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In order to improve the filtration efficiency of electrospinning poly(lactic acid) (PLA) membrane on particulate matter (PM), endow the membrane with good antibacterial properties, and accelerate the degradation effect of PLA materials in natural water and soil environments, ZIF-8@chitosan (ZIF-8@CS) was prepared by in situ growth method and was combined with PLA to manufacture the PLA/ZIF-8@CS electrospinning membranes. The PLA/ZIF-8@CS (3 wt%) membrane exhibited filtration efficiencies of 96.79 % for PM2.5 and 91.21 % for PM10, which were significantly higher than that of PP melt-blown cloth. Due to the inherently positive charge and the synergistic interaction between CS and ZIF-8, the antibacterial rates of PLA/ZIF-8@CS membranes were up to 100 % for E. coli and S. aureus after contact for 8 h. The addition of ZIF-8@CS in the membranes also influenced the degradation behavior of PLA/ZIF-8@CS membranes evidently.
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Antibacterianos , Quitosana , Escherichia coli , Filtração , Membranas Artificiais , Material Particulado , Poliésteres , Staphylococcus aureus , Poliésteres/química , Quitosana/química , Antibacterianos/farmacologia , Antibacterianos/química , Escherichia coli/efeitos dos fármacos , Staphylococcus aureus/efeitos dos fármacos , Filtração/métodos , Material Particulado/química , Estruturas Metalorgânicas/química , Estruturas Metalorgânicas/farmacologia , Testes de Sensibilidade Microbiana , ImidazóisRESUMO
Inorganic materials doped with chromium (Cr) ions generate remarkable and adjustable broadband near-infrared (NIR) light, offering promising applications in the fields of imaging and night vision technology. However, achieving high efficiency and thermal stability in these broadband NIR phosphors poses a significant challenge for their practical application. Here, we employ crystal field engineering to modulate the NIR characteristics of Cr3+-doped Gd3Ga5O12 (GGG). The Gd3MgxGa5-2xGexO12 (GMGG):7.5% Cr3+ (x = 0, 0.05, 0.15, 0.20, and 0.40) phosphors with NIR emission are developed through the cosubstitution of Mg2+ and Ge4+ for Ga3+ sites. This cosubstitution strategy also effectively reduces the crystal field strength around Cr3+ ions, which results in a significant enhancement of the photoluminescence (PL) full width at half-maximum (fwhm) from 97 to 165 nm, alongside a red shift in the PL peak and an enhancement of the PL intensity up to 2.3 times. Notably, the thermal stability of the PL behaviors is also improved. The developed phosphors demonstrate significant potential in biological tissue penetration and night vision, as well as an exceptional scintillation performance for NIR scintillator imaging. This research paves a new perspective on the development of high-performance NIR technology in light-emitting diodes (LEDs) and X-ray imaging applications.
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A series of novel 2-arylmethoxy-4-(2-fluoromethyl-biphenyl-3-ylmethoxy) benzylamine derivatives was designed, synthesized, and evaluated for their antitumor effects as PD-1/PD-L1 inhibitors both in vitro and in vivo. Firstly, the ability of these compounds to block the PD-1/PD-L1 immune checkpoint was assessed using the homogeneous time-resolved fluorescence (HTRF) assay. Two of the compounds can strongly block the PD-1/PD-L1 interaction, with IC50 values of less than 10 nM, notably, compound HD10 exhibited significant clinical potential by inhibiting the PD-1/PD-L1 interaction with an IC50 value of 3.1 nM. Further microscale thermophoresis (MST) analysis demonstrated that HD10 had strong interaction with PD-L1 protein. Co-crystal structure (2.7 Å) analysis of HD10 in complex with the PD-L1 protein revealed a strong affinity between the compound and the target PD-L1 dimer. This provides a solid theoretical basis for further in vitro and in vivo studies. Next, a typical cell-based experiment demonstrated that HD10 could remarkably prevent the interaction of hPD-1 293 T cells from human recombinant PD-L1 protein, effectively restoring T cell function, and promoting IFN-γ secretion in a dose-dependent manner. Moreover, HD10 was effective in suppressing tumor growth (TGI = 57.31 %) in a PD-1/PD-L1 humanized mouse model without obvious toxicity. Flow cytometry, qPCR, and immunohistochemistry data suggested that HD10 inhibits tumor growth by activating the immune system in vivo. Based on these results, it seems likely that HD10 is a promising clinical candidate that should be further investigated.
