Berberine Degradation Characteristics and its Degradation Pathway by a Newly Isolated Berberine-Utilizing Agrobacterium.

Berberine (BBR) is widely used as a botanical pesticide due to its broad-spectrum antibacterial and antifungal activities. However, BBR degradation pathway in soil microorganisms, which determines its impact on soil environment, remains poorly understood. Herein, a novel BBR-degrading bacterium Agrobacterium sp. V1 was isolated and characterized. Agrobacterium sp. V1 was able to utilize BBR as the sole carbon source for cell growth, and 50 µg/mL of BBR was completely degraded within 48 h. To reveal the possible BBR degradation pathway, whole genome sequencing of Agrobacterium sp. V1 was conducted, and proteins in Agrobacterium sp. V1 were aligned with enzymes involved in BBR biosynthesis in Rhizoma Coptidis. The results indicated that more than 60% of enzymes in BBR biosynthesis pathway had orthologs in Agrobacterium sp. V1. Combined with the primary mass spectra of BBR metabolites, a novel BBR degradation pathway in this bacterium was proposed. In summary, the proposed BBR degradation pathway offered new insights into the impact of BBR to the environment and also provided a reference for studying BBR metabolism in microorganisms.

Carborane-Cluster-Wrapped Copper Cluster with Cyclodextrin-like Cavities for Chiral Recognition.

Chiral atomically precise metal clusters, known for their remarkable chiroptical properties, hold great potential for applications in chirality recognition. However, advancements in this field have been constrained by the limited exploration of host-guest chemistry, involving metal clusters. This study reports the synthesis of a chiral Cu16(C2B10H10S2)8 (denoted as Cu16@CB8, where C2B10H12S2H2 = 9,12-(HS)2-1,2-closo-carborane) cluster by an achiral carboranylthiolate ligand. The chiral R-/S-Cu16@CB8 cluster features chiral cavities reminiscent of cyclodextrins, which are surrounded by carborane clusters, yet they crystallize in a racemate. These cyclodextrin-like cavities demonstrated the specific recognition of amino acids, as indicated by the responsive output of circular dichroism and circularly polarized luminescence signals of Cu16 moieties of the Cu16@CB8 cluster. Notably, a quantitative chiroptical analysis of amino acids in a short time and a concomitant deracemization of Cu16@CB8 were achieved. Density functional tight-binding molecular dynamics simulation and noncovalent interaction analysis further unraveled the great importance of the cavities and binding sites for chiral recognition. Dipeptide, tripeptide, and polypeptide containing the corresponding amino acids (Cys, Arg, or His residues) display the same chiral recognition, showing the generality of this approach. The functional synergy of dual clusters, comprising carborane and metal clusters, is for the first time demonstrated in the Cu16@CB8 cluster, resulting in the valuable quantification of the enantiomeric excess (ee) value of amino acids. This work opens a new avenue for chirality sensors based on chiral metal clusters with unique chiroptical properties and inspires the development of carborane clusters in host-guest chemistry.

Dietary Provision, GLIM-Defined Malnutrition and Their Association with Clinical Outcome: Results from the First Decade of nutritionDay in China.

Malnutrition is a common and serious issue that worsens patient outcomes. The effects of dietary provision on the clinical outcomes of patients of different nutritional status needs to be verified. This study aimed to identify dietary provision in patients with eaten quantities of meal consumption and investigate the effects of dietary provision and different nutritional statuses defined by the GLIM criteria on clinical outcomes based on data from the nutritionDay surveys in China. A total of 5821 adult in-patients from 2010 to 2020 were included in this study's descriptive and Cox regression analyses. Rehabilitation and home discharge of 30-day outcomes were considered a good outcome. The prevalence of malnutrition defined by the GLIM criteria was 22.8%. On nutritionDay, 51.8% of all patients received dietary provisions, including hospital food and a special diet. In multivariable models adjusting for other variables, the patients receiving dietary provision had a nearly 1.5 higher chance of a good 30-day outcome than those who did not. Malnourished patients receiving dietary provision had a 1.58 (95% CI [1.36-1.83], p < 0.001) higher chance of having a good 30-day outcome and had a shortened length of hospital stay after nutritionDay (median: 7 days, 95% CI [6-8]) compared to those not receiving dietary provision (median: 11 days, 95% CI [10-13]). These results highlight the potential impacts of the dietary provision and nutritional status of in-patients on follow-up outcomes and provide knowledge on implementing targeted nutrition care.

