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BACKGROUND: Chemotherapy-Induced Peripheral Neuropathy (CIPN) is a common complication that arises from the use of anticancer drugs. Huangqi Guizhi Wuwu Decoction (HGWWD) is an effective classic prescription for treating CIPN however, the mechanism of the activity is not entirely understood. OBJECTIVE: This study aimed to investigate the remedial effects and mechanisms of HGWWD on CIPN. METHODS: Changes in behavioral biochemical histopathological and biomarker indices were used to evaluate the efficacy of HGWWD treatment. Ultra-high-performance liquid chromatography/mass spectrometry combined with the pattern recognition method was used to screen biomarkers and metabolic pathways related to CIPN. The results of pathway analyses were verified by protein blotting experiments. RESULTS: A total of 29 potential biomarkers were identified and 13 metabolic pathways were found to be involved in CIPN. In addition HGWWD reversed the levels of 19 biomarkers. Prostaglandin H2 and 17α 21-dihydroxypregnenolone were targeted as core biomarkers. CONCLUSION: This study provides scientific evidence to support the finding that HGWWD mainly inhibits the inflammatory response during CIPN by regulating arachidonic acid metabolism.
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The benzofuran core inhibitors HCV-796, BMS-929075, MK-8876, compound 2, and compound 9B exhibit good pan-genotypic activity against various genotypes of NS5B polymerase. To elucidate their mechanism of action, multiple molecular simulation methods were used to investigate the complex systems of these inhibitors binding to GT1a, 1b, 2a, and 2b NS5B polymerases. The calculation results indicated that these five inhibitors can not only interact with the residues in the palm II subdomain of NS5B polymerase, but also with the residues in the palm I subdomain or the palm I/III overlap region. Interestingly, the binding of inhibitors with longer substituents at the C5 position (BMS-929075, MK-8876, compound 2, and compound 9B) to the GT1a and 2b NS5B polymerases exhibits different binding patterns compared to the binding to the GT1b and 2a NS5B polymerases. The interactions between the para-fluorophenyl groups at the C2 positions of the inhibitors and the residues at the binding pockets, together with the interactions between the substituents at the C5 positions and the residues at the reverse ß-fold (residues 441-456), play a key role in recognition and the induction of the binding. The relevant studies could provide valuable information for further research and development of novel anti-HCV benzofuran core pan-genotypic inhibitors.
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Antivirales , Benzofuranos , Genotipo , Hepacivirus , Proteínas no Estructurales Virales , Proteínas no Estructurales Virales/antagonistas & inhibidores , Proteínas no Estructurales Virales/metabolismo , Proteínas no Estructurales Virales/química , Benzofuranos/química , Benzofuranos/farmacología , Hepacivirus/efectos de los fármacos , Hepacivirus/enzimología , Hepacivirus/genética , Antivirales/farmacología , Antivirales/química , Simulación de Dinámica Molecular , Simulación del Acoplamiento Molecular , Sitios de Unión , Unión Proteica , Humanos , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/química , ARN Polimerasa Dependiente del ARNRESUMEN
PURPOSE: The KUNPENG study aimed to evaluate the efficacy and safety of vebreltinib (also known as bozitinib, APL-101, PLB-1001, and CBT-101), a potent and highly selective inhibitor of c-mesenchymal-epithelial transition (MET), in patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) harboring c-Met alterations. METHODS: This multicenter, multicohort, open-label, single-arm, phase II trial enrolled patients with c-Met dysregulated, locally advanced or metastatic NSCLC from January 2020 to August 2022 across 17 centers. Cohort 1 included patients with MET exon 14 skipping (METex14)-mutant NSCLC who had not previously received MET inhibitors. Participants were administered vebreltinib at a dosage of 200 mg twice a day in 28-day cycles. The primary end point was the objective response rate (ORR), and the key secondary end point was the duration of response (DoR), both evaluated by a blinded independent review committee according to the RECIST version 1.1. RESULTS: As of August 9, 2022, 52 patients had been enrolled in cohort 1, of whom 35 (67.3%) were treatment-naïve. The ORR reached 75% (95% CI, 61.1 to 86). Among treatment-naïve patients, the ORR was 77.1% (95% CI, 59.9 to 89.6), and in previously treated patients, it was 70.6% (95% CI, 44.0 to 89.7). The disease control rate was 96.2%, with a median DoR of 15.9 months, a median progression-free survival of 14.1 months, and a median overall survival of 20.7 months. The most common treatment-related adverse events were peripheral edema (82.7%), QT prolongation (30.8%), and elevated serum creatinine (28.8%). CONCLUSION: Vebreltinib has shown promising efficacy and a favorable safety profile in patients with METex14-mutant NSCLC.
