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A simple, inexpensive and versatile patterned removal of C-C grafts has been realized for scalable multicomponent micropatterned functionalization.
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Major depressive disorder is a chronic mental health condition that seriously impacts afflicted individuals. Although electroacupuncture has proven to be an effective therapy for depression, its underlying biological mechanism remains largely unknown. In this study, we aimed to investigate the effects of electroacupuncture on depression-like behavior and to identify potential target genes related to those effects. To achieve this, we subjected rats to chronic unpredictable mild stress (CUMS) and used sucrose preference, forced swimming, and open-field tests to determine their depression-like behavior in the absence or after receipt of electroacupuncture treatment. RNA sequencing technology was then used to reveal the differentially expressed genes associated with depression and electroacupuncture treatment effects in the medial prefrontal cortex (mPFC). Repeated electroacupuncture treatments at the Baihui (GV20) and Taichong (LR3) acupoints significantly alleviated depression-like behavioral defects in the animals. Genomic RNA sequencing revealed several significant changes in the mPFC transcriptome of rats that received treatment. Through differential gene expression analysis, we found that electroacupuncture reversed the CUMS-induced downregulation of 46 genes and upregulation of 13 genes. Among the differentially expressed genes, Casr, Bdkrb2, Gnb3, and Ccl1 were found to be associated with depression and electroacupuncture treatment effects. In conclusion, we verified that electroacupuncture treatment has an effective antidepressant effect, and the underlying mechanism involves multiple systems and targets.
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BACKGROUND: The aim of this study was to investigate the frequency dependence of electroacupuncture (EA) in alleviating chronic visceral pain in patients with irritable bowel syndrome (IBS) and the differences in the gut microbiota and metabolites as potential mechanisms to explain frequency dependence. METHODS: A visceral hyperalgesia model was established by colorectal instillation of 2,4,6-trinitrobenzene sulfonic acid in rats, and EA treatment at 2/10 Hz, 2/50 Hz and 2/100 Hz was applied at ST25. Visceral sensation was quantified by the abdominal withdrawal reflex score and the area under the curve of the rectus abdominis electromyogram in response to colorectal distension. Ultrastructural morphological damage of colonic tissue of the rats was examined by transmission electron microscopy. 16S rRNA gene sequencing and 1H-nuclear magnetic resonance spectroscopy were applied to study the differences in the gut microbiota and to perform metabonomic profiling of the colonic tissue. KEY RESULTS: EA at ST25 at different frequencies attenuated chronic visceral pain, ultrastructural morphological damage to colonic tissue and disruption of the gut microbiota in IBS rats. The frequency of 2/100 Hz has more regulatory pathways than 2/10 Hz and 2/50 Hz. In addition, IBS rats exhibited colonic metabolic disorders, and pantothenate was significantly upregulated after EA treatment at different frequencies. Very low-density lipoprotein and 2-hydroxybutyrate were significantly increased in the 2/10 Hz group, while low density lipoprotein, very low-density lipoprotein, 2-hydroxybutyrate, methylmalonate and alpha-hydroxyisobutyric acid were significantly increased in the 2/100 Hz group. CONCLUSIONS AND INFERENCES: EA at ST25 at different frequencies attenuated chronic visceral pain through different gut microbiota and metabolic pathways.
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Type 1 insulin-like growth factor receptor (IGF1R) plays an important role in cancer, however, posttranscriptional regulation such as N6-methyladenosine (m6A) of IGF1R remains unclear. Here, we reveal a role for a lncRNA Downregulated RNA in Cancer (DRAIC) suppress tumor growth and metastasis in clear cell Renal Carcinoma (ccRCC). Mechanistically, DRAIC physically interacts with heterogeneous nuclear ribonucleoprotein A2B1 (hnRNPA2B1) and enhances its protein stability by blocking E3 ligase F-box protein 11 (FBXO11)-mediated ubiquitination and proteasome-dependent degradation. Subsequently, hnRNPA2B1 destabilizes m6A modified-IGF1R, leading to inhibition of ccRCC progression. Moreover, four m6A modification sites are identified to be responsible for the mRNA degradation of IGF1R. Collectively, our findings reveal that DRAIC/hnRNPA2B1 axis regulates IGF1R mRNA stability in an m6A-dependent manner and highlights an important mechanism of IGF1R fate. These findings shed light on DRAIC/hnRNPA2B1/FBXO11/IGF1R axis as potential therapeutic targets in ccRCC and build a link of molecular fate between m6A-modified RNA and ubiquitin-modified protein.
