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1.
EMBO Rep ; 24(10): e56098, 2023 10 09.
Artigo em Inglês | MEDLINE | ID: mdl-37522391

RESUMO

A11 dopaminergic neurons regulate somatosensory transduction by projecting from the diencephalon to the spinal cord, but the function of this descending projection in itch remained elusive. Here, we report that dopaminergic projection neurons from the A11 nucleus to the spinal dorsal horn (dopaminergicA11-SDH ) are activated by pruritogens. Inhibition of these neurons alleviates itch-induced scratching behaviors. Furthermore, chemogenetic inhibition of spinal dopamine receptor D1-expressing (DRD1+ ) neurons decreases acute or chronic itch-induced scratching. Mechanistically, spinal DRD1+ neurons are excitatory and mostly co-localize with gastrin-releasing peptide (GRP), an endogenous neuropeptide for itch. In addition, DRD1+ neurons form synapses with GRP receptor-expressing (GRPR+ ) neurons and activate these neurons via AMPA receptor (AMPAR). Finally, spontaneous itch and enhanced acute itch induced by activating spinal DRD1+ neurons are relieved by antagonists against AMPAR and GRPR. Thus, the descending dopaminergic pathway facilitates spinal itch transmission via activating DRD1+ neurons and releasing glutamate and GRP, which directly augments GRPR signaling. Interruption of this descending pathway may be used to treat chronic itch.


Assuntos
Receptores da Bombesina , Medula Espinal , Humanos , Receptores da Bombesina/genética , Receptores da Bombesina/metabolismo , Peptídeo Liberador de Gastrina/genética , Peptídeo Liberador de Gastrina/metabolismo , Medula Espinal/metabolismo , Ácido Glutâmico/metabolismo , Dopamina/metabolismo , Prurido/genética , Prurido/metabolismo , Neurônios Dopaminérgicos/metabolismo , Receptores de AMPA/genética , Receptores de AMPA/metabolismo
2.
Chemphyschem ; 25(5): e202300693, 2024 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-38183359

RESUMO

Lithium-sulfur batteries (LSBs) are considered as the development direction of the new generation energy storage system due to their high energy density and low cost. The slow redox kinetics of sulfur and the shuttle effect of lithium polysulfide (LiPS) are considered to be the main obstacles to the practical application of LSBs. Transition-metal sulfide as the cathode host can improve the Li-S redox chemistry. However, there has been no investigation of the application of FeS2 host in Li-S redox chemistry. Applying the first-principles calculations, we investigated the formation energy, band gap, Li+ diffusion, adsorption energy, catalytic performance and Li2 S decomposition barrier of FeAx S2-x (A=N, P, O, Se; x=0, 0.125, 0.25, 0.375) to explore the Li-S redox chemistry and finally select excellent host material. FeA0.25 S1.75 (A=P, Se) has a low Li+ diffusion barrier and superior electronic conductivity. FeO0.25 S1.75 is more favorable for LiPS adsorption, followed by FeP0.25 S1.75 . FeP0.25 S1.75 (001) shows a low overpotential for the Li-S redox chemistry. In summary, FeP0.25 S1.75 has more application potential in LSBs due to its physical and chemical properties, followed by FeSe0.25 S1.75 . This work provides theoretical guidance for the design and selection of the sulfur cathode host materials in LSBs.

3.
Bioorg Med Chem ; 112: 117880, 2024 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-39216382

RESUMO

Berberine is a quaternary ammonium isoquinoline alkaloid derived from traditional Chinese medicines Coptis chinensis and Phellodendron chinense. It has many pharmacological activities such as hypoglycemic, hypolipidemic, anti-tumor, antimicrobial and anti-inflammatory. Through structural modifications at various sites of berberine, the introduction of different groups can change berberine's physical and chemical properties, thereby improving the biological activity and clinical efficacy, and expanding the scope of application. This paper reviews the research progress and structure-activity relationships of berberine in recent years, aiming to provide valuable insights for the exploration of novel berberine derivatives.