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The stimulator of interferon genes (STING) plays a significant role in immune defense and protection against tumor proliferation. Many cyclic dinucleotide (CDN) analogues have been reported to regulate its activity, but the dynamic process involved when the ligands activate STING remains unclear. In this work, all-atom molecular dynamics simulations were performed to explore the binding mode between human STING (hSTING) and four cyclic adenosine-inosine monophosphate analogs (cAIMPs), as well as 2',3'-cGMP-AMP (2',3'-cGAMP). The results indicate that these cAIMPs adopt a U-shaped configuration within the binding pocket, forming extensive non-covalent interaction networks with hSTING. These interactions play a significant role in augmenting the binding, particularly in interactions with Tyr167, Arg238, Thr263, and Thr267. Additionally, the presence of hydrophobic interactions between the ligand and the receptor further contributes to the overall stability of the binding. In this work, the conformational changes in hSTING upon binding these cAIMPs were also studied and a significant tendency for hSTING to shift from open to closed state was observed after binding some of the cAIMP ligands.
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Proteínas de la Membrana , Simulación de Dinámica Molecular , Unión Proteica , Humanos , Proteínas de la Membrana/química , Proteínas de la Membrana/metabolismo , Sitios de Unión , Nucleótidos Cíclicos/química , Nucleótidos Cíclicos/metabolismo , Ligandos , Interacciones Hidrofóbicas e HidrofílicasRESUMEN
The design and construction of highly efficient electrocatalysts for overall water splitting and urea electrolysis are significantly important for promoting energy conversion and realizing green hydrogen production. In this work, we constructed a multi-phase heterojunction through a simple hydrothermal and phosphorization process. The P-doped NiFe2O4 (P-NiFe2O4) nanoparticles were uniformly anchored on the bamboo-like N-doped carbon nanotubes (NCNTs) grown via a NiFe-alloy autocatalysis. The electronic structure and coordination environment of active species were optimized by the synergistic action of P doping, well-dispersed ultrafine NiFe2O4, and NCNTs matrix with good conductivity, enhancing their quantity and activity for electrocatalysis. Consequently, the P-NiFe2O4/NCNTs/NiFe exhibits excellent HER and OER activities with an overpotential of 111 and 266â mV at 10â mA cm-2 in 1â M KOH, respectively. The symmetrical overall water-splitting cell using P-NiFe2O4/NCNTs/NiFe as both anode and cathode delivers 10â mA cm-2 at a voltage of 1.604â V in 1â M KOH. Notably, the two-electrode cell requires a low voltage of 1.467â V to achieve a current density of 10â mA cm-2 in 1â M KOH solution with 0.6â M urea. This designed catalysts display outstanding reaction kinetics and catalytic stability. This work provides useful guidance for applying transition metal-based catalysts for hydrogen production.
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Globally, prostate cancer is the most commonly diagnosed tumor and a cause of death in older men. Abiraterone, an orally administered irreversible CYP17 inhibitor, is employed to treat prostate cancer. However, abiraterone has several clinical limitations, such as poor water solubility, low dissolution rate, low bioavailability, and toxic side effects in the liver and kidney. Therefore, there is a need to identify high-efficiency and low-toxicity water-soluble abiraterone derivatives. In this work, we aimed to design and synthesize a series of abiraterone derivatives by methoxypoly(ethylene glycol) (mPEG) modification. Their antitumor activities and toxicology were analyzed in vitro and in vivo. The most potent compound, 2e, retained the principle of action on the CYP17 enzyme target and significantly improved the abiraterone water solubility, cell permeability, and blood safety. No significant abnormalities were observed in toxicology. mPEG-modification significantly improved abiraterone's antitumor activity and efficiency while reducing the associated toxic effects. The finding will provide a theoretical basis for future clinical application of mPEG-modified abiraterone.