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Antineoplásicos , Antígeno B7-H1 , Benzilaminas , Desenho de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Receptor de Morte Celular Programada 1 , Humanos , Antineoplásicos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/metabolismo , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/metabolismo , Animais , Camundongos , Relação Estrutura-Atividade , Benzilaminas/farmacologia , Benzilaminas/química , Benzilaminas/síntese química , Estrutura Molecular , Relação Dose-Resposta a Droga , Proliferação de Células/efeitos dos fármacos , Inibidores de Checkpoint Imunológico/farmacologia , Inibidores de Checkpoint Imunológico/síntese química , Inibidores de Checkpoint Imunológico/química , Linhagem Celular Tumoral , Feminino , Modelos MolecularesRESUMO
ETHNOPHARMACOLOGICAL RELEVANCE: Uncaria rhynchophylla (Miq.) Miq.ex Havil. was a classical medicinal plant exhibiting the properties of extinguishing wind, arresting convulsions, clearing heat and pacifying the liver. Clinically, it could be utilized for the treatment of central nervous system-related diseases, such as Alzheimer's disease. U. rhynchophylla (UR) and its major ingredient alkaloid compounds (URA) have been proved to exert significant neuroprotective effects. However, the potential mechanism aren't fully understood. AIM OF THE STUDY: This study systematically examined the therapeutic effects of URA on AD pathology in APP-PS1 mice, and revealed the potential mechanism of action. MATERIALS AND METHODS: The cognitive ability was evaluated by morris water maze test in APP-PS1 mice. The H&E staining was used to observe the tissue pathological changes. The ELISA kits were used to detect the level of inflammatory factors. The flow cytometry was used to analyze the percentage of CD4+ effector T cells (Teffs) in spleen. The immunofluorescent staining was performed to count the Teffs and microglia in brain. The protein expression was analyzed by western blot. In vitro, the lymphocyte proliferation induced by ConA was performed by CCK-8 kits. The IFN-γ, IL-17, and TNF-α production were detected by ELISA kits. The effects of URA on glycolysis and the involvement of PI3K/Akt/mTOR signaling pathway was analyzed by Lactic Acid assay kit and western blot in ConA-induced naive T cell. RESULTS: URA treatment improved AD pathology effectively as demonstrated by enhanced cognitive ability, decreased Aß deposit and Tau phosphorylation, as well as reduced neuron apoptosis. Also, the neuroinflammation was significantly alleviated as evidenced by decreased IFN-γ, IL-17 and increased IL-10, TGF-ß. Notably, URA treatment down-regulated the percentage of Teffs (Th1 and Th17) in spleen, and reduced the infiltration of Teffs and microglia in brain. Meanwhile, the Treg cell was up-regulated both in spleen and brain. In vitro, URA was capable of attenuating the spleen lymphocyte proliferation and release of inflammatory factors provoked by ConA. Interestingly, glycolysis was inhibited by URA treatment as evidenced by the decrease in Lactic Acid production and expression of HK2 and GLUT1 via regulating PI3K/Akt/mTOR signaling pathway in ConA-induced naive T cell. CONCLUSION: This study proved that URA could improve AD pathology which was possibly attributable to the restraints of CD4+ T cell mediated neuroinflammation via inhibiting glycolysis.