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Ribonucleoproteína Heterogénea-Nuclear Grupo A-B , Neoplasias Renales , Receptor IGF Tipo 1 , Humanos , Receptor IGF Tipo 1/metabolismo , Receptor IGF Tipo 1/genética , Ratones , Neoplasias Renales/genética , Neoplasias Renales/patología , Neoplasias Renales/metabolismo , Animales , Ribonucleoproteína Heterogénea-Nuclear Grupo A-B/metabolismo , Ribonucleoproteína Heterogénea-Nuclear Grupo A-B/genética , Progresión de la Enfermedad , Estabilidad del ARN/genética , Carcinoma de Células Renales/patología , Carcinoma de Células Renales/genética , Carcinoma de Células Renales/metabolismo , ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismo , Línea Celular Tumoral , Regulación Neoplásica de la Expresión Génica , Estabilidad Proteica , Adenosina/análogos & derivados , Adenosina/metabolismo , Ubiquitinación , Proliferación Celular/genética , Ratones DesnudosRESUMEN
BACKGROUND: Currently, a variety of Western medical interventions are available for the treatment of diarrhea-predominant irritable bowel syndrome (IBS-D) with comorbid anxiety and depression. However, the attendant negative effects also emerge, putting pressure on healthcare resources and socio-economic structures. In recent years, the benefits of acupuncture (ACU) and moxibustion in the treatment of IBS-D with anxiety and depression have gradually emerged. However, there are many types of ACU-moxibustion-related treatments, and the aim of this study is to examine the effectiveness of different ACU-moxibustion therapies in the treatment of anxiety and depression in IBS-D patients. METHODS: Searched and identified randomized controlled trials (RCTS) of ACU for the treatment of anxiety and depression in patients with irritable bowel syndrome (IBS). The search spanned from the establishment of the database until September 1, 2023. Revman 5.4 and Stata 15.0 software were used for network meta-analysis (NMA), and the included interventions were ranked by the area under the cumulative ranking curve. RESULTS: A total of 26 articles involving 8 interventions were included. In terms of improving HAMA score, MOX was superior to EA, combined therapies, CH, WM and placebo; In terms of improving HAMD score, MOX was superior to ACU, EA, combined therapies, WM and placebo; In terms of improving the SAS score, The combined therapies were superior to EA, CH and WM; In terms of improving SDS scores, The combined therapies were superior to EA, CH and WM; In terms of improving IBS-SSS score, The combined therapies were superior to WM; In terms of reducing recurrence rates, CH was superior to combined therapies; In terms of improving total effective rates, MOX was superior to EA, CH, WM and placebo; MOX, combined therapies, ACU and EA ranked higher in SUCRA of different outcome indicators. CONCLUSION: MOX, combined therapies, ACU and EA have certain curative effect on anxiety and depression in patients with IBS-D, and their safety is high. ACU and MOX combined with other therapies also have significant advantages in the treatment effect.
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Terapia por Acupuntura , Ansiedad , Depresión , Síndrome del Colon Irritable , Moxibustión , Metaanálisis en Red , Humanos , Moxibustión/métodos , Terapia por Acupuntura/métodos , Síndrome del Colon Irritable/terapia , Síndrome del Colon Irritable/psicología , Síndrome del Colon Irritable/complicaciones , Ansiedad/terapia , Ansiedad/etiología , Depresión/terapia , Depresión/etiología , Ensayos Clínicos Controlados Aleatorios como Asunto , Resultado del TratamientoRESUMEN
Visceral hypersensitivity, a common clinical manifestation of irritable bowel syndrome, may contribute to the development of chronic visceral pain, which is a major challenge for both patients and health providers. Neural circuits in the brain encode, store, and transfer pain information across brain regions. In this review, we focus on the anterior cingulate cortex and paraventricular nucleus of the hypothalamus to highlight the progress in identifying the neural circuits involved in visceral pain. We also discuss several neural circuit mechanisms and emphasize the importance of cross-species, multiangle approaches and the identification of specific neurons in determining the neural circuits that control visceral pain.