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Androstenos , Antineoplásicos , Polietilenglicoles , Neoplasias de la Próstata , Solubilidad , Masculino , Humanos , Androstenos/farmacología , Androstenos/química , Animales , Neoplasias de la Próstata/tratamiento farmacológico , Neoplasias de la Próstata/patología , Antineoplásicos/farmacología , Antineoplásicos/química , Polietilenglicoles/química , Ratones , Línea Celular Tumoral , Ensayos Antitumor por Modelo de Xenoinjerto , Esteroide 17-alfa-Hidroxilasa/antagonistas & inhibidores , Esteroide 17-alfa-Hidroxilasa/metabolismoRESUMEN
Type 2 diabetes mellitus (T2DM) is a metabolic disease. Diabetes increases the risk of benign prostatic hyperplasia (BPH). Capsaicin is extracted from chili peppers and possesses many pharmacological properties, including anti-diabetic, pain-relieving, and anti-cancer properties. This study aimed to investigate the effects of capsaicin on glucose metabolism and prostate growth in T2DM mice and uncover the related mechanisms. Mice model of diabetes was established by administering a high-fat diet and streptozotocin. Oral administration of capsaicin for 2 weeks inhibited prostate growth in testosterone propionate (TP)-treated mice. Furthermore, oral administration of capsaicin (5 mg/kg) for 2 weeks decreased fasting blood glucose, prostate weight, and prostate index in diabetic and TP-DM mice. Histopathological alterations were measured using hematoxylin & eosin (H&E) staining. The protein expression of 5α-reductase type II, androgen receptor (AR), and prostate-specific antigen (PSA) were upregulated in diabetic and TP-DM mice, but capsaicin reversed these effects. Capsaicin decreased the protein expression of p-AKT, insulin-like growth factor-1 (IGF-1), IGF-1R, and the receptor for advanced glycation end products (RAGE) in diabetic and TP-DM mice. Capsaicin also regulated epithelial-mesenchymal transition (EMT) and modulated the expression of fibrosis-related proteins, including E-cadherin, N-cadherin, vimentin, fibronectin, α-SMA, TGFBR2, TGF-ß1, and p-Smad in TP-DM mice. In this study, capsaicin alleviated diabetic prostate growth by attenuating EMT. Mechanistically, capsaicin affected EMT by regulating RAGE/IGF-1/AKT, AR, and TGF-ß/Smad signalling pathways. These results provide with new therapeutic approach for treating T2DM or T2DM-induced prostate growth.
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We previously demonstrated that baicalin had efficacy against gouty arthritis (GA) by oral administration. In this paper, a novel baicalin-loaded microemulsion-based gel (B-MEG) was prepared and assessed for the transdermal delivery of baicalin against GA. The preparation method and transdermal capability of B-MEG was screened and optimized using the central composite design, Franz diffusion cell experiments, and the split-split plot design. Skin irritation tests were performed in guinea pigs. The anti-gout effects were evaluated using mice. The optimized B-MEG comprised of 50 % pH 7.4 phosphate buffered saline, 4.48 % ethyl oleate, 31.64 % tween 80, 13.88 % glycerin, 2 % borneol, 0.5 % clove oil and 0.5 % xanthan gum, with a baicalin content of (10.42 ± 0.08) mg/g and particle size of (15.71 ± 0.41) nm. After 12 h, the cumulative amount of baicalin permeated from B-MEG was (672.14 ± 44.11) µg·cm-2. No significant skin irritation was observed following B-MEG application. Compared to the model group, B-MEG groups significantly decreased the rate of auricular swelling (P < 0.01) and number of twists observed in mice (P < 0.01); and also reduced the rate of paw swelling (P < 0.01) and inflammatory cell infiltration in a mouse model of GA. In conclusion, B-MEG represents a promising transdermal carrier for baicalin delivery and can be used as a potential therapy for GA.