Protein Containing the GGDEF Domain Affects Motility and Biofilm Formation in Vibrio cholerae and is Negatively Regulated by Fur and HapR.

Objective: This study aimed to investigate whether the VCA0560 gene acts as an active diguanylate cyclase (DGC) in Vibrio cholerae and how its transcription is regulated by Fur and HapR. Methods: The roles of VCA0560 was investigated by utilizing various phenotypic assays, including colony morphological characterization, crystal violet staining, Cyclic di-GMP (c-di-GMP) quantification, and swimming motility assay. The regulation of the VCA0560 gene by Fur and HapR was analyzed by luminescence assay, electrophoretic mobility shift assay, and DNase I footprinting. Results: VCA0560 gene mutation did not affect biofilm formation, motility, and c-di-GMP synthesis in V. cholerae, and its overexpression remarkably enhanced biofilm formation and intracellular c-di-GMP level but reduced motility capacity. The transcription of the VCA0560 gene was directly repressed by Fur and the master quorum sensing regulator HapR. Conclusion: Overexpressed VCA0560 functions as an active DGC in V. cholerae, and its transcription is repressed by Fur and HapR.

Quantitative Assessment of Balance Function Characteristics in Older Patients with Orthostatic Hypotension.

BACKGROUND: Orthostatic hypotension (OH) is a common blood pressure abnormality in older adults that makes them prone to balance disorders and falls. The maintenance of balance relies on a complex regulatory system. The use of computerized dynamic posturography (CDP) can provide a quantitative evaluation of balance function. The objective of this study was to utilize CDP to measure balance indicators in older individuals with OH. METHODS: A total of 303 older adults were divided into an OH group of 91 and a non-OH group of 212. Various factors, including chronic diseases, medication history, laboratory tests, and balance indicators, were compared between the two groups. RESULTS: ① Participants with OH had more chronic diseases, including coronary heart disease (p = 0.049) and a history of falls (p < 0.001), than those without OH. A history of multiple medications in the OH group was significantly more likely than in the non-OH group (p = 0.006). ② There was a significant reduction in the composite equilibrium score (SOT-COM) (p < 0.001), vision ratio score (VIS) (p < 0.001), vestibular ratio score (VEST) (p < 0.001), and directional control (DCL) (p = 0.028) in the OH group. ③ A logistic regression analysis revealed that SOT-COM was a significant independent factor associated with OH. The area under the curve (AUC) of SOT-COM was 0.833 (95% confidence interval: 0.778-0.887, p < 0.001), with a sensitivity of 0.826 and a specificity of 0.759. CONCLUSIONS: This study demonstrates that older individuals with OH are more prone to falls, due to decreased sensory integration for balance.

Quantitative analysis of balance function characteristics in older patients with mild to moderate cognitive impairment.

BACKGROUND: Cognitive decline in older adults may affect balance function, but the relationship between the two is not fully understood, especially in the early stages of cognitive impairment. Mild to moderate cognitive impairment can be assessed with the Montreal Cognitive Assessment (MOCA). AIM: This study quantitatively analyzed balance function in older adults with mild to moderate cognitive impairment using computerized dynamic posturography (CDP) testing. METHODS: 248 older patients were divided into a cognitive impaired group (MOCA <26, n = 126) and a normal group (MOCA ≥26, n = 122) based on the Montreal Cognitive Assessment (MOCA) Beijing Version. Patients underwent CDP testing, which included the sensory organization test (SOT) and the limits of stability test (LOS). RESULTS: The cognitive impaired group had significantly lower SOT composite and visual scores, as well as reaction time (RT), movement velocity (MVL), endpoint excursion (EPE), maximum excursion (MXE), and directional control (DCL) of the LOS test. Binary logistic regression analysis revealed that RT and MXE were independent factors significantly associated with MOCA, even after adjustment for age and sex. CONCLUSIONS: Older patients with mild to moderate cognitive impairment may have reduced sensory integration and balance stability limits, mainly manifested as prolonged motor reaction time and shortened maximum movement distance.