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Alcaloides , Doença de Alzheimer , Linfócitos T CD4-Positivos , Glicólise , Doenças Neuroinflamatórias , Uncaria , Animais , Uncaria/química , Glicólise/efeitos dos fármacos , Camundongos , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Linfócitos T CD4-Positivos/efeitos dos fármacos , Alcaloides/farmacologia , Masculino , Doenças Neuroinflamatórias/tratamento farmacológico , Camundongos Transgênicos , Modelos Animais de Doenças , Camundongos Endogâmicos C57BL , Fármacos Neuroprotetores/farmacologia , Transdução de Sinais/efeitos dos fármacosRESUMO
OBJECTIVES: Although Geobacillus are significant thermophilic bacteria source, there are no reports of thermostable esterase gene in Geobacillus jurassicus or rational design strategies to increase the thermal stability of esterases. RESULTS: Gene gju768 showed a highest similarity of 15.20% to esterases from Geobacillus sp. with detail enzymatic properties. Using a combination of Gibbs Unfolding Free Energy (∆∆G) calculator and the distance from the mutation site to the catalytic site (DsCα-Cα) to screen suitable mutation sites with elimination of negative surface charge, the mutants (D24N, E221Q, and E253Q) displayed stable mutants with higher thermal stability than the wild-type (WT). Mutant E253Q exhibited the best thermal stability, with a half-life (T1/2) at 65 °C of 32.4 min, which was 1.8-fold of the WT (17.9 min). CONCLUSION: Cloning of gene gju768 and rational design based on surface charge engineering contributed to the identification of thermostable esterase from Geobacillus sp. and the exploration of evolutionary strategies for thermal stability.
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Estabilidade Enzimática , Esterases , Geobacillus , Geobacillus/enzimologia , Geobacillus/genética , Esterases/genética , Esterases/química , Esterases/metabolismo , Proteínas de Bactérias/genética , Proteínas de Bactérias/química , Proteínas de Bactérias/metabolismo , Desenho Assistido por Computador , Clonagem MolecularRESUMO
The fluxonium qubits have emerged as a promising platform for gate-based quantum information processing. However, their extraordinary protection against charge fluctuations comes at a cost: when coupled capacitively, the qubit-qubit interactions are restricted to XX interactions. Consequently, effective ZZ or XZ interactions are only constructed either by temporarily populating higher-energy states, or by exploiting perturbative effects under microwave driving. Instead, we propose and demonstrate an inductive coupling scheme, which offers a wide selection of native qubit-qubit interactions for fluxonium. In particular, we leverage a built-in, flux-controlled ZZ interaction to perform qubit entanglement. To combat the increased flux-noise-induced dephasing away from the flux-insensitive position, we use a continuous version of the dynamical decoupling scheme to perform noise filtering. Combining these, we demonstrate a 20 ns controlled-z gate with a mean fidelity of 99.53%. More than confirming the efficacy of our gate scheme, this high-fidelity result also reveals a promising but rarely explored parameter space uniquely suitable for gate operations between fluxonium qubits.
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OBJECTIVE(S): Recently directed methods of inner ear drug delivery underscore the necessity for understanding critical anatomical dimensions. This study examines anatomical measurements of the human middle and inner ear relevant for inner ear drug delivery studied with three different imaging modalities. METHODS: Post-mortem human temporal bones were analyzed using human temporal bone histopathology (N = 24), micro computerized tomography (µCT; N = 4), and synchrotron radiation phase-contrast imaging (SR-PCI; N = 7). Nine measurements involving the oval and round windows were performed when relevant anatomical structures were visualized for subsequent age-controlled analysis, and comparisons were made between imaging methods. RESULTS: Combined human temporal bone histopathology showed the mean distance to the saccule from the center of the stapes footplate (FP) was 2.07 ± 0.357 mm and the minimum distance was 1.23 mm. The mean distance from the round window membrane (RWM) to the osseous spiral lamina (OSL) was 1.75 ± 0.199 mm and the minimum distance was 1.43 mm. Instruments inserted up to 1 mm past the center of the FP are unlikely to cause saccular damage, provided there are no endolymphatic hydrops. Similarly, instruments inserted up to 1 mm through the RWM in the trajectory toward the OSL are unlikely to cause OSL damage. CONCLUSION: The combined analyses of inner-ear dimensions of age-controlled groups and imaging modalities demonstrate critical dimensions of importance to consider when inserting delivery vehicles into the human cochlea. LEVEL OF EVIDENCE: N/A Laryngoscope, 134:2879-2888, 2024.