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Herein, we investigate the product type and distribution during the synthesis of azido-functionalized larger polyhedral oligomeric silsesquioxanes (POSSs) using 3-chloropropyl- and chloromethyldimethylsilylethyl-functionalized T8, T10, and T12 POSSs as precursors. Our findings indicate that cage rearrangement occurs for the 3-chloropropyl-functionalized POSS cages with a stability order of T12 > T10 > T8, while the chloromethyldimethylsilylethyl-functionalized POSS cages remain structurally intact after the nucleophilic substitution.
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OBJECTIVE: This study aimed to evaluate preoperative (pre-op) radiographic characteristics and specific surgical interventions in patients with degenerative lumbar spondylolisthesis (DLS) who underwent lumbar fusion surgery (LFS), with a focus on analyzing predictors of postoperative restoration of segmental lumbar lordosis (SLL). METHODS: A retrospective review at a single center identified consecutive single-level DLS patients who underwent LFS between 2016 and 2022. Radiographic measures included disc angle (DA), SLL, lumbar lordosis (LL), anterior/posterior disc height (ADH/PDH), spondylolisthesis percentage (SP), intervertebral disc degeneration, and paraspinal muscle quality. Surgery-related measures included cage position, screw insertion depth, spondylolisthesis reduction rate, and disc height restoration rate. A change in SLL ≥ 4° indicated increased segmental lumbar lordosis (ISLL), and unincreased segmental lumbar lordosis (UISLL) < 4°. Propensity score matching was employed for a 1:1 match between ISLL and UISLL patients based on age, gender, body mass index, smoking status, and osteoporosis condition. RESULTS: A total of 192 patients with an average follow-up of 20.9 months were enrolled. Compared to UISLL patients, ISLL patients had significantly lower pre-op DA (6.78° vs. 11.84°), SLL (10.73° vs. 18.24°), LL (42.59° vs. 45.75°), and ADH (10.09 mm vs. 12.21 mm) (all, P < 0.05). ISLL patients were predisposed to more severe intervertebral disc degeneration (P = 0.047) and higher SP (21.30% vs. 19.39%, P = 0.019). The cage was positioned more anteriorly in ISLL patients (67.00% vs. 60.08%, P = 0.000), with more extensive reduction of spondylolisthesis (- 73.70% vs. - 56.16%, P = 0.000) and higher restoration of ADH (33.34% vs. 8.11%, P = 0.000). Multivariate regression showed that lower pre-op SLL (OR 0.750, P = 0.000), more anterior cage position (OR 1.269, P = 0.000), and a greater spondylolisthesis reduction rate (OR 0.965, P = 0.000) significantly impacted SLL restoration. CONCLUSIONS: Pre-op SLL, cage position, and spondylolisthesis reduction rate were identified as significant predictors of SLL restoration after LFS for DLS. Surgeons are advised to meticulously select patients based on pre-op SLL and strive to position the cage more anteriorly while minimizing spondylolisthesis to maximize SLL restoration.