Effects of early mental state changes on physical functions in elderly patients with a history of falls.

BACKGROUND: Fear of falling is a potential consequence for older adults who have experienced a fall. Whether such psychological concerns related to falls, in turn, affect physical function? Especially those who have a history of falling but have not been diagnosed with anxiety, depression, or both. This study aimed to clarify the effects of early psychological changes on the physical function of older patients. METHODS: The 111 participants with falling history were divided into the poor physical function (PPF) group with the Short Physical Performance Battery (SPPB) ≤ 9 and the good physical function (GPF) group with SPPB > 9. Their physical function was assessed through 4-m gait speed (4MGS), five times sit-to-stand test (FTSST), grip strength, and Timed Up and Go tests TUGT. Their mental state was assessed by the self-rating anxiety/depression scale (SAS/SDS). RESULTS: (1) SAS/SDS scores were negatively correlated with the SPPB score, gait speed, and maximum grip strength (males). (2) Multivariate logistic regression analysis showed that the SPPB score was subject to such independent influence factors: cerebrovascular disease (OR = 11.805; P = 0.005), normal ratio of grip strength (OR = 0.046; P = 0.016), TUGT (OR = 1.717; P < 0.001), and SDS score (OR = 1.154; P = 0.008). (3) The area under the ROC curve was 0.699 (0.601, 0.797) for SAS score, with a sensitivity of 0.776 and a specificity of 0.547; the AUC was 0.694 (0.596, 0.792) for SDS score, with a sensitivity of 0.586 and a specificity of 0.755. CONCLUSIONS: In older adults with a history of falls without a diagnosis of anxiety or depression, higher SAS/SDS scores were associated with worse fall-related physical function, and there was a statistically significant correlation between the two. This may indicate a risk of falling again in the future.

Normal Workflow and Key Strategies for Data Cleaning Toward Real-World Data: Viewpoint.

With the rapid development of science, technology, and engineering, large amounts of data have been generated in many fields in the past 20 years. In the process of medical research, data are constantly generated, and large amounts of real-world data form a "data disaster." Effective data analysis and mining are based on data availability and high data quality. The premise of high data quality is the need to clean the data. Data cleaning is the process of detecting and correcting "dirty data," which is the basis of data analysis and management. Moreover, data cleaning is a common technology for improving data quality. However, the current literature on real-world research provides little guidance on how to efficiently and ethically set up and perform data cleaning. To address this issue, we proposed a data cleaning framework for real-world research, focusing on the 3 most common types of dirty data (duplicate, missing, and outlier data), and a normal workflow for data cleaning to serve as a reference for the application of such technologies in future studies. We also provided relevant suggestions for common problems in data cleaning.

Ultrasound-guided acupotomy for trigger finger: a systematic review and meta-analysis.

BACKGROUND: Trigger finger is a common condition in the hand, and ultrasound-guided acupotomy for trigger finger has been widely used in recent years. PURPOSE: This study aims to investigate the efficacy and safety of ultrasound-guided acupotomy for trigger finger. METHODS: We searched for relevant studies in the Cochrane Library, China National Knowledge Infrastructure (CNKI), Embase, PubMed, Chinese Biomedical Literature Database (CBM), Wanfang Data, and other resources from their inception to January 2023. Randomized controlled trials of ultrasound-guided acupotomy for trigger finger were included. The meta-analysis was carried out using Review Manager 5.4 and Stata 15.1. RESULTS: Overall, 15 studies with 988 patients were included. The experimental group was treated with ultrasound-guided acupotomy, and the Control group received traditional acupotomy, traditional operation or injection of medication. Meta-analysis showed that the overall clinical effectiveness (OR = 4.83; 95% CI 2.49-9.37; I2 = 73.1%; P < 0.001) in the experimental group was significantly better than that of the control group. And the Visual Analogue Scale (VAS) score (WMD = - 1; 95% CI - 1.24, - 0.76; I2 = 99%; P < 0.001), the QuinneII classification (WMD = - 0.84; 95% CI - 1.28, - 0.39; I2 = 99.1%, P < 0.001), the incidence of complications (RR = 0.26; 95% CI 0.11, 0.63; I2 = 0%, P = 0.003), and the recurrence rate (RR = 0.14; 95% CI 0.03, 0.74; I2 = 0%; P = 0.021) were significantly lower in the experimental group. CONCLUSION: Our systematic review and meta-analysis can prove the effectiveness and safety of ultrasound-guided acupotomy in the treatment of trigger finger, but this still needs to be verified by a clinical standard large sample test.

