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Diabetic cardiomyopathy (DCM) is a prevalent complication of type 2 diabetes (T2D). 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3) is a glycolysis regulator. However, the potential effects of PFKFB3 in the DCM remain unclear. In comparison to db/m mice, PFKFB3 levels decreased in the hearts of db/db mice. Cardiac-specific PFKFB3 overexpression inhibited myocardial oxidative stress and cardiomyocyte apoptosis, suppressed mitochondrial fragmentation, and partly restored mitochondrial function in db/db mice. Moreover, PFKFB3 overexpression stimulated glycolysis. Interestingly, based on the inhibition of glycolysis, PFKFB3 overexpression still suppressed oxidative stress and apoptosis of cardiomyocytes in vitro, which indicated that PFKFB3 overexpression could alleviate DCM independent of glycolysis. Using mass spectrometry combined with co-immunoprecipitation, we identified optic atrophy 1 (OPA1) interacting with PFKFB3. In db/db mice, the knockdown of OPA1 receded the effects of PFKFB3 overexpression in alleviating cardiac remodeling and dysfunction. Mechanistically, PFKFB3 stabilized OPA1 expression by promoting E3 ligase NEDD4L-mediated atypical K6-linked polyubiquitination and thus prevented the degradation of OPA1 by the proteasomal pathway. Our study indicates that PFKFB3/OPA1 could be potential therapeutic targets for DCM. [ABSTRACT FROM AUTHOR]

Purpose: This review aims to provides a comprehensive overview of the latest research progress on IP-III inner ear malformation, focusing on its geneticbasis, imaging features, cochlear implantation, and outcome. Methods: Review the literature on clinical and genetic mechanisms associated with IP-III. Results: Mutations in the POU3F4 gene emerge as the principal pathogenic contributors to IP-III anomalies, primarily manifesting through inner ear potential irregularities leading to deafness. While cochlear implantation stands as the primary intervention for restoring hearing, the unique nature of the inner ear anomaly escalates the complexity of surgical procedures and postoperative results. Hence, meticulous preoperative assessment to ascertain surgical feasibility and postoperative verification of electrode placement are imperative. Additionally, gene therapy holds promise as a prospective treatment modality. Conclusions: IP-III denotes X-linked recessive hereditary deafness, with cochlear implantation currently serving as the predominant therapeutic approach. Clinicians are tasked with preoperative assement and individualized postoperative rehabilitation. [ABSTRACT FROM AUTHOR]

Highlights: A large-scale metabolic adaptation in M1-polarized macrophages compared with M2 macrophages, along with multiple altered metabolite parameters that can serve as potential targets, have been discussed. Nanomaterial-based repurposing of macrophage metabolism and its applications are systematically summarized and illustrated using representative examples. Potential challenges, additional information about future research objectives, and priorities of nanomaterial-based macrophage immunotherapy are highlighted. Macrophage immunotherapy represents an emerging therapeutic approach aimed at modulating the immune response to alleviate disease symptoms. Nanomaterials (NMs) have been engineered to monitor macrophage metabolism, enabling the evaluation of disease progression and the replication of intricate physiological signal patterns. They achieve this either directly or by delivering regulatory signals, thereby mapping phenotype to effector functions through metabolic repurposing to customize macrophage fate for therapy. However, a comprehensive summary regarding NM-mediated macrophage visualization and coordinated metabolic rewiring to maintain phenotypic equilibrium is currently lacking. This review aims to address this gap by outlining recent advancements in NM-based metabolic immunotherapy. We initially explore the relationship between metabolism, polarization, and disease, before delving into recent NM innovations that visualize macrophage activity to elucidate disease onset and fine-tune its fate through metabolic remodeling for macrophage-centered immunotherapy. Finally, we discuss the prospects and challenges of NM-mediated metabolic immunotherapy, aiming to accelerate clinical translation. We anticipate that this review will serve as a valuable reference for researchers seeking to leverage novel metabolic intervention-matched immunomodulators in macrophages or other fields of immune engineering. [ABSTRACT FROM AUTHOR]

With the extensive applications of nanomaterials in drug delivery in recent years, nanocarriers with composite polymers, represented by liposomal gels, have been studied for drug delivery for numerous diseases. The drug is loaded inside the liposomal gel and is endowed with specific temperature, pH, enzyme, light, electric field and other stimulating materials; further, the release of the loaded drug is controlled by specific stimuli. Liposomal gels provide better stability for drug formulation and obtaining higher targeting and stimulus responsiveness compared to single nano-drug-loaded materials. Hence, the toxic side effects of drugs can be effectively reduced and the drug delivery efficiency, therapeutic efficacy and safety can be considerably improved. At present, research on liposome gels as drug delivery carriers is still under developing stage, and their advantages as drug carriers will be more useful in practice and become a powerful tool for human beings to cure diseases in the future. In the future studies, the synthesis and stimuli-responsive mechanism of liposomal gels can be further explored to expand their applications in the field of disease treatment and provide more innovative solutions for precision medicine and individualised therapy. This review explores the application of liposome gels with stimuli-responsiveness as drug carriers for treating diseases, the advantages of liposome gels as drug carriers, the methods and principles of their fabrication, the stimuli-responsiveness of liposome gels for targeted release against diseases and its current challenges and opportunities to suggest certain methods and ideas for the development of smarter precision-targeted hybrid nanosystems in the future. [ABSTRACT FROM AUTHOR]

Cyclophilin A (CypA), the first member of cyclophilins, is distributed extensively in eukaryotic and prokaryotic cells, primarily localized in the cytoplasm. In addition to acting as an intracellular receptor for cyclosporin A (CSA), CypA plays a crucial role in diseases such as aging and tumorigenesis. Apoptosis, a form of programmed cell death, is able to balance the rate of cell viability and death. In this review, we focus on the effects of CypA on apoptosis and the relationship between specific mechanisms of CypA promoting or inhibiting apoptosis and diseases, including tumorigenesis, cardiovascular diseases, organ injury, and microbial infections. Notably, the process of CypA promoting or inhibiting apoptosis is closely related to disease development. Finally, future prospects for the association of CypA and apoptosis are discussed, and a comprehensive understanding of the effects of CypA on apoptosis in relation to diseases is expected to provide new insights into the design of CypA as a therapeutic target for diseases. Key points: • Understand the effect of CypA on apoptosis. • CypA affects apoptosis through specific pathways. • The effect of CypA on apoptosis is associated with a variety of disease processes. [ABSTRACT FROM AUTHOR]