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Hipersensibilidad , Síndrome del Colon Irritable , Dolor Visceral , Humanos , Encéfalo , NeuronasRESUMEN
Objective: This study aims to evaluate the efficacy and safety of various acupuncture treatments in conjunction with multimodal analgesia (MA) for managing postoperative pain and improving knee function in patients undergoing total knee arthroplasty (TKA), based on the findings from clinical research indicating the potential benefits of acupuncture-related therapies in this context. Methods: We searched Web of Science, PubMed, SCI-hub, Embase, Cochrane Library, China Biology Medicine (CBM), China National Knowledge Infrastructure (CNKI), Wanfang Data, and Chinese Scientific Journal Database (VIP) to collect randomized controlled trials of acupuncture-related therapies for post-TKA pain. After independent screening and data extraction, the quality of the included literature was evaluated. The potential for bias in the studies incorporated in the analysis was assessed according to the guidelines outlined in the Cochrane Handbook 5.1. Network meta-analysis (NMA) was conducted using RevMan 5.4 and Stata 16.0 software, with primary outcome measures including visual analog scale (VAS), pain pressure threshold (PPT), hospital for special surgery knee score (HSS), and knee joint range of motion (ROM). Furthermore, the interventions were ranked based on the SUCRA value. Results: We conducted an analysis of 41 qualifying studies encompassing 3,003 patients, examining the efficacy of four acupuncture therapies (acupuncture ACU, electroacupuncture EA, transcutaneous electrical acupoint stimulation TEAS, and auricular acupoint therapy AAT) in conjunction with multimodal analgesia (MA) and MA alone. The VAS results showed no significant difference in efficacy among the five interventions for VAS-3 score. However, TEAS+MA (SMD: 0.67; 95%CI: 0.01, 1.32) was more effective than MA alone for VAS-7 score. There was no significant difference in PPT score among the three interventions. ACU + MA (SMD: 6.45; 95%CI: 3.30, 9.60), EA + MA (SMD: 4.89; 95%CI: 1.46, 8.32), and TEAS+MA (SMD: 5.31; 95%CI: 0.85, 9.78) were found to be more effective than MA alone for HSS score. For ROM score, ACU + MA was more efficacious than EA + MA, TEAS+MA, and AAT + MA, MA. Regarding the incidence of postoperative adverse reactions, nausea and vomiting were more prevalent after using only MA. Additionally, the incidence of postoperative dizziness and drowsiness following ACU + MA (OR = 4.98; 95%CI: 1.01, 24.42) was observed to be higher compared to that after AAT + MA intervention. Similarly, the occurrence of dizziness and drowsiness after MA was found to be significantly higher compared to the following interventions: TEAS+MA (OR = 0.36; 95%CI: 0.18, 0.70) and AAT + MA (OR = 0.20; 95%CI: 0.08, 0.50). The SUCRA ranking indicated that ACU + MA, EA + MA, TEAS+MA, and AAT + MA displayed superior SUCRA scores for each outcome index, respectively. Conclusion: For the clinical treatment of post-TKA pain, acupuncture-related therapies can be selected as a complementary and alternative therapy. EA + MA and TEAS+MA demonstrate superior efficacy in alleviating postoperative pain among TKA patients. ACU + MA is the optimal choice for promoting postoperative knee joint function recovery in TKA patients. AAT + MA is recommended for preventing postoperative adverse reactions. Systematic review registration: https://www.crd.york.ac.uk/, identifier (CRD42023492859).