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Lordosis , Vértebras Lumbares , Fusión Vertebral , Espondilolistesis , Humanos , Espondilolistesis/cirugía , Espondilolistesis/diagnóstico por imagen , Masculino , Fusión Vertebral/métodos , Femenino , Lordosis/cirugía , Lordosis/diagnóstico por imagen , Vértebras Lumbares/cirugía , Vértebras Lumbares/diagnóstico por imagen , Persona de Mediana Edad , Anciano , Estudios Retrospectivos , Degeneración del Disco Intervertebral/cirugía , Degeneración del Disco Intervertebral/diagnóstico por imagen , Resultado del Tratamiento , Radiografía/métodosRESUMEN
Repair of bone defects exceeding a critical size has been always a big challenge in clinical practice. Tissue engineering has exhibited great potential to effectively repair the defects with less adverse effect than traditional bone grafts, during which how to induce vascularized bone formation has been recognized as a critical issue. Therefore, recently many studies have been launched to attempt to promote osteogenesis-angiogenesis coupling. This review summarized comprehensively and explored in depth current efforts to ameliorate the coupling of osteogenesis and angiogenesis from four aspects, namely the optimization of scaffold components, modification of scaffold structures, loading strategies for bioactive substances, and employment tricks for appropriate cells. Especially, the advantages and the possible reasons for every strategy, as well as the challenges, were elaborated. Furthermore, some promising research directions were proposed based on an in-depth analysis of the current research. This paper will hopefully spark new ideas and approaches for more efficiently boosting new vascularized bone formations.
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Huesos , Neovascularización Fisiológica , Osteogénesis , Ingeniería de Tejidos , Andamios del Tejido , Osteogénesis/efectos de los fármacos , Humanos , Neovascularización Fisiológica/efectos de los fármacos , Animales , Andamios del Tejido/química , AngiogénesisRESUMEN
The 2-hydroxy-4-(methylthio) butanoic acid isopropyl ester (HMBi), a rumen protective methionine, has been extensively studied in dairy cows and beef cattle and has been shown to regulate gastrointestinal microbiota and improve production performance. However, knowledge of the application of HMBi on cashmere goats and the simultaneous study of rumen and hindgut microbiota is still limited. In this study, HMBi supplementation increased the concentration of total serum protein, the production of microbial protein in the rumen and feces, as well as butyrate production in the feces. The results of PCoA and PERMANOVA showed no significant difference between the rumen microbiota, but there was a dramatic difference between the fecal microbiota of the two groups of Cashmere goats after the HMBi supplementation. Specifically, in the rumen, HMBi significantly increased the relative abundance of some fiber-degrading bacteria (such as Fibrobacter) compared with the CON group. In the feces, as well as a similar effect as in the rumen (increasing the relative abundance of some fiber-degrading bacteria, such as Lachnospiraceae FCS020 group and ASV32), HMBi diets also increased the proliferation of butyrate-producing bacteria (including Oscillospiraceae UCG-005 and Christensenellaceae R-7 group). Overall, these results demonstrated that HMBi could regulate the rumen and fecal microbial composition of Liaoning cashmere goats and benefit the host.
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Ésteres , Microbiota , Animales , Bovinos , Femenino , Ácido Butírico/farmacología , Ácido Butírico/metabolismo , Ésteres/metabolismo , Rumen/microbiología , Fermentación , Cabras , Dieta/veterinaria , Heces , Bacterias/metabolismo , Suplementos Dietéticos , Alimentación Animal/análisis , Lactancia/fisiologíaRESUMEN
To counteract the high level of reactive oxygen species (ROS) caused by rapid growth, tumor cells resist oxidative stress by accelerating the production and regeneration of intracellular glutathione (GSH). Numerous studies focus on the consumption of GSH, but the regeneration of GSH will enhance the reduction level of tumor cells to resist oxidative stress. Therefore, inhibiting the regeneration of GSH; while, consuming GSH is of great significance for breaking the redox balance of tumor cells. Herein, a simple termed MnOx-coated Au (AMO) nanoflower, as a nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX) nanoenzyme, is reported for efficient tumor therapy. Au nanoparticles exhibit the capability to catalyze the oxidation of NADPH, hindering GSH regeneration; while, concurrently functioning as a photothermal agent. During the process of eliminating intracellular GSH, MnOx releases Mn2+ that subsequently engages in Fenton-like reactions, ultimately facilitating the implementation of chemodynamic therapy (CDT). Overall, this NOX enzyme-based nanoplatform enhances ROS generation and disrupts the state of reduction equilibrium, inducing apoptosis and ferroptosis by blocking GSH regeneration and increasing GSH consumption, thereby achieving collaborative treatments involving photothermal therapy (PTT), CDT, and catalytic therapy. This research contributes to NADPH and GSH targeted tumor therapy and showcases the potential of nanozymes.