Cortical activation of neuromuscular electrical stimulation synchronized mirror neuron rehabilitation strategies: an fNIRS study.

Background: The mirror neuron system (MNS) plays a key role in the neural mechanism underlying motor learning and neural plasticity. Action observation (AO), action execution (AE), and a combination of both, known as action imitation (AI), are the most commonly used rehabilitation strategies based on MNS. It is possible to enhance the cortical activation area and amplitude by combining traditional neuromuscular electrical stimulation (NMES) with other top-down and active rehabilitation strategies based on the MNS theory. Objective: This study aimed to explore the cortical activation patterns induced by NMES synchronized with rehabilitation strategies based on MNS, namely NMES+AO, NMES+AE, and NMES+AI. In addition, the study aimed to assess the feasibility of these three novel rehabilitative treatments in order to provide insights and evidence for the design, implementation, and application of brain-computer interfaces. Methods: A total of 70 healthy adults were recruited from July 2022 to February 2023, and 66 of them were finally included in the analysis. The cortical activation patterns during NMES+AO, NMES+AE, and NMES+AI were detected using the functional Near-Infrared Spectroscopy (fNIRS) technique. The action to be observed, executed, or imitated was right wrist and hand extension, and two square-shaped NMES electrodes were placed on the right extensor digitorum communis. A block design was adopted to evaluate the activation intensity of the left MNS brain regions. Results: General linear model results showed that compared with the control condition, the number of channels significantly activated (PFDR < 0.05) in the NMES+AO, NMES+AE, and NMES+AI conditions were 3, 9, and 9, respectively. Region of interest (ROI) analysis showed that 2 ROIs were significantly activated (PFDR < 0.05) in the NMES+AO condition, including BA6 and BA44; 5 ROIs were significantly activated in the NMES+AE condition, including BA6, BA40, BA44, BA45, and BA46; and 6 ROIs were significantly activated in the NMES+AI condition, including BA6, BA7, BA40, BA44, BA45, and BA46. Conclusion: The MNS was activated during neuromuscular electrical stimulation combined with an AO, AE, and AI intervention. The synchronous application of NMES and mirror neuron rehabilitation strategies is feasible in clinical rehabilitation. The fNIRS signal patterns observed in this study could be used to develop brain-computer interface and neurofeedback therapy rehabilitation devices.

A novel cuproptosis-related signature predicts prognosis and immunotherapy efficacy in lung adenocarcinoma.

BACKGROUND: Lung adenocarcinoma (LUAD) is the leading histological subtype of lung cancer worldwide, causing high annual mortality. Tsvetkov et al. recently found a new form of regulated cell death, termed cuproptosis. The prognostic value of cuproptosis-related gene signature in LUAD remains uncertain. METHODS: A training cohort is identified by the TCGA-LUAD dataset, whereas validation cohorts one and two are identified by GSE72094 and GSE68465, respectively. GeneCard and GSEA were used to extract genes related to cuproptosis. Cox regression, Kaplan-Meier regression, and LASSO regression were used to construct a gene signature. The model's applicability was evaluated by Kaplan-Meier estimators, Cox models, ROC, and tAUC across two independent validation cohorts. We examined the model's connections with other forms of regulated cell death. The immunotherapy ability of the signature was demonstrated by applying TMB, immune relevant signatures, and TIDE. The GSEA and immune infiltration analysis offer a better understanding of how the signature functions and the role of immune cells in its prognostic power. RESULTS: A ten-gene signature was built and demonstrated owning prognostic power by being applied to the validation cohorts. The GSEA uncovered that the unfolded protein response, glycolysis/gluconeogenesis, and MYC were highly related to the gene signature. The ten-gene signature is closely related to related genes of apoptosis, necroptosis, pyroptosis, and ferroptosis. Our signature may have utility in predicting immunotherapy efficacy in LUADs. Mast cells were identified as key players that support the predicting capacity of the ten-gene signature through the immune infiltrating analysis. CONCLUSIONS: The novel ten-gene signature associated with apoptosis in cuproptosis that we obtained may contribute to improved LUAD management strategies and the ability to predict response to LUAD immunotherapy. It is suggested that mast cell infiltration might be related to the prognostic power of this signature.