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Depression is characterized by the loss of pleasure and a depressed mood, and it is a common mental disorder in the twenty-first century. Multiple gene imbalances, which are considered pathological factors in depression, were detected in the brain. Electroacupuncture is an effective therapeutic approach for depression that has minimal side effects. As a crucial structure in the hypothalamus-pituitary-adrenal, the hypothalamus plays a key role in depression. Our study focused on the transcriptome level in the hypothalamus of depressive rats. After chronic unpredictable mild stress, the rats exhibited depressive-like behaviors, such as decreased sucrose consumption in the SPT, increased time in the central area of the OFT and increased immobility in the FST. Moreover, electroacupuncture alleviated depressive behaviors. Because of the importance of the hypothalamus in depression, we next detected gene expression in the hypothalamus. A total of 510 genes (125 upregulated genes and 385 downregulated genes) were detected in the hypothalamus of depressive rats. 15 of the 125 upregulated genes and 63 of the 385 downregulated genes could be altered by electroacupuncture, which suggests the antidepressant effect of electroacupuncture. Our study also provided the evidence that regulation of transcriptome in the hypothalamus might be a potential mechanism of electroacupuncture treatment.
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Depresión , Electroacupuntura , Humanos , Ratas , Animales , Depresión/terapia , Depresión/tratamiento farmacológico , Ratas Sprague-Dawley , Hipotálamo/metabolismo , Expresión Génica , Estrés Psicológico/terapia , Estrés Psicológico/metabolismo , Modelos Animales de Enfermedad , HipocampoRESUMEN
Introduction: The rhizosphere microbiome is critical to plant health and resistance. PGPR are well known as plant-beneficial bacteria and generally regulate nutrient utilization as well as plant responses to environmental stimuli. In our previous work, one typical PGPR strain, Pseudomonas chlororaphis IRHB3, isolated from the soybean rhizosphere, had positive impacts on soil-borne disease suppression and growth promotion in the greenhouse, but its biocontrol mechanism and application in the field are not unclear. Methods: In the current study, IRHB3 was introduced into field soil, and its effects on the local rhizosphere microbiome, disease resistance, and soybean growth were comprehensively analyzed through high-throughput sequencing and physiological and molecular methods. Results and discussion: We found that IRHB3 significantly increased the richness of the bacterial community but not the structure of the soybean rhizosphere. Functional bacteria related to phosphorus solubilization and nitrogen fixation, such as Geobacter, Geomonas, Candidatus Solibacter, Occallatibacter, and Candidatus Koribacter, were recruited in rich abundance by IRHB3 to the soybean rhizosphere as compared to those without IRHB3. In addition, the IRHB3 supplement obviously maintained the homeostasis of the rhizosphere microbiome that was disturbed by F. oxysporum, resulting in a lower disease index of root rot when compared with F. oxysporum. Furthermore, JA-mediated induced resistance was rapidly activated by IRHB3 following PDF1.2 and LOX2 expression, and meanwhile, a set of nodulation genes, GmENOD40b, GmNIN-2b, and GmRIC1, were also considerably induced by IRHB3 to improve nitrogen fixation ability and promote soybean yield, even when plants were infected by F. oxysporum. Thus, IRHB3 tends to synergistically interact with local rhizosphere microbes to promote host growth and induce host resistance in the field.
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Pseudomonas syringae pv. actinidiae causes kiwifruit bacterial canker and poses a major threat to the kiwifruit industry. This study aimed to investigate the genetic characteristics of the P. syringae pv. actinidiae population from kiwifruit in Sichuan, China. Sixty-seven isolates obtained from diseased plants were characterized using morphological features, multiplex-PCR, and multilocus sequence analysis (MLSA). The isolates exhibited the typical colony morphology of P. syringae pv. actinidiae. Multiplex PCR amplification identified every isolate as P. syringae pv. actinidiae biovar 3. MLSA of the three housekeeping genes gapA, gyrB, and pfk, revealed that the reference strains of the five described biovars were clearly distinguished by a combined phylogenetic tree, and all of the tested isolates clustered with the reference strains of P. syringae pv. actinidiae biovar 3. Through a phylogenetic tree constructed from a single gene, it was found that pkf gene alone could distinguish biovar 3 from the other biovars. Furthermore, all P. syringae pv. actinidiae isolates analyzed by BOX-A1R-based repetitive extragenic palindromic (BOX)-PCR and enterobacterial repetitive intergenic consensus (ERIC)-PCR clustered into four groups. The clustering results of BOX- and ERIC-PCR indicated that group III had the largest number of isolates, accounting for 56.72 and 61.19% of all 67 isolates, respectively, and the two characterization methods were similar and complementary. The results of this study revealed that the genomes of P. syringae pv. actinidiae isolates from Sichuan had rich genetic diversity but no obvious correlation was found between clustering and geographical region. This research provides novel methodologies for rapidly detecting kiwifruit bacterial canker pathogen and a molecular differentiation at genetic level of P. syringae pv. actinidiae biovar diversity in China.