Assuntos
Berberina , Berberina/química , Berberina/farmacologia , Berberina/análogos & derivados , Relação Estrutura-Atividade , Humanos , Estrutura Molecular , Hipoglicemiantes/química , Hipoglicemiantes/farmacologia , Hipoglicemiantes/síntese química , Animais , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química
4.
Chem Biodivers ; 21(8): e202400954, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38844419

RESUMO

Lycopodiales, an order comprising 388 distinct species, is the source of Lycopodium alkaloids (LAs), a group of naturally occurring alkaloids that share a common biosynthesis and structural attributes. These remarkable organisms are considered vestiges of ancient ferns, with fossil evidence dating their existence back to an impressive 300 million years. LAs usually are tricyclic or tetracyclic compounds with C16N or C16N2 skeleton. But then there are also have a few C11N, C15N, C15N2, C22N2, and C27N3 skeleton. LAs have attracted much scientific attention because of their important biological activities related to acetylcholinesterase and unique structural characteristics. From 1881 to December 2023, there are 593 LAs from 49 species of Lycopodiales have been reported. Because the total amount of LAs is nearly five times that of 1994, the classification and group allocation of some newly isolated LAs is often challenging and not unambiguous by Ayer's simple classification. This review makes a more systematic and detailed classification for it and provides extensive coverage of naturally occurring LAs discovered from 1881 to December 2023. Until now, there is no comprehensively summary of biological activity of the LAs. This review is the first time covered the biological activity of the all LAs.


Assuntos
Alcaloides , Lycopodium , Alcaloides/química , Alcaloides/isolamento & purificação , Alcaloides/farmacologia , Lycopodium/química , Humanos , Estrutura Molecular
5.
Chem Biodivers ; 21(6): e202400399, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38634752

RESUMO

Four undescribed prenylated flavonoids, sophoratones A-D (1-4), and 17 known flavonoids, were obtained from the aerial parts of Sophora tonkinensis. Their structures with absolute configurations were elucidated by detailed interpretation of NMR spectroscopy, mass spectrometry, and ECD calculations. Meanwhile, the ability of these compounds to inhibit the release of nitric oxide (NO) by a lipopolysaccharide induced mouse in RAW 264.7 cells was assayed. The results indicated that some compounds exhibited clear inhibitory effects, with IC50 ranging from 19.91±1.08 to 35.72±2.92 µM. These results suggest that prenylated flavonoids from the aerial parts of S. tonkinensis could potentially be used as a latent source of anti-inflammatory agents.


Assuntos
Flavonoides , Lipopolissacarídeos , Óxido Nítrico , Componentes Aéreos da Planta , Sophora , Sophora/química , Animais , Camundongos , Flavonoides/farmacologia , Flavonoides/isolamento & purificação , Flavonoides/química , Células RAW 264.7 , Componentes Aéreos da Planta/química , Óxido Nítrico/antagonistas & inibidores , Óxido Nítrico/metabolismo , Óxido Nítrico/biossíntese , Lipopolissacarídeos/farmacologia , Lipopolissacarídeos/antagonistas & inibidores , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/química , Anti-Inflamatórios/isolamento & purificação , Relação Estrutura-Atividade , Anti-Inflamatórios não Esteroides/farmacologia , Anti-Inflamatórios não Esteroides/química , Anti-Inflamatórios não Esteroides/isolamento & purificação , Estrutura Molecular , Relação Dose-Resposta a Droga , Sobrevivência Celular/efeitos dos fármacos
6.
Artigo em Inglês | MEDLINE | ID: mdl-39332935