Effect of Stenotrophomonas maltophilia on Tuberculosis.

Tuberculosis (TB) is an important infectious disease suffered by many countries, including China. In this stage, accurate diagnosis and treatment are key measures for the prevention and control of TB. Stenotrophomonas maltophilia is a global emerging Gram-negative, multidrug-resistant (MDR) organism characterized by its high contribution to the increase in crude mortality rates. By single cell preparation and strain identification, we isolated S. maltophilia from stored cultures of Mycobacterium tuberculosis (Mtb). We found that S. maltophilia could not be removed from sputum by alkali treatment or inhibited by antibiotic mixture added to MGIT 960 indicator tubes. When co-cultured with Mtb on a Löwenstein-Jensen (L-J) slant, it could inhibit the growth of Mtb and liquefy the medium. More seriously, it was resistant to 10 of the 12 anti-TB drugs, including isoniazid and rifampin, and made the mixed samples display multidrug-resistant Mtb (MDR-TB) results in the drug sensitivity test, which might change a treatment regimen and increase disease burden. Following, we conducted a small-scale surveillance which showed that the isolation rate of S. maltophilia in TB patients was 6.74%, but these patients had no special characteristics and the presence of S. maltophilia was hidden. The effect of S. maltophilus on TB and its mechanism are unclear and require more attention. IMPORTANCE China is a high-burden country for tuberculosis (TB), multidrug-resistant/rifampicin-resistant tuberculosis (MDR/RR-TB), and HIV-associated TB. Increasing the positive rate of culture and the accuracy of antibiotic susceptibility testing (AST) are important for diagnosis, treatment, and control of TB. In our study, we found that the isolation rate of Stenotrophomonas maltophilia in TB patients was not neglectable and that this bacterium affects the isolation and AST results of TB. Due to a lack of relevant research, the impact of S. maltophilia on the course and outcome of TB is unclear. However, the characteristics of S. maltophilia that increase disease mortality require attention. Therefore, in the clinical testing of TB, in addition to mycobacteria, it is recommended to increase the detection of co-infected bacteria and improve the awareness of TB clinicians of these bacteria.

Diagnostic value of circular free DNA for colorectal cancer detection.

BACKGROUND: Minimally invasive or noninvasive, sensitive and accurate detection of colorectal cancer (CRC) is urgently needed in clinical practice. AIM: To identify a noninvasive, sensitive and accurate circular free DNA marker detected by digital polymerase chain reaction (dPCR) for the early diagnosis of clinical CRC. METHODS: A total of 195 healthy control (HC) individuals and 101 CRC patients (38 in the early CRC group and 63 in the advanced CRC group) were enrolled to establish the diagnostic model. In addition, 100 HC individuals and 62 patients with CRC (30 early CRC and 32 advanced CRC groups) were included separately to validate the model. CAMK1D was dPCR. Binary logistic regression analysis was used to establish a diagnostic model including CAMK1D and CEA. RESULTS: To differentiate between the 195 HCs and 101 CRC patients (38 early CRC and 63 advanced CRC patients), the common biomarkers CEA and CAMK1D were used alone or in combination to evaluate their diagnostic value. The area under the curves (AUCs) of CEA and CAMK1D were 0.773 (0.711, 0.834) and 0.935 (0.907, 0.964), respectively. When CEA and CAMK1D were analyzed together, the AUC was 0.964 (0.945, 0.982). In differentiating between the HC and early CRC groups, the AUC was 0.978 (0.960, 0.995), and the sensitivity and specificity were 88.90% and 90.80%, respectively. In differentiating between the HC and advanced CRC groups, the AUC was 0.956 (0.930, 0.981), and the sensitivity and specificity were 81.30% and 95.90%, respectively. After building the diagnostic model containing CEA and CAMK1D, the AUC of the CEA and CAMK1D joint model was 0.906 (0.858, 0.954) for the validation group. In differentiating between the HC and early CRC groups, the AUC was 0.909 (0.844, 0.973), and the sensitivity and specificity were 93.00% and 83.30%, respectively. In differentiating between the HC and advanced CRC groups, the AUC was 0.904 (0.849, 0.959), and the sensitivity and specificity were 93.00% and 75.00%, respectively. CONCLUSION: We built a diagnostic model including CEA and CAMK1D for differentiating between HC individuals and CRC patients. Compared with the common biomarker CEA alone, the diagnostic model exhibited significant improvement.