Purpose: The incidence of linezolid-induced thrombocytopenia (LIT) has been reported to vary widely across studies. We performed a meta-analysis to identify the risk factors for thrombocytopenia among patients who received linezolid treatment. Methods: The PubMed, Embase and Cochrane Library databases were searched from inception to November 2022 to identify eligible studies. Data on the potential predictors of incidence in LIT were pooled using a random effects model. Sensitivity analyses were performed to determine the robustness of the results when significant heterogeneity was observed. Results: Forty observational studies involving 6454 patients treated with linezolid were included in the analysis. LIT was estimated to occur in 37% of patients. The following important factors were associated with the incidence of LIT: advanced age, body mass index, concurrent renal impairment or liver disease, abnormal laboratory parameters (including white blood cell count, serum creatinine, baseline platelet count, albumin, creatinine clearance rate, and estimated glomerular filtration rate), treatment duration and renal replacement therapy. Conclusions: A variety of risk factors related to the occurrence of LIT were revealed in our analysis. Early identification of these factors could help patients improve clinical outcomes. [ABSTRACT FROM AUTHOR]

There is an increasing interest in non-pharmacological treatments for children with attention-deficit/hyperactivity disorder (AD/HD), especially digital techniques that can be remotely delivered, such as neurofeedback (NFT) and computerized cognitive training (CCT). In this study, a randomized controlled design was used to compare training outcomes between remotely delivered NFT, CCT, and combined NFT/CCT training approaches. A total of 121 children with AD/HD were randomly assigned to the NFT, CCT, or NFT/CCT training groups, with 80 children completing the training program. Pre- and post-training symptoms (primary outcome), executive and daily functions were measured using questionnaires as well as resting EEG during eyes-closed (EC) and eyes-open (EO) conditions. After 3 months of training, the inattentive and hyperactive/impulsive symptoms, inhibition, working memory, learning and life skills of the three groups of children were significantly improved. The objective EEG activity showed a consistent increase in the relative alpha power in the EO condition among the three training groups. Training differences were not observed between groups. There was a positive correlation between pre-training EO relative alpha power and symptom improvement scores of inattention and hyperactivity/impulsivity, as well as a negative correlation between pre-training inattention scores and change in EO relative alpha. This study verified the training effects of NFT, CCT, and combined NFT/CCT training in children with AD/HD and revealed an objective therapeutic role for individual relative alpha activity. The verified feasibility and effectiveness of home-based digital training support promotion and application of digital remote training. [ABSTRACT FROM AUTHOR]

Traumatic brain injury (TBI) is a prevalent neurological disorder and a leading cause of death and disability worldwide. The high mortality rates result in a tremendous burden on society and families in terms of public health and economic costs. Despite advances in biomedical research, treatment options for TBI still remain limited, and there is no effective therapy to restore the structure and function of the injured brain. Regrettably, due to the excessive heterogeneity of TBI and the lack of objective and reliable efficacy evaluation indicators, no proven therapeutic drugs or drugs with clear benefits on functional outcomes have been successfully developed to date. Therefore, it is urgent to explore new therapeutic approaches to protect or regenerate the injured brain from different perspectives. In this review, we first provide a brief overview of the causes and current status of TBI and then summarize the preclinical and clinical research status of cutting-edge treatment methods, including nerve regeneration therapy and gene therapy, with the aim of providing valuable references for effective therapeutic strategies for TBI. [ABSTRACT FROM AUTHOR]

Osteoporosis, an age-related metabolic bone disease, is mainly caused by an imbalance between osteoblast-mediated bone formation and osteoclast-mediated bone resorption. At present, there are many osteoporosis drugs that can promote bone formation or inhibit bone resorption. However, there were few therapeutic drugs that can simultaneously promote bone formation and inhibit bone resorption. Oridonin (ORI), a tetracyclic diterpenoid compound isolated from Rabdosia rubescens, has been proved to have anti-inflammatory, anti-tumor effects. However, little is known about the osteoprotective effect of oridonin. Thioacetamide (TAA) is a common organic compound with significant hepatotoxicity. Recent studies have found that there was a certain association between TAA and bone injury. In this work, we investigated the effect and mechanism of ORI on TAA-induced osteoclastogenesis and inhibition of osteoblast differentiation. The results showed that TAA could promote the osteoclastogenesis of RAW264.7 by promoting the MAPK/NF-κB pathway, and also promoted p65 nuclear translocation and activated intracellular ROS generation, and ORI can inhibit these effects to inhibit TAA-induced osteoclastogenesis. Moreover, ORI can also promote the osteogenic differentiation pathway and inhibit adipogenic differentiation of BMSCs to promote bone formation. In conclusion, our results revealed that ORI, as a potential therapeutic drug for osteoporosis, could protect against TAA-induced bone loss and TAA-inhibited bone formation. [ABSTRACT FROM AUTHOR]