RESUMO

BACKGROUND: Hepatocellular carcinoma (HCC) is a common malignancy with high mortality. Liver resection (LR) is a curative treatment for early-stage HCC, but the prognosis of HCC patients after LR is unsatisfactory because of tumor recurrence. Prognostic prediction models with great performance are urgently needed. The present study aimed to establish a novel prognostic nomogram to predict tumor recurrence in HCC patients after LR. METHODS: We retrospectively analyzed 726 HCC patients who underwent LR between October 2011 and December 2016. Patients were randomly divided into the training cohort (n = 508) and the testing cohort (n = 218). The protein expression of 14 biomarkers in tumor tissues was assessed by immunohistochemistry. The nomogram predicting recurrence-free survival (RFS) was established by a multivariate Cox regression analysis model and was evaluated by calibration curves, Kaplan-Meier survival curves, time-dependent areas under the receiver operating characteristic (ROC) curves (AUCs), and decision curve analyses in both the training and testing cohorts. RESULTS: Alpha-fetoprotein [hazard ratio (HR) = 1.013, P = 0.002], portal vein tumor thrombosis (HR = 1.833, P < 0.001), ascites (HR = 2.024, P = 0.014), tumor diameter (HR = 1.075, P < 0.001), E-cadherin (HR = 0.859, P = 0.011), EMA (HR = 1.196, P = 0.022), and PCNA (HR = 1.174, P = 0.031) immunohistochemistry scores were found to be independent factors for RFS. The 1-year and 3-year AUCs of the nomogram for RFS were 0.813 and 0.739, respectively. The patients were divided into the high-risk group and the low-risk group by median value which was generated from the nomogram, and Kaplan-Meier analysis revealed that the high-risk group had a shorter RFS than the low-risk group in both the training (P < 0.001) and testing cohorts (P < 0.001). CONCLUSIONS: Our newly developed nomogram integrated clinicopathological data and key gene expression data, and was verified to have high accuracy in predicting the RFS of HCC patients after LR. This model could be used for early identification of patients at high-risk of postoperative recurrence.

7.
Molecules ; 29(4)2024 Feb 19.
Artigo em Inglês | MEDLINE | ID: mdl-38398659

RESUMO

In our research on naturally occurring sesquiterpenes, eight shizukaol-type dimers, one chlorahololide-type dimer, and one sarcanolide-type dimer were isolated from the roots of Chloranthus fortunei. As the project was implemented, we accidentally discovered that shizukaol-type dimers can be converted into peroxidized chlorahololide-type dimers. This potential change was discovered after simulations of the changes in corresponding shizukaols showed that three peroxide products were generated (1-3), indicating that peroxidation reactions occurred. HPLC-HR-MS analysis results obtained for the shizukaol derivatives further demonstrate that the reaction occurred, and the type of substituent of small organic ester moieties at positions C-15' and C-13' of unit B were not decisively related to the reaction. Quantum chemical calculations of the mode dimer further demonstrated this phenomenon. The highest occupied molecular orbital (HOMO)-lowest unoccupied molecular orbital (LUMO) energy of the precursor and production revealed the advantageous yield of 4ß-hydroperoxyl production. Additionally, the potential reaction mechanism was speculated and validated using the free energy in the reaction which successfully explained the feasibility of the reaction. Finally, the anti-inflammatory activity of the precursors and products was evaluated, and the products of peroxidation showed better anti-inflammatory activity.


Assuntos
Artefatos , Sesquiterpenos , Anti-Inflamatórios/farmacologia , Sesquiterpenos/química
8.
Biochemistry ; 62(22): 3214-3221, 2023 11 21.
Artigo em Inglês | MEDLINE | ID: mdl-37902563

RESUMO

Cytochrome P450 monooxygenases (CYP450s) play an important role in the biosynthesis of natural products by activating inert C-H bonds and inserting hydroxyl groups. However, the activities of most plant-derived CYP450s are extremely low, limiting the heterologous biosynthesis of natural products. Traditional enzyme engineering methods, either rational or screening-based, are not suitable for CYP450s because of the lack of crystal structures and high-throughput screening methods for this class of enzymes. CYP725A4 is the first hydroxylase involved in the biosynthesis pathway of Taxol. Its low activity, promiscuity, and multispecificity make it a bottleneck in Taxol biosynthesis. Here, we identified key amino acids that affect the in vivo activity of CYP725A4 by constructing the ancestral enzymes of CYP725A4. We obtained positive mutants that showed an improved yield of hydroxylated products based on the key amino acids identified, providing guidance for the modification of other CYP450s involved in the biosynthesis of natural products.