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Actinidia , Pseudomonas syringae , Filogenia , Enfermedades de las Plantas/microbiología , Tipificación de Secuencias Multilocus , Actinidia/microbiología , ChinaRESUMEN
Virtual screening is an efficient way to obtain new drugs, which has become an important method in the field of pesticide research. Protein neural wiskott-Aldrich syndrome isoform X1 (PcnWAS) is a target protein that exists in the haemocytes of Pomacea canaliculata, and in this study, isothermal titration calorimetry (ITC) was used to evaluate the binding ability of protein PcnWAS and pedunsaponin A in vitro. Furthermore, it was set as a receptor, and the design of molluscicidal compounds based on protein PcnWAS was carried out. Results showed that, pedunsaponin A had high binding capacity with protein PcnWAS, and the binding constant (Ka) was 2.98 ± 1.74 × 10-4. A new potential molluscicidal compound thionicotinamide-adenine-dinucleotide (thionicotinamide-DPN) was obtained by virtual screening. In-vivo bioassay indicated that, the LC50 value was 57.7102 mg/L (72 h), and the oxygen consumption rate, ammonia excretion rate, oxygen nitrogen ratio and hemocyanin content of P. canaliculata declined after 60 mg/L thionicotinamide-DPN treated. Furthermore, the treatment of thionicotinamide-DPN also decreased gene expression level of protein PcnWAS. The results of ITC test showed that thionicotinamide-DPN can bind with protein PcnWAS efficiently, which means that it has the same target with pedunsaponin A when interacted with P. canaliculata. All the above results lay a foundation for the development of new molluscicides.
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Moluscocidas , Saponinas , Triterpenos , Animales , Caracoles , Moluscocidas/farmacología , ProteínasRESUMEN
OBJECTIVE: To study whether electroacupuncture (EA) of "Zusanli" (ST36) combined with "Tianshu" (ST25) has a synergistic effect in regulating the colonic function and autonomic nerve balance in rats with irritable bowel syndrome (IBS). METHODS: Male Wistar rats were randomly divided into control, model, EA-ST36, and EA-ST36+ST25 groups, with 14 rats in each group. The IBS model was established by using water avoidance stress method. The visceral hypersensitivity was measured using the abdominal wall retraction reflex (AWR). The rectus abdominis electromyogram (EMG), intestinal electrical activity, and electrocardiogram (ECG) were recorded using a PowerLab data acquisition and analysis system. The contents of serum cAMP and cGMP were determined by ELISA, the expression levels of colonic tyrosine hydroxylase (TH) and choline acetyl-transferase (ChAT) proteins were determined by immunofluorescence staining and Western blot, respectively. RESULTS: Compared with the control group, the model group had an evident increase in the levels of AWR, LF, LF/HF, ChAT protein expression, cAMP and cGMP contents and cAMP/cGMP ratio (P<0.001, P<0.05), and a marked decrease in the levels of HF, frequency of slow waves of intestinal EMG, visceral pain threshold (PT), immunoactivity and expression of TH protein (P<0.05, P<0.001). In contrast to the model group, the levels of AWR, LF, LF/HF, ChAT protein expression and immunoactivity, cAMP and cGMP contents and ratio of cAMP/cGMP were significantly reduced (P<0.001, P<0.05, P<0.01), whereas the levels of frequency of slow waves of intestinal EMG, PT, and the immunoactivity and expression of TH were considerably increased (P<0.001, P<0.05) in both EA-ST36 and EA-ST36+ST25 groups. CONCLUSION: EA of both ST36 and ST36+ST25 can relieve visceral pain, and reduce sympathetic activity to improve autonomic nerve balance, but without apparent synergistic effect between EA-ST36 and EA-ST25 in rats with IBS.