Objective: To compare the clinical efficacy and safety of oral administration of Buxue Yimu Pills (BYP, 补血益母丸), ferrous sulfate (FS), and the combination of BYP and FS on gynecological anemia, and investigate the mechanisms using network pharmacology. Methods: A randomized, controlled, multi-center clinical trial was conducted. Totally 150 patients with hemoglobin of 70–110 g/L due to gynecological conditions were recruited and randomized (using the block randomization method) into Buxue Yimu Pills group (24 g/d), oral iron group (FS Tablets, 0.9 g/d), and combined treatment group (BYP, 24 g/d plus FS Tablets, 0.9 g/d), 50 patients in each group. At the enrollment and 4-week treatment, complete blood count, serum iron indexes were evaluated. Adverse events, liver and renal functions, as well as blood coagulation were observed. Network pharmacology was conducted to identify the active ingredients and explore the potential mechanisms of BYP. Results: Ten (20%) and 7 (14%) participants discontinued the therapy due to gastrointestinal symptoms in oral iron and combination treatment groups. All 3 groups showed elevated hemoglobin. The patients in the iron group exhibited typically elevated in serum iron and ferritin and decreased in total iron-binding capacity. No change in iron indexes was observed in BYP group. The patients in the combination treatment group neither showed significant changes in serum ferritin nor total iron-binding capacity. No significant adverse reactions were observed in the BYP group. The network pharmacology identified 27 bioactive compounds and 145 targets of BYP on gynecological anemia. Biological processes and pathways including regulation of inflammation, hormone, angiogenesis and hemostasis, response to decreased oxygen levels, effects on myeloma cell, and response to metal ions were identified. Conclusion: BYP contributes to the practical improvement on gynecological anemia potentially through multi-target mechanisms and optimized iron re-distribution. (Trial registration: No. NCT03232554) [ABSTRACT FROM AUTHOR]

Nonalcoholic steatohepatitis (NASH), a common clinical disease, is becoming a leading cause of hepatocellular carcinoma (HCC). Dual specificity phosphatase 22 (DUSP22, also known as JKAP or JSP-1) expressed in numerous tissues plays essential biological functions in immune responses and tumor growth. However, the effects of DUSP22 on NASH still remain unknown. Here, we find a significant decrease of DUSP22 expression in human and murine fatty liver, which is mediated by reactive oxygen species (ROS) generation. Hepatic-specific DUSP22 deletion particularly exacerbates lipid deposition, inflammatory response and fibrosis in liver, facilitating NASH and non-alcoholic fatty liver disease (NAFLD)-associated HCC progression. In contrast, transgenic over-expression, lentivirus or adeno-associated virus (AAV)-mediated DUSP22 gene therapy substantially inhibit NASH-related phenotypes and HCC development in mice. We provide mechanistic evidence that DUSP22 directly interacts with focal adhesion kinase (FAK) and restrains its phosphorylation at Tyr397 (Y397) and Y576 + Y577 residues, subsequently prohibiting downstream activation of extracellular signal-regulated kinase 1/2 (ERK1/2) and nuclear factor-κB (NF-κB) cascades. The binding of DUSP22 to FAK and the dephosphorylation of FAK are indispensable for DUSP22-meliorated NASH progression. Collectively, our findings identify DUSP22 as a key suppressor of NASH-HCC, and underscore the DUSP22-FAK axis as a promising therapeutic target for treatment of the disease. Mechanisms underlying the pathogenesis of nonalcoholic steatohepatitis are unclear. Here, the authors show that ROS-mediated DUSP22 degradation participates in the progression of fatty liver, contributing to the development of NASH and associated HCC via regulating FAK and its downstream ERK1/2 and NF-κB signaling cascade. [ABSTRACT FROM AUTHOR]

No FDA approved pharmacological therapy is available to reduce neuroinflammation following heatstroke. Previous studies have indicated that dexmedetomidine (DEX) could protect against inflammation and brain injury in various inflammation-associated diseases. However, no one has tested whether DEX has neuro-protective effects in heatstroke. In this study, we focused on microglial phenotypic modulation to investigate the mechanisms underlying the anti-inflammatory effects of DEX in vivo and in vitro. We found that DEX treatment reduced the expression of CD68, iNOS, TNF-α, and IL-1β, and increased the expression of CD206, Arg1, IL-10 and TGF-β in microglia, ameliorating heatstroke induced neuroinflammation and brain injury in mice. TREM2, whose neuro-protective function has been validated by genetic studies in Alzheimer's disease and Nasu-Hakola disease, was significantly promoted by DEX in the microglia. TREM2 esiRNA reversed the DEX-induced activation of PI3K/Akt signalling. Overall these findings indicated that DEX may serve, as a potential therapeutic approach to ameliorate heatstroke induced neuroinflammation and brain injury via TREM2 by activating PI3K/Akt signalling. [ABSTRACT FROM AUTHOR]

Objective: The lack of appropriate preclinical models of ovarian yolk sac tumor (OYST) is currently hindering the pursuit of new methods of treatment and investigation of the pathogenesis of the disease. We developed and characterized an OYST patient-derived xenograft (PDX) model in this study. Methods: Tumor fragments from a patient with an OYST were implanted subcutaneously into BALB/c Nude mice. Engrafted xenografts were compared with the original tumor according to histology, immunohistochemistry, humanized identified, and drug efficacy testing with in vivo treatment programs. Results: There was a high degree of histologic and immunohistochemical (IHC) resemblance between the established PDX model and its corresponding human tumors. Bleomycin, etoposide, and cisplatin (JEB) chemotherapy regimens were effective in clinical patients and were effective in the OYST PDX model; therefore, the effect of PDX intervention was consistent with clinical outcomes of OYSTs. Conclusion: We have successfully established an OYST PDX model. This OYST model preserves the basic molecular features of the primary human tumor, thereby providing a valuable method to preclinically evaluate new treatments and explore disease pathogenesis. [ABSTRACT FROM AUTHOR]

Heart failure with reduced ejection fraction (HFrEF) is associated with high mortality, highlighting an urgent need for new therapeutic strategies. As stress-activated cardiac signaling cascades converge on the nucleus to drive maladaptive gene programs, interdicting pathological transcription is a conceptually attractive approach for HFrEF therapy. Here, we demonstrate that CDK7/12/13 are critical regulators of transcription activation in the heart that can be pharmacologically inhibited to improve HFrEF. CDK7/12/13 inhibition using the first-in-class inhibitor THZ1 or RNAi blocks stress-induced transcription and pathologic hypertrophy in cultured rodent cardiomyocytes. THZ1 potently attenuates adverse cardiac remodeling and HFrEF pathogenesis in mice and blocks cardinal features of disease in human iPSC-derived cardiomyocytes. THZ1 suppresses Pol II enrichment at stress-transactivated cardiac genes and inhibits a specific pathologic gene program in the failing mouse heart. These data identify CDK7/12/13 as druggable regulators of cardiac gene transactivation during disease-related stress, suggesting that HFrEF features a critical dependency on transcription that can be therapeutically exploited. In this study, Hsu et al. show that inhibition of CDK7/12/13 attenuates maladaptive transcriptional activation in cultured cardiomyocytes and a mouse model of heart failure, suggesting that targeting the transcription machinery might be a therapeutic approach to treat heart failure with reduced ejection fraction. [ABSTRACT FROM AUTHOR]