Assuntos
Aminoácidos , Produtos Biológicos , Aminoácidos/genética , Sistema Enzimático do Citocromo P-450/metabolismo , Paclitaxel/química , Paclitaxel/metabolismo
9.
Mol Pain ; 19: 17448069231178176, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37220667

RESUMO

Chronic pain is a refractory health disease worldwide causing an enormous economic burden on individuals and society. Accumulating evidence suggests that inflammation in the peripheral nervous system (PNS) and central nervous system (CNS) is the major factor in the pathogenesis of chronic pain. The inflammation in the early- and late phase may have distinctive effects on the initiation and resolution of pain, which can be viewed as friend or foe. On the one hand, painful injuries lead to the activation of glial cells and immune cells in the PNS, releasing pro-inflammatory mediators, which contribute to the sensitization of nociceptors, leading to chronic pain; neuroinflammation in the CNS drives central sensitization and promotes the development of chronic pain. On the other hand, macrophages and glial cells of PNS and CNS promote pain resolution via anti-inflammatory mediators and specialized pro-resolving mediators (SPMs). In this review, we provide an overview of the current understanding of inflammation in the deterioration and resolution of pain. Further, we summarize a number of novel strategies that can be used to prevent and treat chronic pain by controlling inflammation. This comprehensive view of the relationship between inflammation and chronic pain and its specific mechanism will provide novel targets for the treatment of chronic pain.


Assuntos
Dor Crônica , Humanos , Inflamação , Sistema Nervoso Central , Sensibilização do Sistema Nervoso Central , Neuroglia
10.
Brain Behav Immun ; 108: 98-117, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-36427810

RESUMO

Growing evidence suggests the involvement of the microbiota-gut-brain axis in cognitive impairment induced by sleep deprivation (SD), however how the microbiota-gut-brain axis work remains elusive. Here, we discovered that chronic SD induced intestinal dysbiosis, activated NLRP3 inflammasome in the colon and brain, destructed intestinal/blood-brain barrier, and impaired cognitive function in mice. Transplantation of "SD microbiota" could almost mimic the pathological and behavioral changes caused by chronic SD. Furthermore, all the behavioral and pathological abnormalities were practically reversed in chronic sleep-deprived NLRP3-/- mice. Regional knockdown NLRP3 expression in the gut and hippocampus, respectively. We observed that down-regulation of NLRP3 in the hippocampus inhibited neuroinflammation, and ameliorated synaptic dysfunction and cognitive impairment induced by chronic SD. More intriguingly, the down-regulation of NLRP3 in the gut protected the intestinal barrier, attenuated the levels of peripheral inflammatory factors, down-regulated the expression of NLRP3 in the brain, and improved cognitive function in chronic SD mice. Our results identified gut microbiota as a driver in chronic SD and highlighted the NLRP3 inflammasome as a key regulator within the microbiota-gut-brain axis.


Assuntos
Disfunção Cognitiva , Inflamassomos , Camundongos , Animais , Inflamassomos/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Privação do Sono/complicações , Disbiose/induzido quimicamente , Hipocampo/metabolismo , Disfunção Cognitiva/metabolismo , Intestinos
11.
Biotechnol Bioeng ; 120(7): 1773-1783, 2023 07.
Artigo em Inglês | MEDLINE | ID: mdl-37130074

RESUMO

The key precursors for nylon synthesis, that is, 6-aminocaproic acid (6-ACA) and 1,6-hexamethylenediamine (HMD), are produced from petroleum-based feedstocks. A sustainable biocatalytic alternative method from bio-based adipic acid has been demonstrated recently. However, the low efficiency and specificity of carboxylic acid reductases (CARs) used in the process hampers its further application. Herein, we describe a highly accurate protein structure prediction-based virtual screening method for the discovery of new CARs, which relies on near attack conformation frequency and the Rosetta Energy Score. Through virtual screening and functional detection, five new CARs were selected, each with a broad substrate scope and the highest activities toward various di- and ω-aminated carboxylic acids. Compared with the reported CARs, KiCAR was highly specific with regard to adipic acid without detectable activity to 6-ACA, indicating a potential for 6-ACA biosynthesis. In addition, MabCAR3 had a lower Km with regard to 6-ACA than the previously validated CAR MAB4714, resulting in twice conversion in the enzymatic cascade synthesis of HMD. The present work highlights the use of structure-based virtual screening for the rapid discovery of pertinent new biocatalysts.