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Glutatión , NADPH Oxidasas , Especies Reactivas de Oxígeno , Glutatión/metabolismo , Humanos , Animales , Ratones , Especies Reactivas de Oxígeno/metabolismo , NADPH Oxidasas/metabolismo , Oro/química , Línea Celular Tumoral , Nanopartículas del Metal/química , Neoplasias/tratamiento farmacológico , Neoplasias/metabolismo , Neoplasias/terapia , Neoplasias/patología , Óxidos/química , Óxidos/farmacología , Compuestos de Manganeso/química , Compuestos de Manganeso/farmacología , Terapia Fototérmica , Apoptosis/efectos de los fármacos , NADP/metabolismo , Ferroptosis/efectos de los fármacosRESUMEN
Lysine-specific demethylase 1 (LSD1/KDM1A) has emerged as a promising therapeutic target for treating various cancers (such as breast cancer, liver cancer, etc.) and other diseases (blood diseases, cardiovascular diseases, etc.), owing to its observed overexpression, thereby presenting significant opportunities in drug development. Since its discovery in 2004, extensive research has been conducted on LSD1 inhibitors, with notable contributions from computational approaches. This review systematically summarizes LSD1 inhibitors investigated through computer-aided drug design (CADD) technologies since 2010, showcasing a diverse range of chemical scaffolds, including phenelzine derivatives, tranylcypromine (abbreviated as TCP or 2-PCPA) derivatives, nitrogen-containing heterocyclic (pyridine, pyrimidine, azole, thieno[3,2-b]pyrrole, indole, quinoline and benzoxazole) derivatives, natural products (including sanguinarine, phenolic compounds and resveratrol derivatives, flavonoids and other natural products) and others (including thiourea compounds, Fenoldopam and Raloxifene, (4-cyanophenyl)glycine derivatives, propargylamine and benzohydrazide derivatives and inhibitors discovered through AI techniques). Computational techniques, such as virtual screening, molecular docking and 3D-QSAR models, have played a pivotal role in elucidating the interactions between these inhibitors and LSD1. Moreover, the integration of cutting-edge technologies such as artificial intelligence holds promise in facilitating the discovery of novel LSD1 inhibitors. The comprehensive insights presented in this review aim to provide valuable information for advancing further research on LSD1 inhibitors.
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Productos Biológicos , Inhibidores Enzimáticos , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/química , Lisina , Simulación del Acoplamiento Molecular , Inteligencia Artificial , Diseño de Fármacos , Histona Demetilasas/metabolismo , Relación Estructura-ActividadRESUMEN
Mesoporous silica nanoparticles (MSNs) have been widely praised as nanoadjuvants in vaccine/tumor immunotherapy thanks to their excellent biocompatibility, easy-to-modify surface, adjustable particle size, and remarkable immuno-enhancing activity. However, the application of MSNs is still greatly limited by some severe challenges including the unclear and complicated relationships of structure and immune effect. Herein, three commonly used MSNs with different skeletons including MSN with tetrasulfide bonds (TMSN), MSN containing ethoxy framework (EMSN), and pure -Si-O-Si- framework of MSN (MSN) are comprehensively compared to study the impact of chemical construction on immune effect. The results fully demonstrate that the three MSNs have great promise in improving cellular immunity for tumor immunotherapy. Moreover, the TMSN performs better than the other two MSNs in antigen loading, cellular uptake, reactive oxygen species (ROS) generation, lymph node targeting, immune activation, and therapeutic efficiency. The findings provide a new paradigm for revealing the structure-function relationship of mesoporous silica nanoadjuvants, paving the way for their future clinical application.