Purpose: Tumor heterogeneity limits the predictive value of PD-L1 expression and influences the outcomes of the immunohistochemical assay for therapy-induced changes in PD-L1 levels. This study aimed to determine the predictive value of PD-L1 for non-small cell lung carcinoma (NSCLC), thereby developing imaging agents to non-invasively image and examine the effect of the therapeutic response to PD-L1 blockade therapy. Methods: A cohort of 102 patients with lung cancer was analyzed, and the prognostic significance of PD-L1 expression level was investigated. Recombinant human PD-1 ECD protein (rhPD1) was expressed, purified, and labeled with 64Cu for the evaluation of PD-L1 status in tumors. Mice subcutaneously bearing PD-L1 high-expressing tumor HCC827 and PD-L1 low-expressing tumor A549 were used to determine tracer-target specificity and examine the effect of therapeutic response to PD-L1 blockade therapy. Results: PD-L1 was proved to be a good prognosis marker for NSCLC, and its expression was correlated with the histology of NSCLC. PET imaging revealed high tumor accumulation of 64Cu-NOTA-rhPD1 in HCC827 tumors (9.0 ± 0.5%ID/g), whereas it was 3.2 ± 0.4%ID/g in A549 tumors at 3 h post-injection. The lower tumor uptake (3.1 ± 0.3%ID/g) of 64Cu-labeled denatured rhPD1 in HCC827 tumors at 3 h post-injection (p < 0.001) demonstrated the target specificity of 64Cu-NOTA-rhPD1. Furthermore, PET showed that 64Cu-NOTA-rhPD1 sensitively monitored treatment-related changes in PD-L1 expression, and seemed to be superior to [18F]FDG. Conclusion: We identified PD-L1 as a good prognosis marker for surgically resected NSCLC and developed the PET tracer 64Cu-NOTA-rhPD1 with high target specificity for PD-L1. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the protective effects of salvianolate on percutaneous coronary intervention (PCI) related myocardial injury or myocardial infarction after elective PCI in non-ST-segment elevation acute coronary syndrome (NSTE-ACS) patients. Methods: A total of 149 patients with NSTE-ACS who underwent elective PCI were enrolled. The patients were randomly allocated in a 1:1 ratio to the salvianolate group (74 cases) or the control group (75 cases). After exclusion criteria of coronary angiography, 60 patients with PCI therapy remained in the salvianolate group and 68 in the control group. The incidence and the severity of PCI related myocardial injury or myocardial infarction, in addition to major adverse cardiac events (MACEs) during 1 year follow-up after PCI were studied between the two groups. Multivariate logistic regression analysis was used to determine the independent factors for PCI related myocardial injury or myocardial infarction after elective PCI. Results: Compared with the control group, salvianolate treatment reduced the incidence of PCI related severe myocardial injury or myocardial infarction (11.7% vs. 26.5%, P=0.035). The rate of MACEs or all-cause death within 1 month or 1 year after the procedure was not significantly different between the two groups. Conclusions: Periprocedural treatment with salvianolate reduces the incidence of PCI related severe myocardial injury or myocardial infarction, although it does not influence clinical prognosis. [Chinese clinical trial registry: ChiCTR1800016992] [ABSTRACT FROM AUTHOR]

Mesenchymal stem cells (MSCs) have become a promising tool for neurorestorative therapy of neurodegenerative diseases (NDDs), which are mainly characterized by the progressive and irreversible loss of neuronal structure and function in the central or peripheral nervous system. Recently, studies have reported that genetic manipulation mediated by noncoding RNAs (ncRNAs) can increase survival and neural regeneration of transplanted MSCs, offering a new strategy for clinical translation. In this review, we summarize the potential role and regulatory mechanism of two major types of ncRNAs, including microRNAs (miRNAs) and long noncoding RNAs (lncRNAs), during the neurogenesis of MSCs with gene expression profile analyses. We also overview the realization of MSC-based therapy mediated by ncRNAs in the treatment of spinal cord injury, stroke, Alzheimer's disease and peripheral nerve injury. It is expected that ncRNAs will become promising therapeutic targets for NDD on stem cells, while the underlying mechanisms require further exploration. [ABSTRACT FROM AUTHOR]

The human aorta is a high-risk area for vascular diseases, which are commonly restored by thoracic endovascular aortic repair. In this paper, we report a promising shear-activated targeted nanoparticle drug delivery strategy to assist in the treatment of coarctation of the aorta and aortic aneurysm. Idealized three-dimensional geometric models of coarctation of the aorta and aortic aneurysm are designed, respectively. The unique hemodynamic environment of the diseased aorta is used to improve nanoparticle drug delivery. Micro-carriers with nanoparticle drugs would be targeting activated to release nanoparticle drugs by local abnormal shear stress rate (SSR). Coarctation of the aorta provides a high SSR hemodynamic environment, while the aortic aneurysm is exposed to low SSR. We propose a method to calculate the SSR thresholds for the diseased aorta. Results show that the upstream near-wall area of the diseased location is an ideal injection location for the micro-carriers, which could be activated by the abnormal SSR. Released nanoparticle drugs would be successfully targeted delivered to the aortic diseased wall. Besides, the high diffusivity of the micro-carriers and nanoparticle drugs has a significant impact on the surface drug concentrations of the diseased aortic walls, especially for aortic aneurysms. This study preliminary demonstrates the feasibility of shear-activated targeted nanoparticle drug delivery in the treatment of aortic diseases and provides a theoretical basis for developing the drug delivery system and novel therapy. [ABSTRACT FROM AUTHOR]