Assuntos
Ácido Aminocaproico , Oxirredutases , Oxirredutases/metabolismo , Adipatos
12.
Crit Rev Food Sci Nutr ; 63(14): 2277-2317, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-34542344

RESUMO

The bitterness of foodstuffs is often associated with toxicity, which negatively influences product acceptability. However, bitter compounds have many benefits, and a slight bitter taste is sometimes favored. In this review, we summarize the methods used to isolate and evaluate the taste of bitter compounds in different foods. The chemical structures and threshold concentrations of these compounds are also recapped. Although the structures and thresholds of many bitter compounds have been confirmed, further studies are needed to develop detailed bitter-masking strategies and establish the relation between functional groups (hetero-cyclic substituents and bonding types) and taste quality. Furthermore, a comprehensive bitterness database and chemometric data must be provided in order to quickly assess the bitterness of unfamiliar products.


Assuntos
Percepção Gustatória , Paladar , Alimentos
13.
Bioorg Chem ; 139: 106652, 2023 10.
Artigo em Inglês | MEDLINE | ID: mdl-37390632

RESUMO

Primary liver cancer is one of the most common malignant cancers of the digestive system that lacks effective chemotherapeutic drugs in clinical settings. Camptothecin (CPT) and its derivatives have been approved for cancer treatment; however, their application is limited by their systemic toxicity. For lead optimization in new drug discovery stages, fluorination is an effective and robust approach to increase the bioavailability and optimize the pharmacokinetics of candidate compounds, thereby improving their efficacy. To obtain new and highly active CPT derivatives, we designed, synthesized, and evaluated two new fluorinated CPT derivatives, 9-fluorocamptothecin (A1) and 7-ethyl-9-fluorocamptothecin (A2), in this study. In vitro, A1 and A2 exhibited more robust anti-tumor activity than topotecan (TPT) in various cancer cells, particularly hepatocellular carcinoma (HCC) cells. In vivo, A1 and A2 exhibited greater anti-tumor activity than TPT in both AKT/Met induced primary HCC mouse models and implanted HepG2 cell xenografts. Acute toxicity tests revealed that A1 and A2 were not lethal and did not cause significant body weight loss at high doses. Moreover, A1 and A2 exhibited no significant toxicity in the mouse liver, heart, lung, spleen, kidney, and hematopoietic systems at therapeutic doses. Mechanistically, A1 and A2 blocked HCC cell proliferation by inhibiting the enzymatic activity of Topo I, subsequently inducing DNA damage, cell cycle arrest, and apoptosis. In summary, our results indicate that fluorination improves the anti-tumor activity of CPT while decreasing its toxicity and highlight the application potential of fluorination products A1 and A2 in clinical settings.


Assuntos
Antineoplásicos , Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Animais , Camundongos , Camptotecina/farmacologia , Camptotecina/uso terapêutico , Carcinoma Hepatocelular/tratamento farmacológico , DNA Topoisomerases Tipo I/metabolismo , Neoplasias Hepáticas/tratamento farmacológico , Topotecan/farmacologia , Inibidores da Topoisomerase I/farmacologia , Inibidores da Topoisomerase I/uso terapêutico , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico
14.
Appl Microbiol Biotechnol ; 107(18): 5727-5737, 2023 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-37477695