The Effect of Swallowing Action Observation Therapy on Resting fMRI in Stroke Patients with Dysphagia.

Objective: Many stroke victims have severe swallowing problems. Previous neuroimaging studies have found that several brain regions scattered in the frontal, temporal, and parietal lobes, such as Brodmann's areas (BA) 6, 21, and 40, are associated with swallowing function. This study sought to investigate changes in swallowing function and resting-state functional magnetic resonance imaging (rs-fMRI) in stroke patients with dysphagia following action observation treatment. It also sought to detect changes in brain regions associated with swallowing in stroke patients. Methods: In this study, 12 healthy controls (HCs) and 12 stroke patients were recruited. Stroke patients were given 4 weeks of action observation therapy. In order to assess the differences in mfALFF values between patients before treatment and HCs, the fractional amplitude of low-frequency fluctuations (fALFF) in three frequency bands (conventional frequency band, slow-4, and slow-5) were calculated for fMRI data. The significant brain regions were selected as regions of interest (ROIs) for subsequent analysis. The mfALFF values were extracted from ROIs of the three groups (patients before and after treatment and HCs) and compared to assess the therapeutic efficacy. Results: In the conventional band, stroke patients before treatment had higher mfALFF in the inferior temporal gyrus and lower mfALFF in the calcarine fissure and surrounding cortex and thalamus compared to HCs. In the slow-4 band, there was no significant difference in related brain regions between stroke patients before treatment and HCs. In the slow-5 band, stroke patients before treatment had higher mfALFF in inferior cerebellum, inferior temporal gyrus, middle frontal gyrus, and lower mfALFF in calcarine fissure and surrounding cortex compared to HCs. We also assessed changes in aberrant brain activity that occurred both before and after action observation therapy. The mfALFF between stroke patients after therapy was closed to HCs in comparison to the patients before treatment. Conclusion: Action observation therapy can affect the excitability of certain brain regions. The changes in brain function brought about by this treatment may help to further understand the potential mechanism of network remodeling of swallowing function.

Linarin Ameliorates Diabetic Liver Injury by Alleviating Oxidative Stress and Inflammation through the Inhibition of AKR1B1.

AIMS: The study aims to find a new functional additive for diabetic liver injury. BACKGROUND: It is well-established that type 2 diabetes mellitus (T2DM) is a metabolic disease with multiple complications and places a significant health and economic burden on modern society. Linarin is a natural flavonoid isolated from Asteraceae and Lamiaceae, which has beneficial effects in preventing and treating metabolic diseases such as nonalcoholic steatohepatitis and diabetes. OBJECTIVE: We aimed to investigate the pharmacological effect and underlying mechanism of linarin on T2DM-associated liver injury in vivo and in vitro. METHODS: Using a high-glucose and high-palmitic acid-induced hepatocyte injury model and a type 2 diabetic rat model. Following linarin treatment, serum biochemical parameters, liver histology, and lipid profiles of rats were examined. Oxidative stress index and inflammatory response were detected in vivo and in vitro. The expression level of AKR1B1 in rat liver tissues and in vitro cells was detected by western blot and by real-time fluorescent quantitative PCR. RESULTS: The present study found that linarin could prevent oxidative stress and inflammation. In high-fat-fed diabetic rats, linarin administration (15, 30, and 60 mg/kg/day) reduced hepatic lipid accumulation, oxidative stress, and inflammation. Linarin (20 µM) significantly alleviated oxidative stress, inflammation, and apoptosis induced by high glucose combined with palmitic acid in LX-2 cells. Western blotting and overexpression experiments showed that these effects were related to AKR1B1 inhibition in vivo and in vitro. CONCLUSION: This study indicated that linarin could protect against liver injury in T2DM by alleviating oxidative stress and inflammation mediated by AKR1B1 and may be a promising additive for diabetic liver injury therapy.