Introduction: Sierra Leone has one of the highest burdens of febrile illnesses in the world. As the incidence of malaria diminishes, a better understanding of the spectrum of etiological agents was important for accurate diagnosis and empirical treatment of febrile illness. Methods: Blood, nasopharyngeal, and fecal specimens were collected from febrile patients for serological, molecular detection, and microbiologic culture to identify potential pathogens. Results: For this prospective study, 142 febrile patients were enrolled. The prevalence of malaria was higher in children aged 5–15 years old (P = 0.185) and adults (P = 0.018). Acute respiratory infection (ARI) presented more commonly in the under 5 years old group (P = 0.009). For diarrhea, all children groups (P = 0.024) were predominant. A total of 22.5% of the febrile patients had malaria infection, 19.7% had typhoid infection, and 2.8% were coinfected with malaria and typhoid. ARI was the most common causes of fever, accounting for 31.7% of patients, influenza A virus, Mycoplasma pneumoniae, and five other respiratory pathogens were found. Diarrhea accounted for 16.2%, and seven kinds of diarrhea bacteria were isolated. Hepatitis B accounted for 8.5%, including five cases of spontaneous bacterial peritonitis, and ascites smear staining were both Gram-negative bacteria. Tuberculous encephalitis, parasitic diseases (ascaris and filariasis), and skin infection caused by Staphylococcus aureus accounted for 0.7%, 2.1%, and 0.7%, respectively. Conclusions: Evidence of a wide spectrum of febrile etiological agents other than malaria was identified. The spread of malaria rapid diagnostic tests (RDTs) out of hospital and establishment of a national standard for Widal test will reduce the misdiagnosis of febrile diseases. Antibiotics against Gram-negative bacteria are helpful for empirical treatment. Plain Language Summary: Sierra Leone has one of the highest burdens of febrile illnesses in the world. Evidence of a wide spectrum of febrile pathogens other than malaria has been proven in this study. We considered that the etiology of febrile patients was closely related to local geography, heredity, immune features, economic industry, living habits, air pollution, medical and health conditions, and this was fully analyzed and discussed. The screening process used in this study can further simplify and identify the etiological agents of fever in more than 70% of the study population. This laid the foundation for the establishment of a more simplified and efficient diagnosis and treatment process in the local area. We also found the characteristics of age distribution of different febrile diseases. Children were an important susceptible population to fever. This study indicated the importance of reliable diagnostic tests for febrile pathogens and provided the necessary information for RDT requirements. The spread of malaria RDTs out of hospital and establishment of a national standard for Widal test will reduce the misdiagnosis of febrile diseases. For empirical treatment, antimalarial treatment was still targeted at falciparum malaria in Sierra Leone. Antibiotics against Gram-negative bacteria contributed to the empirical treatment of febrile diseases. For patients with acute respiratory tract infection, Gram-positive coccal antibiotics could be candidates for treatment. In addition, systematic and professional treatment of liver diseases should be promoted to reduce infection complications. [ABSTRACT FROM AUTHOR]

Kidney stones are a common threat to the health of elderly patients with a high incidence of disease. However, the specific molecular mechanism of the formation of kidney stones has not been elucidated. Here, we combined signalling molecules with signalling pathways in a double positive circulation regulation model. In addition, we found that LCN2 plays a role in promoting kidney stones through regulation of the ERK signalling pathway and expression of other kidney stone-related genes. LCN2 expression was upregulated upon oxalate stimulation. P-ERK1/2 inhibition by U0126 in kidney epithelial cells resulted in decreased expression of LCN2. Furthermore, the upregulation of LCN2 not only depended on the activation of the ERK signalling pathway but also regulated the activation of the ERK signalling pathway. Importantly, upregulation of LCN2 not only caused kidney epithelial cell damage but also promoted the expression of other kidney stone-related genes. Our findings improved the understanding of LCN2 and might lead to the development of new therapeutic and prognostic markers for kidney stones. [ABSTRACT FROM AUTHOR]

Rational: Minocycline is a second-generation, semi-synthetic tetracycline, and has broad spectrum-antibacterial activity. Interestingly, many studies have demonstrated that minocycline is beneficial for depression, which may be due to its effects on neuroinflammation modulation. Recently, gut microbiota imbalance has been found in depression patient and animal models. Objectives: Based on the fact of minocycline usually acting as an antibiotic and the relationship between depression, gut microbiota, and neuroinflammation, we designed this study to detect the effects of chronic minocycline treatment on antidepression, neuroinflammation, and gut microbiota modulation. Results: Our results showed that minocycline treatment for 4 weeks, not acute treatment, exerted antidepressant effect in mice exposed to unpredictable chronic mild stress (CUMS). Further results suggested that chronic minocycline treatment inhibited neuroinflammation of hippocampus and altered species abundance and metabolites of gut microbiota. Meantime, we found that chronic minocycline treatment ameliorated intestinal barrier disruption and reduced the bacteriological indexes, such as diamine oxidase, C-reaction protein, and endotoxin in peripheral blood of CUMS mice. Conclusions: To sum up, our findings confirm that chronic minocycline treatment exerts the antidepressant effect, inhibits neuroinflammation, and modulates gut microbiota. All of these imply that the antidepressant mechanism of chronic minocycline treatment is maybe due to the combined action of neuroinflammation and gut microbiota modulation, which need further prospective studies. [ABSTRACT FROM AUTHOR]

COVID-19 has become a global concern. A large number of reports have explained the clinical characteristics and treatment strategies of COVID-19, but the characteristics and treatment of COVID-19 patient with systemic lupus erythematosus (SLE) are still unclear. Here, we report the clinical features and treatment of the first SLE patient with confirmed COVID-19 pneumonia. This was a 39-year-old woman, diagnosed with SLE 15 years ago, whose overall clinical characteristics (symptoms, laboratory tests, and chest CTs) were similar to those of the general COVID-19 patients. She continued to take the previous SLE drugs (doses of glucocorticoids, hydroxychloroquine, and immunosuppressive agents were not reduced) and was treated with strict antiviral and infection prevention treatment. After the first discharge, she got a recurrence of COVID-19 during her home isolation, and then returned to hospital and continued the previous therapy. Finally, this long-term immune suppressive patient's COVID-19 was successfully cured. The successful recovery of this case has significant reference value for the future treatment of COVID-19 patients with SLE. Key Points • COVID-19 patients with SLE is advocated to continue the medical treatment for SLE. • Hydroxychloroquine may have potential benefits for COVID-19 patients with SLE. • COVID-19 patients with SLE is prone to relapse, and multiple follow-ups are necessary. [ABSTRACT FROM AUTHOR]