RESUMO

Cytochrome P450 monooxygenases CYP120As are the unique non-membrane P450s, which are extensively involved in retinoid biodegradation. As the O-functionalized 1,3,3-trimethylcyclohex-1-ene moiety exists in many bioactive compounds which could only be catalyzed by Class II P450s, exploration of the catalytic repertoire of CYP120As is therefore highly attractive. However, up to date, only one bacteriogenic candidate (CYP120A1) was demonstrated for the hydroxylation of C16 and C17 of retinoic acid, by utilizing the integral membrane protein cytochrome P450 reductase redox partner for the electron transfer. Herein, we provided an efficient prokaryotic functional expression system of CYP120As in E. coli by expression of the CYP120A1 coupled with several reductase partners. Fusion redox partners to the C-terminal of the heme-domain are also working on other CYP120A members. Among them, the fusion protein of CYP120A29 and FAD/FMN reductase from Bacillus megaterium P450BM3 (CYP101A2) showed the highest expression level. Based on the available translational fusion systems, the regioselectivity and the substrate scope of the CYP120As have also been explored. This work represents a good starting point for further expanding the catalytic potential of CYP120 family. KEY POINTS: • Characterization of CYP120As in E. coli is firstly achieved by constructing fusion proteins. • The feasibility of three P450 reductase domains to CYP120As was evaluated. • Hydroxylated products of retinoic acid by six CYP120As were sorted and analyzed.


Assuntos
Proteínas de Bactérias , Escherichia coli , Escherichia coli/genética , Escherichia coli/metabolismo , Proteínas de Bactérias/metabolismo , Oxirredução , Transporte de Elétrons , NADPH-Ferri-Hemoproteína Redutase/genética , NADPH-Ferri-Hemoproteína Redutase/metabolismo , Tretinoína/metabolismo
15.
Chem Biodivers ; 20(11): e202300998, 2023 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-37755070

RESUMO

Based on the research strategy of "drug repurposing", a series of derivatives and marketed drugs that containing salicylic acid skeleton were tested for their antibacterial activities against phytopathogens. Salicylic acid can not only regulate some important growth metabolism of plants, but also induce plant disease resistance. The bioassay results showed that the salicylamides exhibited excellent antibacterial activity. Especially, oxyclozanide showed the best antibacterial effect against Xanthomonas oryzae, Xanthomonas axonopodis pv. citri and Pectobacterium atroseptica with MICs of 0.78, 3.12 and 12.5 µg.mL-1, respectively. In vivo experiments with rice bacterial leaf blight had further demonstrated that oxyclozanide exhibited stronger antibacterial activity than the commercial bactericide, thiodiazole copper. Oxyclozanide could induce plant defense responses through the determination of salicylic acid content and the activities of defense-related enzymes including CAT, POD, and SOD in rice. The preliminarily antibacterial mechanism study indicated that oxyclozanide exhibited the antibacterial activity by disrupting cell integrity and reducing bacterial pathogenicity. Additionally, oxyclozanide could induce plant defense responses through the determination of salicylic acid content.


Assuntos
Oryza , Xanthomonas , Salicilamidas/farmacologia , Reposicionamento de Medicamentos , Oxiclozanida/farmacologia , Antibacterianos/farmacologia , Oryza/microbiologia , Testes de Sensibilidade Microbiana , Ácido Salicílico/farmacologia , Doenças das Plantas/prevenção & controle , Doenças das Plantas/microbiologia , Oxidiazóis/farmacologia
16.
Knee Surg Sports Traumatol Arthrosc ; 31(11): 5162-5170, 2023 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-37789216