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Electroacupuntura , Síndrome del Colon Irritable , Masculino , Ratas , Animales , Ratas Wistar , Defecación , Vías Autónomas , GMP CíclicoRESUMEN
Overexpression of Ras, in addition to the oncogenic mutations, occurs in various human cancers. However, the mechanisms for epitranscriptic regulation of RAS in tumorigenesis remain unclear. Here, we report that the widespread N6-methyladenosine (m6A) modification of HRAS, but not KRAS and NRAS, is higher in cancer tissues compared with the adjacent tissues, which results in the increased expression of H-Ras protein, thus promoting cancer cell proliferation and metastasis. Mechanistically, three m6A modification sites of HRAS 3' UTR, which is regulated by FTO and bound by YTHDF1, but not YTHDF2 nor YTHDF3, promote its protein expression by the enhanced translational elongation. In addition, targeting HRAS m6A modification decreases cancer proliferation and metastasis. Clinically, up-regulated H-Ras expression correlates with down-regulated FTO and up-regulated YTHDF1 expression in various cancers. Collectively, our study reveals a linking between specific m6A modification sites of HRAS and tumor progression, which provides a new strategy to target oncogenic Ras signaling.
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Neoplasias , Humanos , Dioxigenasa FTO Dependiente de Alfa-Cetoglutarato/genética , Carcinogénesis , Transformación Celular Neoplásica/genética , Neoplasias/genética , Proteínas Proto-Oncogénicas p21(ras) , Transducción de Señal , Transcripción GenéticaRESUMEN
Soybean (Glycine max L.) is one of the important oilseed and vegetable crop worldwide and provides the main source of vegetable oil and proteins for human and livestock (Hartman et al. 2011). In October 2021, approximately 35% of soybean pods suffered from anthracnose in the farmer's field in Chongzhou, Sichuan Province, China (103°40'12"E, 30°37'48"N), and the occurrence area accounted for about 3.3 hm2. Symptoms of soybean were characterized by yellow spots at the initial stage, gradually expanded into dark brown spots, and eventually amounts of small black particles were densely arranged in the wheel shape on dead spots. Diseased spots of soybean pods were cut into pieces and sequentially sterilized in 75% alcohol for 30 s, 4% sodium hypochlorite for 30 s, sterile water for 3 times. After that, these pieces were placed on potato dextrose agar (PDA), and incubated at 25±2°C in the dark for 5-7 days. Single spore was separately picked and transferred to a fresh PDA plate to obtain pure culture isolates. Total six pure isolates were collected, and among them the hyphae of representative isolate 8-B were initially white, turned grey gradually on PDA medium, and the colonial reverse were radiating, whorled or a mixture of both. Conidia of 8-B were septate, hyaline, unicellular, cylindrical, obtusely rounded at both ends with 1 or 2 oil balls inside, and 10.5-17.6 µm in length and 7.0 µm-3.6 µm in width (n=100). The conidial appressoria were brown subspherical, 6.9 µm-13.3 µm in length and 5.6 µm-10.1 µm (n=50) in width. Based on morphological and cultural characteristics, the isolate 8-B was tentatively identified as Colletotrichum gloeosporioides species complexï¼Weir et al. 2012). To test pathogenicity, the mycelial plugs were inoculated on 20 detached soybean pods at full seed (R6) stage, and three areas of each pod were lightly scratched using a needle prior to inoculation. As controls, the PDA plugs were attached to the pinned-treated pods. Three independent replicates were conducted for control and inoculated pods, respectively. All pods were incubated in a greenhouse at 25 ± 2°C with a relative humidity of approximately 90%. After 4-5 days post-inoculation, typical anthracnose lesions were observed on the inoculated pods while the control pods remained healthy only with small wound spots. The pathogen re-isolated from all the inoculated pods were morphologically identical to the inoculation isolate (8-B). For further molecular verification, the six gene fragments including the internal transcribed spacer (ITS), glyceraldehyde-3-phosphate dehydrogenase (GAPDH), chitin synthase 1 (CHS-1), actin (ACT), ß-tubulin 2 (TUB2) and calmodulin (CAL) were amplified and sequenced (Weir et al. 2012, Damm et al. 2012), and the obtained sequences were deposited in GenBank (Accession numbers ON960278, ON685214, ON964475, ON974476, ON685215 and ON964477, respectively). All six gene sequences of 8-B had a high identity to C. fructicola (the stand isolate ICMP 18581) with the accession numbers ON960278 (100%), ON974476 (96%), ON685214 (99%), ON964475 (99%), ON685215 (100%), and ON964477 100%), respectively. Anthracnose disease caused by C. fructicola has previously been reported to affect a range of plant hosts worldwide (Guarnaccia et al. 2017). However, it is still unknown on C. fructicola causing anthracnose in soybean in China. This study firstly reports C. fructicola as the causal agent of anthracnose on soybean in the country, and provides a theoretical basis for the diagnosis and control of this disease.