Background: Sigmoid colon cancer is a lethal disease and has a strong indication for surgery. Robotic-assisted surgery is one of the promising alternative treatment for this disease. Nowadays, the MicroHand S surgical system and the Da Vinci surgical system have been assembled in China. However, there is still no report to study the therapeutic effects of the two robotic-assisted surgical systems. Thus, the purpose of this study was to compare clinical and economic outcomes of patients with sigmoid colon cancer undergoing robot-assisted radical surgery via The MicroHand S or Da Vinci surgical system.Methods: The clinical data of 45 patients with sigmoid colon cancer undergoing the MicroHand S or Da Vinci robotic-assisted surgery at The Third Xiangya Hospital of Central South University from January 2017 to January 2019 were retrospectively analyzed.Results: Twenty-one patients received MicroHand S robotic-assisted radical surgery and 24 patients received Da Vinci robot-assisted radical surgery. No significant differences were observed in terms of operation time, number of lymph node harvested, blood loss, intestinal exhaust time, time of oral feeding resumption, volume of abdominal cavity 24-h drainage, hospital stay, complication and rate of conversion, removal time of drainage tube and catheter between MicroHand S and Da Vinci group. However, the MicroHand S group had significantly lower hospitalization costs (P = 0.002) and shorter time to get out of bed after surgery (P = 0.04). In addition, no recurrence and metastases were observed in both groups during the follow-up.Conclusions: In patients with sigmoid colon cancer, the Da Vinci surgical system did not show obvious clinical advantages compared to the MicroHand S surgical system in surgical outcomes. However, the MicroHand S surgical platform showed advantages in terms of the hospitalization costs and length of postoperative bedtime. The outcome of this study will probably result in a shift to the MicroHand S surgical system as treatment preference in China. [ABSTRACT FROM AUTHOR]

Background: Because of the increasing demand for drugs addressing life-threatening and rare diseases, regulatory agencies have developed a variety of accelerated regulatory pathways. These programs are aimed at prioritizing the most promising drug candidates for diseases lacking satisfactory treatments. The most prominent accelerated programs introduced have been Breakthrough-Therapy Designation (BTD) in the United States, Priority Medicine (PRIME) in the European Union and Sakigake in Japan. This article reviews these designations and looks at differences in how they are granted across the 3 jurisdictions focusing on neuroscience and oncology. Methods: Our objective was to analyze BTD, PRIME, and Sakigake approvals between 2012 and 2019 with a focus on numerical disparities of designations granted between the 2 therapeutic areas. A search of public sources pertaining to topics of BTD, PRIME, and Sakigake was undertaken. Results: This analysis revealed that 48% of BTD were granted in oncology, while neuroscience received 8% of these designations, for PRIME designations were 27% received by oncology and 15% by neuroscience and in Japan, 50% of Sakigake were granted to oncology and 22% to neuroscience products. Conclusion: Given the global nature of drug development and relative similarity of these regulatory mechanisms, there is an apparent disparity between the US granting special status at 6:1 (oncology: neuroscience) and both the EU and Japan granting at 2:1. This disproportionate ratio is likely impacted by multifactorial issues; however, this difference is worth further investigation. [ABSTRACT FROM AUTHOR]

Oxidative stress is associated with many acute and chronic inflammatory diseases, yet limited treatment is currently available clinically. The development of enzyme-mimicking nanomaterials (nanozymes) with good reactive oxygen species (ROS) scavenging ability and biocompatibility is a promising way for the treatment of ROS-related inflammation. Herein we report a simple and efficient one-step development of ultrasmall Cu5.4O nanoparticles (Cu5.4O USNPs) with multiple enzyme-mimicking and broad-spectrum ROS scavenging ability for the treatment of ROS-related diseases. Cu5.4O USNPs simultaneously possessing catalase-, superoxide dismutase-, and glutathione peroxidase-mimicking enzyme properties exhibit cytoprotective effects against ROS-mediated damage at extremely low dosage and significantly improve treatment outcomes in acute kidney injury, acute liver injury and wound healing. Meanwhile, the ultrasmall size of Cu5.4O USNPs enables rapid renal clearance of the nanomaterial, guaranteeing the biocompatibility. The protective effect and good biocompatibility of Cu5.4O USNPs will facilitate clinical treatment of ROS-related diseases and enable the development of next-generation nanozymes. Oxidative stress is involved in several diseases and is a target for intervention. Here, the authors report on the synthesis of ultrasmall copper-based nanozymes as reactive oxygen species scavengers and demonstrate improved treatment outcomes in acute liver and kidney injury and wound healing in vivo. [ABSTRACT FROM AUTHOR]

Glutathione S-transferase Pi (GSTP1) was originally identified as one of the cytosolic phase II detoxification enzymes and was also considered to function via its non-catalytic, ligand-binding activity. Autophagy is a self-protective mechanism of the cell to remove unnecessary or dysfunctional components, which plays a crucial role in balancing the beneficial and detrimental effects of immunity and inflammation. However, little is known about whether and how GSTP1 mediates autophagy via inhibiting LPS-induced inflammatory response. Here, we show that LPS-induced autophagy and autophagic flux blockade in THP-1 cells in a concentration- and time-dependent manner. Further, we found that the autophagy activation inhibited the activation of inflammatory signaling pathway and the release of inflammatory factors. However, inhibition of autophagy by 3-methyladenine or chloroquine significantly reduced the anti-inflammatory effect of GSTP1. In addition, our findings provide evidence that GSTP1 regulates autophagy through PI3K-Akt-mTOR pathway and inhibits LPS-induced inflammation. Overall, the current study provides an important reference for future applications of GSTP1 in the treatment of inflammatory diseases. [ABSTRACT FROM AUTHOR]