RESUMO

PURPOSE: To compare clinical outcome between recurrent patellar dislocation (RPD) with or without actual tibial tubercle lateralisation (TTL) after medial patellofemoral ligament reconstruction (MPFL-R) combined with tibial tubercle transfer. METHODS: From 2015 to 2018, a total of 172 knees with RPD and a tibial tubercle-trochlear groove (TT-TG) distance of > 20 mm were treated with MPFL-R combined with tibial tubercle transfer. Patients were divided into the lateralisation group (TT-PCL > 24 mm, n = 74) and the nonlateralisation group (TT-PCL ≤ 24 mm, n = 60) based on the presence or absence of actual TTL (TT-PCL > 24 mm). Clinical outcomes were assessed postoperatively at a minimum of 2 years. Second-look arthroscopic evaluations were available for 84 knees to assess cartilage damage. RESULTS: A total of 134 knees with a median follow-up time of 32 months were included. Tibiofemoral rotation (TFR) was significantly higher in the nonlateralisation group than in the lateralisation group (15.4° vs. 9.4°, P < 0.001). At the final follow-up, the nonlateralisation group had significantly lower Kujala (78.2 vs. 86.4, P = 0.001) and Lysholm (80.3 vs. 88.2, P = 0.003) scores than the lateralisation group. At the time of the second-look arthroscopic assessment, 38.9% of the patients in the nonlateralisation group showed cartilage worsening in the medial patellar facet that was significantly higher than that in the lateralisation group (38.9% vs. 12.5%, P = 0.015). CONCLUSION: Patients with RPD and an increased TT-TG distance of > 20 mm but without actual tibial tubercle lateralisation benefit less from tibial tubercle transfer than patients with actual tibial tubercle lateralisation, which may be related to the significantly higher tibiofemoral rotation angle of the former. LEVEL OF EVIDENCE: III.


Assuntos
Luxações Articulares , Instabilidade Articular , Luxação Patelar , Articulação Patelofemoral , Humanos , Luxação Patelar/cirurgia , Articulação Patelofemoral/cirurgia , Rotação , Tíbia/cirurgia , Osteotomia , Estudos Retrospectivos , Instabilidade Articular/etiologia , Instabilidade Articular/cirurgia
17.
Molecules ; 28(5)2023 Feb 22.
Artigo em Inglês | MEDLINE | ID: mdl-36903293

RESUMO

The phytochemical investigation of the roots of the traditional Chinese medicinal plant Sophora flavescens led to the isolation of two novel prenylflavonoids with an unusual cyclohexyl substituent instead of the common aromatic ring B, named 4',4'-dimethoxy-sophvein (17) and sophvein-4'-one (18), and 34 known compounds (1-16, 19-36). The structures of these chemical compounds were determined by spectroscopic techniques, including 1D-, 2D-NMR, and HRESIMS data. Furthermore, evaluations of nitric oxide (NO) production inhibitory activity against lipopolysaccharide (LPS)-treated RAW264.7 cells indicated that some compounds exhibited obvious inhibition effects, with IC50 ranged from 4.6 ± 1.1 to 14.4 ± 0.4 µM. Moreover, additional research demonstrated that some compounds inhibited the growth of HepG2 cells, with an IC50 ranging from 0.46 ± 0.1 to 48.6 ± 0.8 µM. These results suggest that flavonoid derivatives from the roots of S. flavescens can be used as a latent source of antiproliferative or anti-inflammatory agents.


Assuntos
Flavonoides , Sophora , Flavonoides/química , Sophora flavescens , Sophora/química , Anti-Inflamatórios/farmacologia , Raízes de Plantas/química , Extratos Vegetais/farmacologia , Espectroscopia de Ressonância Magnética
18.
Mol Pain ; 18: 17448069221126078, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-36039405

RESUMO

Ginsenoside Rh2 is one of the major bioactive ginsenosides in Panax ginseng. Although Rh2 is known to enhance immune cells activity for treatment of cancer, its anti-inflammatory and neuroprotective effects have yet to be determined. In this study, we investigated the effects of Rh2 on spared nerve injury (SNI)-induced neuropathic pain and elucidated the potential mechanisms. We found that various doses of Rh2 intrathecal injection dose-dependently attenuated SNI-induced mechanical allodynia and thermal hyperalgesia. Rh2 also inhibited microglia and astrocyte activation in the spinal cord of a murine SNI model. Rh2 treatment inhibited SNI-induced increase of proinflammatory cytokines, including tumor necrosis factor-α, interleukin (IL)-1 and IL-6. Expression of miRNA-21, an endogenous ligand of Toll like receptor (TLR)8 was also decreased. Rh2 treatment blocked the mitogen-activated protein kinase (MAPK) signaling pathway by inhibiting of phosphorylated extracellular signal-regulated kinase expression. Finally, intrathecal injection of TLR8 agonist VTX-2337 reversed the analgesic effect of Rh2. These results indicated that Rh2 relieved SNI-induced neuropathic pain via inhibiting the miRNA-21-TLR8-MAPK signaling pathway, thus providing a potential application of Rh2 in pain therapy.