Loss of astrocytic A1 adenosine receptor is involved in a chemotherapeutic agent-induced rodent model of neuropathic pain.

INTRODUCTION/AIMS: Oxaliplatin is a commonly used platinum chemotherapy drug, whereas peripheral neurotoxicity is a widely observed adverse reaction lacking a satisfactory therapeutic strategy. Different adenosine receptors underlying the common neuropathic phenotype play different roles through varied pathophysiological mechanisms. In this study, we investigated the role of adenosine receptor A1 (A1R) in oxaliplatin-induced neuropathic pain and its potential use in an effective therapeutic strategy. METHODS: We established an oxaliplatin-induced neuropathic pain model simulating the mode of chemotherapy administration and observed the related neuropathic behavioral phenotype and implicated mechanisms. RESULTS: Five weekly injections of oxaliplatin for 2 weeks induced a severe and persistent neuropathic pain phenotype in mice. A1R expression in the spinal dorsal horn decreased during this process. Pharmacological intervention against A1R verified its importance in this process. Mechanistically, the loss of A1R expression was mainly attributed to its decreased expression in astrocytes. Consistent with the pharmacological results, the oxaliplatin-induced neuropathic pain phenotype was blocked by specific therapeutic interventions of A1R in astrocytes via lentiviral vectors, and the expression of glutamate metabolism-related proteins was upregulated. Neuropathic pain can be alleviated by pharmacological or astrocytic interventions via this pathway. DISCUSSION: These data reveal a specific adenosine receptor signaling pathway involved in oxaliplatin-induced peripheral neuropathic pain, which is related to the suppression of the astrocyte A1R signaling pathway. This may provide new opportunities for the treatment and management of neuropathic pain observed during oxaliplatin chemotherapy.

Chitinase Is Involved in the Fruiting Body Development of Medicinal Fungus Cordyceps militaris.

Cordyceps militaris is a famous traditional edible and medicinal fungus in Asia, and its fruiting body has rich medicinal value. The molecular mechanism of fruiting body development is still not well understood in C. militaris. In this study, phylogenetically analysis and protein domains prediction of the 14 putative chitinases were performed. The transcription level and enzyme activity of chitinase were significant increased during fruiting body development of C. militaris. Then, two chitinase genes (Chi1 and Chi4) were selected to construct gene silencing strain by RNA interference. When Chi1 and Chi4 genes were knockdown, the differentiation of the primordium was blocked, and the number of fruiting body was significantly decreased approximately by 50% compared to wild-type (WT) strain. The length of the single mature fruiting body was shortened by 27% and 38% in Chi1- and Chi4-silenced strains, respectively. In addition, the chitin content and cell wall thickness were significantly increased in Chi1- and Chi4-silenced strains. These results provide new insights into the biological functions of chitinase in fruiting body development of C. militaris.

Proteasomal inhibitors induce myeloma cell pyroptosis via the BAX/GSDME pathway.