The emergence of antibiotic-resistant beta-hemolytic Streptococcus agalactiae strains poses increasing threat to human beings globally. As an attempt to create a novel lysin with improved activity against S. agalactiae, a chimeric lysin, ClyV, was constructed by fusing the enzymatically active domain (EAD) from PlyGBS lysin (GBS180) and the cell wall binding domain (CBD) from PlyV12 lysin (V12CBD). Plate lysis assay combined with lytic kinetic analysis demonstrated that ClyV has improved activity than its parental enzymatic domain GBS180 against multiple streptococci. Biochemical characterization showed that ClyV is active from pH 7 to 10, with the optimum pH of 9, and is stable under NaCl concentration of < 500 mM. In a S. agalactiae infection model, a single intraperitoneally administration of 0.1 mg/mouse of ClyV protected 100% mice, while it was observed that ~ 29% survive in group that received a single dose of 0.1 mg/mouse of GBS180. Moreover, a high dose of 0.8 mg/mouse ClyV did not show any adverse effects to the health or survival rate of the mice. Considering the robust bactericidal activity and good safety profile of ClyV, it represents a potential candidate for the treatment of S. agalactiae infections. [ABSTRACT FROM AUTHOR]

Ellipticine, a natural product from Ochrosia elliptica, has been broadly investigated for its anticancer effects. Although inflammation has been clearly identified as a key factor in the onset and progression of cancer, the relationship between ellipticine and inflammation remains unknown. Hence, the aims of the present study were to assess the effects of ellipticine on the inflammatory responses to lipopolysaccharide (LPS)-induced macrophages and to potentially identify the underlying mechanisms involved. Viability testing showed that ellipticine was not significantly toxic to Raw264.7 cells and actually conveyed protective effects to LPS-stimulated Raw264.7 cells and human peripheral blood monocytes by decreasing the secretion of inflammatory factors (TNF-α and IL-6). The results of western blot analysis and electrophoretic mobility shift assays showed that ellipticine markedly suppressed LPS-induced activation of the JNK/AP-1 (c-Fos and c-Jun) signaling pathway, but not ERK/p38/NF-κB pathway (p65 and p50) activation. Furthermore, ellipticine reduced the inflammatory response and mortality in a mouse model of LPS-induced endotoxic shock. Collectively, these data indicate that ellipticine may be a potential therapeutic agent for the treatment of inflammation-associated diseases. [ABSTRACT FROM AUTHOR]

The article presents a study evaluating the usefulness of the Tokyo Guidelines 2018 (TG18), a set of diagnostic guidelines for acute cholecystitis. Topics covered include acute general surgical unit (AGSU) treatment, complication risk factors, and acute cholecystitis treatment effectiveness.

Objective: To evaluate the efficacy and safety of salvianolate in elderly patients with unstable angina pectoris (UAP). Methods: A prospective double-blind randomized placebo-controlled multicenter trial in elderly patients with UAP from 13 third-grade class-A hospitals in China was performed. A total of 318 patients were randomly allocated in a 1:1 ratio to an experimental group (160 patients) and a control group (158 patients). The experimental group was treated with salvianolate for 14 days on the basis of conventional medicine, and the control group was given a placebo for 14 days with the same criteria. Follow-up was lasted 28 days in both groups. The primary endpoint was biweekly frequency of angina pectoris attacks. The secondary endpoints included biweekly dosage of nitroglycerin, the Seattle Angina Questionnaire, angina pectoris severity and duration, myocardial injury markers, high-sensitivity C-reactive protein (hs-CRP) and N-terminal pro-B-type natriuretic peptide (NT-proBNP), as well as major adverse cardiovascular events (MACEs). Safety was assessed according to adverse events and serious adverse events. Results: Baseline characteristics were similar between treatment groups. Compared with those in the control group, the frequency of biweekly angina attacks (2.92 vs. 4.08, P=0.025), the biweekly dosage of nitroglycerin, as well as the severity and duration of angina attacks (P<0.01) were reduced by salvianolate. The Seattle Angina Questionnaire score was also significantly improved in the experimental group than in the control group (P<0.05). No significant differences were observed between the two groups with respect to the incidence of MACEs. Salvianolate was well tolerated. Conclusions: Salvianolate appear to have efficacy and well tolerated for elderly patients with UAP. [ClinicalTrials.gov identifier: NCT03037047] [ABSTRACT FROM AUTHOR]

Summary: Osteosarcoma is the most common primary malignancy of bone and characterized by an appendicular primary tumor with a high rate of metastasis to the lungs. Unfortunately, there is no effective strategy to treat osteosarcoma in current clinical practice. In this study, the anticancer effects and potential mechanisms of nifuroxazide, an oral nitrofuran antibiotic, on two osteosarcoma cell lines were investigated. The results of the antiproliferative activity in vitro showed that nifuroxazide inhibited cell proliferation of UMR106 and MG63 cells in a dose- and time-dependent manner. Interestingly, nifuroxazide showed low toxicity to non-tumor cells (HEK 293 T). In addition, ROS-mitochondrial mediated apoptosis was observed after treatment of nifuroxazide. Moreover, nifuroxazide could significantly inhibit osteosarcoma cells migration and invasion via p-Stat3, MMP-2 and MMP-9 mediated signaling pathway. Taken together, our results suggested that nifuroxazide could be a promising agent for osteosarcoma treatment by inhibiting cell proliferation, inducing cell apoptosis and impairing cell migration and invasion. [ABSTRACT FROM AUTHOR]