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Nanopartículas , Neoplasias , Nitrilos , Humanos , Porosidad , Dióxido de Silicio/química , Inmunoterapia , Nanopartículas/química , Neoplasias/terapia , EsqueletoRESUMEN
The cooling power of a radiative cooler is more than halved in the tropics, e.g., Singapore, because of its harsh weather conditions including high humidity (84% on average), strong downward atmospheric radiation (â¼40% higher than elsewhere), abundant rainfall, and intense solar radiation (up to 1200 W/m2 with â¼58% higher UV irradiation). So far, there has been no report of daytime radiative cooling that well achieves effective subambient cooling. Herein, through integrated passive cooling strategies in a hydrogel with desirable optofluidic properties, we demonstrate stable subambient (4-8 °C) cooling even under the strongest solar radiation in Singapore. The integrated passive cooler achieves an ultrahigh cooling power of â¼350 W/m2, 6-10 times higher than a radiative cooler in a tropical climate. An in situ study of radiative cooling with various hydration levels and ambient humidity is conducted to understand the interaction between radiation and evaporative cooling. This work provides insights for the design of an integrated cooler for various climates.
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Candida albicans is responsible for conditions ranging from superficial infections such as oral or vaginal candidiasis to potentially fatal systemic infections. It produces pathogenic factors contributing to its virulence. Iturin A, a lipopeptide derived from Bacillus sp., exhibits a significant inhibitory effect against C. albicans. However, its exact mechanism in mitigating the pathogenic factors of C. albicans remains to be elucidated. This study aimed to explore the influence of iturin A on several pathogenic attributes of C. albicans, including hypha formation, cell membrane permeability, cell adhesion, biofilm formation, and therapeutic efficacy in an oral C. albicans infection model in mice. The minimal inhibitory concentration of iturin A against C. albicans was determined to be 25 µg/mL in both YEPD and RPMI-1640 media. Iturin A effectively inhibited C. albicans hyphal formation, decreased cell viability within biofilms, enhanced cell membrane permeability, and disrupted cell adhesion in vitro. Nonetheless, iturin A did not significantly affect the phospholipase activity or hydrophobicity of C. albicans. A comparative study with nystatin demonstrated the superior therapeutic efficacy of iturin A in a mouse model of oral C. albicans infection, significantly decreasing C. albicans count and inhibiting both fungal hypha formation and tongue surface adhesion. High-dose iturin A treatment (25 µg/mL) in mice had no significant effects on blood indices, tongue condition, or body weight, indicating the potential for iturin A in managing oral infections. This study confirmed the therapeutic potential of iturin A and provided valuable insights for developing effective antifungal therapies targeting C. albicans pathogenic factors.
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Candida albicans , Candidiasis , Femenino , Ratones , Animales , Antifúngicos/farmacología , Antifúngicos/uso terapéutico , Factores de Virulencia , Candidiasis/tratamiento farmacológico , BiopelículasRESUMEN
Eggs rich in polyunsaturated fatty acids (PUFA), known as functional eggs, are animal products deemed beneficial to human health and possess high economic value. The production of functional eggs involves supplementing exogenous additives with the ability to regulate lipid metabolism. As N-Carbamylglutamate (NCG) serves as an endogenous arginine synthesizer, and arginine acts as the substrate for the formation of nitric oxide (NO), the biological function of NCG is partially mediated by NO. NO is a key regulatory molecule in lipid metabolism, suggesting that NCG may also have the ability to modulate lipid metabolism. In order to assess the capacity of NCG in regulating liver lipid metabolism and its potential application in producing functional eggs, we conducted a study to investigate the effects of dietary supplementation of NCG on production performance, serum, and liver NO levels, yolk fatty acid composition, and the liver transcriptome of layers. In this study, we utilized 30 layers of the Jinghong No.1 breed, all aged 45 wk. All the birds were randomly divided into 2 groups. Each group had 5 replicates, and each replicate had 3 birds. We provided them with different diets: one group received the basic diet, and the other group's diet was supplemented with 0.08% NCG. The experiment lasted for 14 wk. The results did not reveal any positive impact of NCG on production performance. However, NCG supplementation elevated NO levels in serum and liver, along with an increase in yolk PUFA, ω-3, and ω-6 fatty acids. Liver transcriptome analysis identified 124 upregulated differentially expressed genes (DEGs) and 43 downregulated DEGs due to NCG supplementation. Functional annotation using the Kyoto Encyclopedia of Genes and Genomes (KEGG) database highlighted 3 upregulated DEGs (CPT1A, MOGAT1, and CHKA) and 2 downregulated DEGs (FASN and ETNPPL) associated with lipid metabolism. Pathway enrichment analysis revealed that CPT1A was enriched in the AMPK signaling pathway and the PPAR signaling pathway, while FASN was enriched in the AMPK signaling pathway. Thus, CPT1A and FASN are potential functional genes related to lipid metabolism facilitated by NCG supplementation. In summary, our study suggests that NCG supplementation modulates liver lipid metabolism, leading to the production of functional eggs in layers.