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Orelha Interna , Terapia Genética , Osso Temporal , Microtomografia por Raio-X , Humanos , Osso Temporal/diagnóstico por imagem , Osso Temporal/anatomia & histologia , Orelha Interna/diagnóstico por imagem , Orelha Interna/anatomia & histologia , Microtomografia por Raio-X/métodos , Terapia Genética/métodos , Cadáver , Pessoa de Meia-Idade , Masculino , Feminino , Síncrotrons , IdosoRESUMO
Pain involves neuroimmune crosstalk, but the mechanisms of this remain unclear. Here we showed that the splenic T helper 2 (TH2) immune cell response is differentially regulated in male mice with acute versus chronic neuropathic pain and that acetylcholinergic neurons in the dorsal motor nucleus of the vagus (AChDMV) directly innervate the spleen. Combined in vivo recording and immune cell profiling revealed the following two distinct circuits involved in pain-mediated peripheral TH2 immune response: glutamatergic neurons in the primary somatosensory cortex (GluS1HL)âAChDMVâspleen circuit and GABAergic neurons in the central nucleus of the amygdala (GABACeA)âAChDMVâspleen circuit. The acute pain condition elicits increased excitation from GluS1HL neurons to spleen-projecting AChDMV neurons and increased the proportion of splenic TH2 immune cells. The chronic pain condition increased inhibition from GABACeA neurons to spleen-projecting AChDMV neurons and decreased splenic TH2 immune cells. Our study thus demonstrates how the brain encodes pain-state-specific immune responses in the spleen.
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Núcleo Central da Amígdala , Neuralgia , Camundongos , Masculino , Animais , Córtex Somatossensorial , Baço , Neurônios GABAérgicos/fisiologia , Nervo Vago , Ácido gama-Aminobutírico/fisiologiaRESUMO
HYPOTHESIS: Trauma to the osseous spiral lamina (OSL) or spiral ligament (SL) during cochlear implant (CI) insertion segregates with electrode type and induces localized intracochlear ossification and fibrosis. BACKGROUND: The goal of atraumatic CI insertion is to preserve intracochlear structures, limit reactive intracochlear tissue formation, and preserve residual hearing. Previous qualitative studies hypothesized a localized effect of trauma on intracochlear tissue formation; however, quantitative studies failed to confirm this. METHODS: Insertional trauma beyond the immediate insertion site was histologically assessed in 21 human temporal bones with a CI. Three-dimensional reconstructions were generated and virtually resectioned perpendicular to the cochlear spiral at high resolution. The cochlear volume occupied by ossification or fibrosis was determined at the midpoint of the trauma and compared with regions proximal and distal to this point. RESULTS: Seven cases, all implanted with precurved electrodes, showed an OSL fracture beyond the immediate insertion site. Significantly more intracochlear ossification was observed at the midpoint of the OSL fracture, compared with the -26 to -18 degrees proximal and 28 to 56 degrees distal to the center. No such pattern was observed for fibrosis. In the 12 cases with a perforation of the SL (9 straight and 3 precurved electrodes), no localized pattern of ossification or fibrosis was observed around these perforations. CONCLUSION: OSL fractures were observed exclusively with precurved electrodes in this study and may serve as a nidus for localized intracochlear ossification. Perforation of the SL, in contrast, predominantly occurred with straight electrodes and was not associated with localized ossification.
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Implante Coclear , Implantes Cocleares , Humanos , Implantes Cocleares/efeitos adversos , Osteogênese , Eletrodos Implantados/efeitos adversos , Implante Coclear/efeitos adversos , Implante Coclear/métodos , Cóclea/diagnóstico por imagem , Cóclea/cirurgia , Cóclea/lesões , Osso Temporal/diagnóstico por imagem , Osso Temporal/cirurgia , Osso Temporal/patologia , FibroseRESUMO
The pulsed electric field (PEF) of µs duration can induce electroporation by causing permanent damage to the membrane, leading to cell death. The microbe was treated by a homemade PEF generator instrument. The sterilization effect of PEF on the Rhizoctonia solani was observed by scanning electron microscope (SEM) and transmission electron microscope (TEM), and the leakage of the intracellular contents was measured with a conductometer and an ultraviolet spectrophotometer. The increases in the electrical conductivity and the optical density (OD) value indicated that the cell membrane was damaged, and the intracellular contents overflowed. As a result, according to our experimental conditions, the optimum condition was the high-pulsed electric voltage of 26 kV, and the treatment time was 4 min. It could be concluded that the PEF could damage the cell membrane, and the ratio of electroporation reached 100%, which provides a new method of killing R. solani efficiently.
