Signal Transduction/drug effects , AMP-Activated Protein Kinases/metabolism , Aging/metabolism , Aging/drug effects , Caenorhabditis elegans Proteins/metabolism , Caenorhabditis elegans Proteins/genetics , Nitrogen Oxides/metabolism
20.
Insects ; 15(6)2024 Jun 05.
Article in English | MEDLINE | ID: mdl-38921140

ABSTRACT

Death-associated protein-1 (DAP-1) plays a crucial role in cell growth, migration, autophagy, and apoptosis in mammals. However, its function in insects remains unclear. In the present study, we cloned and identified Nilaparvata lugens DAP-1 (NlDAP-1). NlDAP-1 was expressed during all developmental stages and in all tissues of N. lugens, being particularly higher in the ovaries of female adults. RNAi with double-stranded NlDAP-1 RNA significantly inhibited the expression of NlDAP-1, leading to premature death (dying seven days earlier), delayed ovarian development, and fewer offspring (76.7% reduction in eggs with 77.4% reduction in egg hatching rate). Additionally, an immunofluorescence experiment showed that NlDAP-1 was highly expressed when yeast-like symbionts (YLSs) entered N. lugens oocytes, and inhibiting the expression of NlDAP-1 disturbed the process; the RNAi of NlDAP-1 caused a 34.9% reduction in the YLSs that entered oocytes. These results indicate that NlDAP-1 plays a crucial role in the reproductive development of N. lugens and the transovarial transmission of its YLSs.

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