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Huevos , Alimentos Funcionales , Glutamatos , Transcriptoma , Animales , Proteínas Quinasas Activadas por AMP/metabolismo , Alimentación Animal/análisis , Arginina/metabolismo , Pollos/genética , Pollos/metabolismo , Suplementos Dietéticos/análisis , Ácidos Grasos Insaturados/metabolismo , Glutamatos/administración & dosificación , Metabolismo de los Lípidos/efectos de los fármacos , Hígado/metabolismo , Transcriptoma/efectos de los fármacos , Distribución AleatoriaRESUMEN
As an important chemical raw material, hydrazine brings convenience to people's lives and provides opportunities for human development. However, the misuse or leakage of hydrazine has brought pollution to the environment, including water, soil and living organisms. At the same time, hydrazine poses a potential threat to human health as a carcinogen. Despite the enormous challenges, it is crucial to develop an effective method to detect hydrazine in environmental samples. In this work, we have synthesized a series of probes based on phenothiazine fluorophore by the introduction of different substituents and developed a novel probe for the detection of hydrazine. The probe is capable of detecting hydrazine in aqueous solutions with high sensitivity and selectivity, and can be easily fabricated into paper test strips for use in in situ samples. In addition, the probe is effective in detecting hydrazine in water, soil, cells, and zebrafish, providing an excellent tool for detecting hydrazine in the environment.
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Colorantes Fluorescentes , Pez Cebra , Animales , Humanos , Colorantes Fluorescentes/química , Hidrazinas/química , Fenotiazinas , Agua , Suelo , Espectrometría de FluorescenciaRESUMEN
PURPOSE: To compare the clinical effectiveness of reduction and fusion with in situ fusion in the management of patients with degenerative lumbar spondylolisthesis (DLS). METHODS: The systematic review was conducted following the PRISMA guidelines. Relevant studies were identified from PubMed, Embase, Scopus, Cochrane Library, ClinicalTrials.gov, and Google Scholar. The inclusion criteria were: (1) comparative studies of reduction and fusion versus in situ fusion for DLS patients, (2) outcomes reported as VAS/NRS, ODI, JOA score, operating time, blood loss, complication rate, fusion rate, or reoperation rate, (3) randomized controlled trials and observational studies published in English from the inception of the databases to January 2023. The exclusion criteria included: (1) reviews, case series, case reports, letters, and conference reports, (2) in vitro biomechanical studies and computational modeling studies, (3) no report on study outcomes. The risk of bias 2 (RoB2) tool and the Newcastle-Ottawa scale was conducted to assess the risk of bias of RCTs and observational studies, respectively. RESULTS: Five studies with a total of 704 patients were included (375 reduction and fusion, 329 in situ fusion). Operating time was significantly longer in the reduction and fusion group compared to in situ fusion group (weighted mean difference 7.20; 95% confidence interval 0.19, 14.21; P = 0.04). No additional significant intergroup differences were noted in terms of other outcomes analyzed. CONCLUSION: While the reduction and fusion group demonstrated a statistically longer operating time compared to the in situ fusion group, the clinical significance of this difference was minimal. The findings suggest no substantial superiority of lumbar fusion with reduction over without reduction for the management of DLS.