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Eletroporação , Rhizoctonia , Eletricidade , Membrana CelularRESUMO
The performance of zinc-ion batteries is severely hindered by the uncontrolled growth of dendrites and the severe side reactions on the zinc anode interface. To address these challenges, a weak-water-coordination electrolyte is realized in a peptone-ZnSO4 -based electrolyte to simultaneously regulate the solvation structure and the interfacial environment. The peptone molecules have stronger interaction with Zn2+ ions than with water molecules, making them more prone to coordinate with Zn2+ ions and then reducing the active water in the solvated sheath. Meantime, the peptone molecules selectively adsorb on the Zn metal surface, and then are reduced to form a stable solid-electrolyte interface layer that can facilitate uniform and dense Zn deposition to inhabit the dendritic growth. Consequently, the Zn||Zn symmetric cell can exhibit exceptional cycling performance over 3200 h at 1.0 mA cm-2 /1.0 mAh cm-2 in the peptone-ZnSO4 -based electrolyte. Moreover, when coupled with a Na2 V6 O16 ·3H2 O cathode, the cell exhibits a long lifespan of 3000 cycles and maintains a high capacity retention rate of 84.3% at 5.0 A g-1 . This study presents an effective approach for enabling simultaneous regulation of the solvation structure and interfacial environment to design a highly reversible Zn anode.
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OBJECTIVES: Current surgical techniques aim to preserve intracochlear structures during cochlear implant (CI) insertion to maintain residual cochlear function. The optimal technique to minimize damage, however, is still under debate. The aim of this study is to histologically compare insertional trauma and intracochlear tissue formation in humans with a CI implanted via different insertion techniques. METHODS: One recent temporal bone from a donor who underwent implantation of a full-length CI (576°) via round window (RW) insertion was compared with nine cases implanted via cochleostomy (CO) or extended round window (ERW) approach. Insertional trauma was assessed on H&E-stained histological sections. 3D reconstructions were generated and virtually re-sectioned to measure intracochlear volumes of fibrosis and neo-ossification. RESULTS: The RW insertion case showed electrode translocation via the spiral ligament. 2/9 CO/ERW cases showed no insertional trauma. The total volume of the cochlea occupied by fibro-osseous tissue was 10.8% in the RW case compared with a mean of 30.6% (range 8.7%-44.8%, N = 9) in the CO/ERW cases. The difference in tissue formation in the basal 5 mm of scala tympani, however, was even more pronounced when the RW case (12.3%) was compared with the cases with a CO/ERW approach (mean of 93.8%, range 81% to 100%, N = 9). CONCLUSIONS: Full-length CI insertions via the RW can be minimally traumatic at the cochlear base without inducing extensive fibro-osseous tissue formation locally. The current study further supports the hypothesis that drilling of the cochleostomy with damage to the endosteum incites a local tissue reaction. LEVEL OF EVIDENCE: 4: Case-control study Laryngoscope, 134:945-953, 2024.
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Implante Coclear , Implantes Cocleares , Humanos , Implante Coclear/métodos , Estudos de Casos e Controles , Cóclea/cirurgia , Janela da Cóclea/cirurgia , Osso Temporal/cirurgia , Eletrodos ImplantadosRESUMO
Aqueous zinc ion batteries are gaining popularity due to their high energy density and environmental friendliness. However, random deposition of zinc ions on the anode and sluggish migration of zinc ions on the interface would lead to the growth of zinc dendrites and poor cycling performance. To address these challenges, we developed a fluorinated solid-state-electrolyte interface layer composed of Ca5 (PO4 )3 F/Zn3 (PO4 )2 via an in situ ion exchange strategy to guide zinc-ion oriented deposition and fast zinc ion migration on the anode during cycling. The introduction of Ca5 (PO4 )3 F (FAP) can increase the nucleation sites of zinc ions and guide the oriented deposition of zinc ions along the (002) crystal plane, while the in situ formation of Zn3 (PO4 )2 during cycling can accelerate the migration of zinc ions. Benefited from our design, the assembled Zn//V2 O5 â H2 O batteries based on FAP-protected Zn anode (FAP-Zn) achieve a higher capacity retention of 84 % (220â mAh g-1 ) than that of bare-Zn based batteries, which have a capacity retention of 23 % (97â mAh g-1 ) at 3.0â A g-1 after 800 cycles. This work provides a new solution for the rational design and development of the solid-state electrolyte interface layer to achieve high-performance zinc-ion batteries.