Proteasomes are overexpressed in multiple myeloma (MM) and proteasomal inhibitors (PIs) have been widely used for the treatment of MM. PIs are reported to induce MM cell apoptosis but impair necroptosis. In the present study, we found that PIs MG132 and bortezomib induce MM cell pyroptosis, a novel type of cell death, in a GSDME-dependent manner. Lack of GSDME totally blocks PI-induced pyroptosis. Interestingly, we found that Caspase-3/6/7/9 are all involved in pyroptosis triggered by PIs because the specific inhibitor of each caspase ablates GSDME activation. PIs markedly reduce mitochondrial membrane potential. Moreover, PIs disrupt the interaction of Bcl-2 and BAX, induce cytochrome c release from mitochondria to cytosol and activate GSDME. Furthermore, we found that overexpression of an N-terminal portion of GSDME suffices to release cytochrome c from mitochondria and to activate Caspase-3/9, suggesting N-GSDME might penetrate the mitochondrial membrane. Consistent with Bcl-2 inhibition, BAX can induce MM cell pyroptosis in a GSDME-dependent manner. In accordance with these findings, inhibition of Bcl-2 synergizes with PIs to induce MM cell pyroptosis. Therefore, the present study indicates that PIs trigger MM cell pyroptosis via the mitochondrial BAX/GSDME pathway and provides a rationale for combined treatment of MM with Bcl-2 and proteasome inhibitors to increase therapeutic efficiency via induction of pyroptosis.

Construction of a Competitive Endogenous RNA Network Related to Exosomes in Diabetic Retinopathy.

BACKGROUND: The competing endogenous RNA (ceRNA) network plays an important role in the occurrence and development of a variety of diseases. This study aimed to construct a ceRNA network related to exosomes in diabetic retinopathy (DR). METHODS: We explored the Gene Expression Omnibus (GEO) database and then analyzed the RNAs of samples to obtain differentially expressed lncRNAs (DELs), miRNAs (DEMs) and mRNAs (DEGs) alongside the progress of DR. Next, Gene Set Enrichment Analysis (GSEA) analysis of DEGs, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis of up-DEGs were performed. In addition, a ceRNA network related to exosomes in DR was constructed on the base of DELs, DEMs and DEGs. Finally, the function of the ceRNA network was explored by GO and KEGG enrichment analysis. RESULTS: Through our analysis, 267 DELs (93 up and 174 down), 114 DEMs (64 up and 50 down) and 2368 DEGs (1252 up and 1116 down) were screened. The GSEA analysis results show that these genes were mainly related to cytokine-cytokine receptor interaction, hippo signaling pathway and JAK-STAT signaling pathway. The GO and KEGG results show that these up-DEGs were mainly enriched in viral gene expression, components of ribosomes, mineral absorption, Wntprotein binding, and TGF-ß signaling pathway. Besides, a ceRNA network, including 15 lncRNAs (e.g., C1orf145, FGF14-IT1, and PRNT), 3 miRNAs (miR-10a-5p, miR-1297 and miR-507) and 11 mRNAs (NCOR2, CHAC1 and LIX1L, etc.) was constructed. Those 5 lncRNAs were up-regulated, 1 miRNA was down-regulated and 5 mRNAs were up-regulated in DR, while 10 lncRNAs were downregulated, 2 miRNAs were up-regulated and 6 mRNAs were down-regulated in DR. CONCLUSION: The novel ceRNA network that we constructed will provide new insights into the underlying molecular mechanisms of exosomes in DR.

Aquatic strength training improves postural stability and walking function in stroke patients.

OBJECTIVE: This study aims to explore the effects of aquatic strength training on the postural balance and walking function of stroke patients. METHODS: A total of 56 chronic stroke patients more than 6 months post-stroke with walking and balance impairments were included in this study. After baseline evaluations, patients were randomly assigned to either the experiment group (n = 29) or control group (n = 27). Patients in the control group underwent conventional hydrotherapy, whereas patients in the experiment group received conventional hydrotherapy combined with aquatic lower extremity strength training. After six weeks of rehabilitation, all patients were evaluated by a blinded assessor, and the functional assessments including: Berg Balance Scale (BBS); Timed Up and Go Test (TUG and mTUG); 2 Minute Walk Test (2MWMT); and Gait analysis. RESULTS: There were no significant differences (P > .05) between the two groups in all evaluation indexes before rehabilitation. Six weeks after treatments, the results from both groups showed significant improvements compared with those in the baseline evaluations (P < .05). Notably, compared with the control group, BBS, TUG and mTUG, 2MWMT, and Gait analysis including stride length in the non-hemiplegic side, stride length, as well as walking speed and stride frequency in the hemiplegic side in experiment group were markedly improved (P < .05). CONCLUSION: Aquatic strength training can improve postural balance and lower extremity motor functions in chronic stroke patients.