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In modern pesticide discovery, target-based drug design is an attractive and cost-effective approach. Previous studies found that protein rootletin (PcRoo) is a target protein of arecoline, when interacted with Pomacea canaliculata. In this study, we modeled the target protein through threading, and the binding energy between arecoline and protein PcRoo was calculated as -5.02 kcal/mol by molecular docking. Furthermore, two target compounds, baclofen and acedoben, with molluscicidal activity in theory were obtained by virtual screening in database DrugBank. The in vivo bioassay showed that baclofen could induce typical poisoning symptoms on P. canaliculata, which were characterized by weakness of foot muscles and loss of gill cilia, and the LC50 value was 16.2437 mg/L (72 h). Additionally, after 15 mg/L baclofen treatment, the oxygen consumption rate, ammonia excretion rate, and oxygen nitrogen ratio of P. canaliculata declined. Furthermore, the treatment of baclofen also decreased the gene expression level of PcRoo. These trends were the same as the changes after 5 mg/L arecoline treatment. The pharmacophore characteristics were further analyzed, and the results showed that the chemical structures of baclofen and arecoline were correlated in molluscicidal activity. These findings indicate that baclofen has the potential to be used as a molluscicide in agricultural production, and other new molluscicides may be obtained by virtual screening based on protein PcRoo.
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Promoting myelination capacity of endogenous oligodendrocyte precursor cells (OPCs) is a promising therapeutic approach for CNS demyelinating disorders such as Multiple Sclerosis (MS). To aid in the discovery of myelination-promoting compounds, we generated a genome-engineered human pluripotent stem cell (hPSC) line that consists of three reporters: identification-and-purification tag, GFP, and secreted-NanoLuc, driven by the endogenous PDGFRA, PLP1, and MBP genes, respectively. Using this cell line, we established a high-throughput drug screening platform and performed a small-molecule screen, which identified at least two myelination-promoting small-molecule (Ro1138452 and SR2211) that target prostacyclin (IP) receptor and retinoic acid receptor-related orphan receptor γ (RORγ), respectively. Single-cell-transcriptomic analysis of differentiating OPCs treated with these molecules further confirmed that they promote oligodendrocyte differentiation and revealed several pathways that are potentially modulated by them. The molecules and their target pathways provide promising targets for the possible development of remyelination-based therapy for MS and other demyelinating disorders.
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This study aimed to examine the effect of venetoclax coupled with azacytidine in treating older adults with relapsed and refractory (R/R) acute myeloid leukemia (AML). The clinical data of 10 senior patients with AML over 65 years old who were treated with venetoclax and azacytidine, including six patients with R/R AML, were retrospectively evaluated. This study comprised seven males and three females with a median age of 71 years. Five patients had at least one relapse, and one patient did not achieve remission after four cycles of azacytidine monotherapy, considering it resistant. AML with myelodysplasia-related changes was found in four cases. One of the 10 patients died early after 1-13 cycles of venetoclax plus azacytidine treatment due to a protracted period of neutropenia and severe lung infection induced by medications. Six of the remaining nine patients, including six R/R patients, achieved a complete remission (CR) or a CR with incomplete hematologic recovery (CRi). After two cycles of therapy, one patient did not react. Neutropenia lasted an average of 10.5 (6-15) days in all patients, with the most severe cases occurring in the second and third weeks of therapy. Three patients who tested positive for the TP53 gene mutation had the following outcomes: One relapsed patient has been in progression-free remission (PFS) for the past 24 months, whereas another has been in full remission but relapsed 2 months later. Another patient experienced complete remission in myelology for 4 months, but the variable allele fraction (VAF) value steadily rose, suggesting that the illness was on the verge of progressing. IDH2 gene alterations were found in three of four patients who obtained maintained CR for more than 18 months following recurrence. Venetoclax in combination with azacytidine is a successful and well-tolerated therapy for R/R AML in the elderly. Venetoclax and azacytidine may help patients with TP53 mutations and reduce VAF. The IDH2 mutation might be a good predictor of veneclax sensitivity. A notable adverse response in the treatment phase of the regimen is severe infection induced by neutropenia.