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α-Amylase (EC 3.2.1.1) from Geobacillus stearothermophilus (generally recognized as safe) exhibited thermal inactivation, hampering its further application in starch-based industries. To address this, we performed structural analyses based on molecular dynamics targeting the flexible regions of α-amylase. Subsequently, we rationally designed a thermostable mutant, AmyS1, by introducing disulfide bonds to stabilize the flexible regions. AmyS1 showed excellent thermostability without any stability-activity trade-off, giving a 40-fold longer T1/2 (1359 min) at 90 °C. Thermostability mechanism analysis revealed that the introduction of disulfide bonds in AmyS1 refined weak spots and reconfigured the protein's force network. Moreover, AmyS1 exhibited improved pH compatibility and enhanced corn starch liquefaction at 100 °C with a 5.1-fold increased product concentration. Baking tests confirmed that AmyS1 enhanced bread quality and extended the shelf life. Therefore, mutant AmyS1 is a robust candidate for the starch-based industry.
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Geobacillus stearothermophilus , alfa-Amilases , alfa-Amilases/química , Geobacillus stearothermophilus/genética , Zea mays/genética , Zea mays/metabolismo , Amido , Pão , Melhoria de Qualidade , Estabilidade Enzimática , Dissulfetos/química , TemperaturaRESUMO
HYPOTHESIS: There are clinically relevant differences in scalae anatomy and spiral ganglion neuron (SGN) quantity between incomplete partition type II (IP-II) and normal cochleae. BACKGROUND: IP-II is a commonly implanted cochlear malformation. Detailed knowledge of intracochlear three-dimensional (3D) morphology may assist with cochlear implant (CI) electrode selection/design and enable optimization of audiologic programming based on SGN maps. METHODS: IP-II (n = 11) human temporal bone histological specimens were identified from the National Institute on Deafness and Other Communication Disorders National Temporal Bone Registry and digitized. The cochlear duct, scalae, and surgically relevant anatomy were reconstructed in 3D. A machine learning algorithm was applied to map the location and number of SGNs. RESULTS: 3D scalae morphology of the basal turn was normal. Scala tympani (ST) remained isolated for 540 degrees before fusing with scala vestibuli. Mean ST volume reduced below 1 mm 2 after the first 340 degrees. Scala media was a distinct endolymphatic compartment throughout; mean ± standard deviation cochlear duct length was 28 ± 3 mm. SGNs were reduced compared with age-matched norms (mean, 48%; range, 5-90%). In some cases, SGNs failed to ascend Rosenthal's canal, remaining in an abnormal basalward modiolar location. Two forms of IP-II were seen: type A and type B. A majority (98-100%) of SGNs were located in the basal modiolus in type B IP-II, compared with 76 to 85% in type A. CONCLUSION: Hallmark features of IP-II cochleae include the following: 1) fusion of the ST and scala vestibuli at a mean of 540 degrees, 2) highly variable and overall reduced SGN quantity compared with normative controls, and 3) abnormal SGN distribution with cell bodies failing to ascend Rosenthal's canal.