Assuntos
Ginsenosídeos , MicroRNAs , Neuralgia , Fármacos Neuroprotetores , Analgésicos/uso terapêutico , Animais , Anti-Inflamatórios/uso terapêutico , MAP Quinases Reguladas por Sinal Extracelular , Ginsenosídeos/farmacologia , Ginsenosídeos/uso terapêutico , Hiperalgesia/tratamento farmacológico , Interleucina-6 , Ligantes , Camundongos , MicroRNAs/genética , Neuralgia/tratamento farmacológico , Neuralgia/metabolismo , Fármacos Neuroprotetores/uso terapêutico , Ratos , Ratos Sprague-Dawley , Receptor 8 Toll-Like , Fator de Necrose Tumoral alfa/metabolismo
19.
Appl Environ Microbiol ; 88(9): e0034122, 2022 05 10.
Artigo em Inglês | MEDLINE | ID: mdl-35442081

RESUMO

Isopropanol dehydrogenase (IPADH) is one of the most attractive options for nicotinamide cofactor regeneration due to its low cost and simple downstream processing. However, poor thermostability and strict cofactor dependency hinder its practical application for bioconversions. In this study, we simultaneously improved the thermostability (433-fold) and catalytic activity (3.3-fold) of IPADH from Brucella suis via a flexible segment engineering strategy. Meanwhile, the cofactor preference of IPADH was successfully switched from NAD(H) to NADP(H) by 1.23 × 106-fold. When these variants were employed in three typical bioredox reactions to drive the synthesis of important chiral pharmaceutical building blocks, they outperformed the commonly used cofactor regeneration systems (glucose dehydrogenase [GDH], formate dehydrogenase [FDH], and lactate dehydrogenase [LDH]) with respect to efficiency of cofactor regeneration. Overall, our study provides two promising IPADH variants with complementary cofactor specificities that have great potential for wide applications. IMPORTANCE Oxidoreductases represent one group of the most important biocatalysts for synthesis of various chiral synthons. However, their practical application was hindered by the expensive nicotinamide cofactors used. Isopropanol dehydrogenase (IPADH) is one of the most attractive biocatalysts for nicotinamide cofactor regeneration. However, poor thermostability and strict cofactor dependency hinder its practical application. In this work, the thermostability and catalytic activity of an IPADH were simultaneously improved via a flexible segment engineering strategy. Meanwhile, the cofactor preference of IPADH was successfully switched from NAD(H) to NADP(H). The resultant variants show great potential for regeneration of nicotinamide cofactors, and the engineering strategy might serve as a useful approach for future engineering of other oxidoreductases.


Assuntos
NAD , Niacinamida , 2-Propanol , Formiato Desidrogenases/genética , NADP , Regeneração
20.
Inorg Chem ; 61(10): 4302-4311, 2022 Mar 14.
Artigo em Inglês | MEDLINE | ID: mdl-35212526

RESUMO

Mechanoluminescence materials that emit light under mechanical stimulation have attracted widespread attention in sensing, anticounterfeiting, and imaging applications. In this study, a series of Sr1-xBixZnSO (0.001 ≤ x ≤ 0.1) samples was synthesized by the method of high temperature solid-state reaction. It is worth noting that the distortion degree of the SrO3S3 octahedron was increased with increasing Bi3+ concentration, and the color manipulated Sr1-xBixZnSO which can emit different photoluminescence (blue to dark blue and finally red) and mechanoluminescence (orange to red) colors is obtained. Moreover, the deep traps can stably store and provide electronic supplements in shallow traps released under mechanical stimulation. Therefore, devices made of SrZnSO:Bi3+ phosphor and polydimethylsiloxane (PDMS) can be used as thermo-mechano-opto three-mode anticounterfeiting. The ML intensity is linear to the external load and can be utilized for stress sensing or imaging.

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