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Leucemia Mieloide Aguda , Neutropenia , Masculino , Femenino , Humanos , Anciano , Azacitidina/efectos adversos , Estudios Retrospectivos , Leucemia Mieloide Aguda/tratamiento farmacológico , Compuestos Bicíclicos Heterocíclicos con Puentes , Neutropenia/inducido químicamente , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéuticoRESUMEN
Blueberry leaf spots and stem cankers caused by Pestalotiopsis spp. have become a serious threat for the production of blueberry in Sichuan Province. To characterize the etiology of the diseases connected with these fungi, samples showing leaf spot and stem canker symptoms were collected from the 12 main blueberry-growing areas of Sichuan Province from 2015 to 2020 and used for pathogen isolation. In total, 91 fungal isolates were obtained with preliminary morphological identification and 48 representative strains were selected for further pathogenicity test and molecular identification. Four species, including Pestalotiopsis clavispora (Neopestalotiopsis clavispora) (57.14%), P. trachicarpicola (28.57%), P. chamaeropis (13.19%), and P. adusta (1.10%), were identified based on conidial morphology, cultural characteristics, and phylogenetic analysis of the internal transcribed spacer region, partial sequence of the ß-tubulin gene, and the translation elongation factor 1-α. Pathogenicity tests showed that four species were pathogenic to leaves and stems of blueberry. Among them, P. clavispora (N. clavispora) was the most aggressive as the predominant species to cause both leaf spot and stem canker. P. trachicarpicola and P. chamaeropis were mainly isolated from leaves but also pathogenic to stems. P. adusta was only isolated from stems but also pathogenic to leaves. To the best of our knowledge, this is the first report of P. chamaeropis and P. adusta as pathogens causing leaf spots and stem canker on blueberry. The results provide helpful information in disease diagnosis and management of blueberry.
Asunto(s)
Arándanos Azules (Planta) , Pestalotiopsis , Filogenia , ChinaRESUMEN
BACKGROUND: The diamondback moth (DBM), Plutella xylostella (L.), is the most destructive pest of cruciferous vegetables worldwide. Chlorfenapyr is an important insecticide for controlling DBM. The impacts of three sublethal doses (LC1 , LC10 and LC30 ) of chlorfenapyr on the chlorfenapyr-exposed DBM individuals and their unexposed F1 and F2 offspring were investigated in order to reveal the non-lethal deleterious effects of chlorfenapyr and its potential hormetic effects. RESULTS: LC1 significantly increased female pupa weight of F0 and F1 generations, and F0 fecundity as well as F1 gross reproduction rate (GRR). The LC1 -elicited rise in emergency rate and fecundity was significantly greater in F0 than in F1 . By contrast, LC30 significantly decreased age-specific survival rates, pupation rate, male pupal weight, emergence rate and fecundity of F0 and F1 generations as well as female adult proportion and GRR, net reproduction rate (R0 ), intrinsic rate of increase (rm ) and finite rate of increase (λ) of F1 generation. The LC30 -induced reductions in pupation rate, adult emergence rate, male and female pupa weight, and fecundity were greater in F1 than in F0 . While LC10 elicited only a mild inhibition (extension of pupal duration) in F0 , it yielded both deleterious (drops in female proportion and age-specific survivals) and hormetic effects (ups in male longevity and female fecundity) in F1 . CONCLUSION: The results demonstrate that the sublethal effects of chlorfenapyr on DBM vary from inhibition to stimulatory hormesis, depending on the dose and generation. © 2022 Society of Chemical Industry.