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Cóclea , Implantes Cocleares , Humanos , Cóclea/diagnóstico por imagem , Rampa do Tímpano , Rampa do Vestíbulo , Ducto CoclearRESUMO
Cancers are a huge threat to human life and health. Every year, many people suffer and die from various cancers, and numerous resources have been used to combat cancer. Due to several disadvantages of anticancer agents, such as drug-induced side effects, drug resistance, etc., there are still wide gaps in their ability to conquer cancer. Therefore, there is an urgent need to discover and develop many novel chemotypes to suppress cancer. In this review, we mainly focus on the anticancer potency of two representative sorts of carbazole-based compounds: carboline derivatives and diazacarbazole derivatives. Diazacarbazole derivatives, which have not been fully explored yet, might bring us a new vision and a valuable opportunity for overcoming the enormous hurdle we are now facing in the cancer campaign. We also provide several synthetic approaches for constructing the critical skeletons of the carbazole-based tricyclic compounds.
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Psychological and physical stressors have been implicated in gastric disorders in humans. The mechanism coupling the brain to the stomach underlying stress-induced gastric dysfunction has remained elusive. Here, we show that the stomach directly receives acetylcholinergic inputs from the dorsal motor nucleus of the vagus (AChDMV), which are innervated by serotonergic neurons in the dorsal raphe nucleus (5-HTDRN). Microendoscopic calcium imaging and multi-tetrode electrophysiological recordings reveal that the 5-HTDRN â AChDMV â stomach circuit is inhibited with chronic stress accompanied by hypoactivate gastric function. Artificial activation of this circuit reverses the gastric dysfunction induced by chronic stress in both male and female mice. Our study demonstrates that this 5-HTDRN â AChDMV â stomach axis drives gastric dysfunction associated with stress, thus providing insights into the circuit basis for brain regulation of the stomach.
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Núcleo Dorsal da Rafe , Serotonina , Camundongos , Masculino , Feminino , Humanos , Animais , Núcleo Dorsal da Rafe/fisiologiaRESUMO
Recent studies on biphenyl-containing compounds, a type of PD-1/PD-L1 blocker which binds to PD-L1 and induces dimerisation, have focussed on its immune function. Herein, 10 novel biphenyl derivatives were designed and synthesised. The results of the CCK-8 showed that compounds have different anti-tumour activities for tumour cells in the absence of T cells. Particularly, 12j-4 can significantly induce the apoptosis of MDA-MB-231 cells (IC50 = 2.68 ± 0.27 µM). In further studies, 12j-4 has been shown to prevent the phosphorylation of AKT by binding to cytoplasmic PD-L1, which induces apoptosis in MDA-MB-231 cells through non-immune pathways. The inhibition of AKT phosphorylation restores the activity of GSK-3ß, ultimately resulting in the degradation of PD-L1. Besides, in vivo study indicated that 12j-4 repressed tumour growth in nude mice. As these biphenyls exert their anti-tumour effects mainly through non-immune pathways, they are worthy of further study as PD-L1 inhibitors.
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Compostos de Bifenilo , Neoplasias da Mama , Proteínas Proto-Oncogênicas c-akt , Animais , Camundongos , Antígeno B7-H1 , Glicogênio Sintase Quinase 3 beta , Camundongos Nus , Neoplasias da Mama/tratamento farmacológico , Compostos de Bifenilo/farmacologiaRESUMO
Novel 2-arylmethoxy-4-(2,2'-dihalogen-substituted biphenyl-3-ylmethoxy) benzylamine derivatives were designed, synthesized, and evaluated in vitro and in vivo against cancers as PD-1/PD-L1 inhibitors. Through the computer-aided structural optimization and the homogeneous time-resolved fluorescence (HTRF) assay, compound A56 was found to most strongly block the PD-1/PD-L1 interaction with an IC50 value of 2.4 ± 0.8 nM and showed the most potent activity. 1H NMR titration results indicated that A56 can tightly bind to the PD-L1 protein with KD < 1 µM. The X-ray diffraction data for the cocrystal structure of the A56/PD-L1 complex (3.5 Å) deciphered a novel binding mode in detail, which can account for its most potent inhibitory activity. Cell-based assays further demonstrated the strong ability of A56 as an hPD-1/hPD-L1 blocker. Especially in an hPD-L1 MC38 humanized mouse model, A56 significantly inhibited tumor growth without obvious toxicity, with a TGI rate of 55.20% (50 mg/kg, i.g.). In conclusion, A56 is a promising clinical candidate worthy of further development.