Objective: To summarize the evidence from systematic reviews (SRs) on the benefits and safety of Tripterygium glycosides (TG) and total glucosides of paeony (TGP), commonly used to treat rheumatoid arthritis (RA) in China, for patients with RA. Methods: SRs of randomized controlled trials (RCTs) on TG or TGP in treating RA were included, by searching 8 databases from their inception until December 2017. Two authors extracted data independently. We assessed the quality of SRs using AMSTAR and graded the quality of evidence according to the GRADE approach. Results: Eleven SRs containing an average of 7.6 RCTs, involving a total of 7,012 participants were included in this overview. On the basis of included SRs, TG and TGP could improve the following indexes for RA patients: American College of Rheumatology (ACR) 20 response rate, ACR50 response rate and ACR70 response rate, swollen joint count, tender joint count, erythrocyte sedimentation rate and C-reactive protein. Moreover, TGP could reduce incidence of hepatotoxicity. The most common adverse effects of TG were gastrointestinal discomfort and gonad toxicity, while for TGP was mild to moderate diarrhea. The overall quality of evidence for these findings ranged from "low" to "moderate". Conclusions: TG and TGP might be 2 potentially effective complementary and alternative drugs for patients with RA. Nevertheless, due to gonad toxicity, TG should only be considered in elderly patients or patients without reproductive needs. More evidence from high quality RCTs and SRs is warranted to support the use of TG and TGP for RA patients. [ABSTRACT FROM AUTHOR]

Arsenic trioxide (As2O3) induces cell apoptosis and reduces the invasive and metastatic activities in various cancer types. However, the role of As2O3 in ovarian cancer angiogenesis remains unclear. In this study, we investigated the role of As2O3 in ovarian cancer angiogenesis and found that a low concentration of As2O3 causes no effects on epithelial ovarian cancer cell viability or apoptosis. Moreover, we found that As2O3-treated epithelial ovarian cancer cells demonstrate a reduced tube formation of endothelial cells in Matrigel. In addition, As2O3-treated epithelial ovarian cancer cells show a decreased VEGFA, VEGFR2 and CD31 mRNA expression. As per the underlying mechanisms involved in As2O3 treatment, we found that As2O3 inhibits VEGFA and VEGFR2 expression that thereby inhibits the VEGFA-VEGFR2-PI3K/ERK signaling pathway. This leads to a suppression in both VEGFA synthesis and angiogenesis-related gene expression. A decreased VEGFA synthesis and secretion also inhibits the VEGFA-VEGFR2-PI3K/ERK signaling pathway in human umbilical vein endothelial cells (HUVECs). In summary, our results may provide strategies for the use of As2O3 in the prevention of tumor angiogenesis. [ABSTRACT FROM AUTHOR]

Objective: Non-steroidal anti-inflammatory drugs have been shown to effectively decrease postoperative pain and reduce opioid requirements. Flurbiprofen axetil is an injectable non-selective cyclooxygenase inhibitor that has a high affinity for inflammatory tissues to achieve targeted drug therapy and prolonged duration of action. This meta-analysis examined the use of preoperative flurbiprofen axetil and its impact on postoperative analgesia. Methods: An electronic literature search of the Library of PubMed, Cochrane CENTRAL, and EMBASE databases was conducted in Feb 2016. Searches were limited to randomized controlled trials. The primary outcome was pain scores. The secondary outcomes included cumulative postoperative opioid consumption and opioid-related adverse effects. Results: A total of nine RCT studies involving 457 patients were included in this study. Compared to patients without perioperative flurbiprofen axetil, patients treated with preoperative flurbiprofen axetil had lower pain scores at 2 h (SMD −1.00; 95% CI −1.57 to −0.43, P = 0.0006), 6 h (SMD −1.22; 95% CI −2.01 to −0.43; P = 0.002), 12 h (SMD −1.19; 95% CI −2.10 to −0.28; P = 0.01), and 24 h (SMD −0.79; 95% CI −1.31 to −0.27; P = 0.003) following surgery. Preoperative flurbiprofen axetil had no significant effect on postoperative opioid consumption (SMD −13.11; 95% CI −34.56 to 8.33; P = 0.23). There was no significant difference between the groups with regard to adverse effects. Compared to patients with postoperative flurbiprofen axetil, however, preoperative flurbiprofen axetil resulted in decreased pain score only at 2 h after operation. Conclusions: Preoperative use of flurbiprofen axetil will result in significantly lower postoperative pain scores, but no difference in nausea, vomiting, and opioid consumption compared to those who did not receive flurbiprofen axetil. However, more homogeneous and well-designed clinical studies are necessary to determine whether preoperative flurbiprofen axetil administration has more efficacy than that given at the end of surgery. [ABSTRACT FROM AUTHOR]

A new platinum(II) complex of [Pt(Chda)(4-MOPIP)]2Cl · HO ( I) (Chda = cyclohexanediamine; 4-MOPIP = (4-methoxy-phenyl)-imidazo[4,5-f][l,10]-phenanthroline) has been synthesized by hydrothermal methods and characterized by elemental analysis, IR, single-crystal X-ray diffraction (CIF file CCDC no. 1472980), UV-Vis and fluorescent spectrum. In complex I, the platinum adopts a four-coordinated square planar geometry. The DNA-binding interaction has been investigated. The complex can bind to DNA by intercalative mode, presenting the high DNA-binding affinity. [ABSTRACT FROM AUTHOR]

Hematopoietic stem cell transplantation (HSCT) using an optimized conditioning regimen is essential for the long-term survival of patients with inherited bone marrow failure syndromes (IBMFS). We report HSCT in 24 children with Fanconi anemia (FA, n = 12), Diamond-Blackfan anemia (DBA, n = 7), and dyskeratosis congenita (DC, n = 5) from a single HSCT center. The graft source was peripheral blood stem cells (n = 19) or cord blood stem cells (n = 5). FA and DC patients received reduced-intensity conditioning, while DBA patients had myeloablative conditioning. The median numbers of infused mononuclear cells and CD34+ cells were 14.20 × 108/kg and 4.3 × 106/kg, respectively. The median time for neutrophil and platelet recovery was 12 and 18 days, respectively. Complete donor engraftment was achieved in 23 of 24 patients. There was one primary graft failure. During a median follow-up of 27.5 months (range, 2-130 months), the overall survival in all patients was 95.8%. The incidence of grade II-III acute graft versus host disease (GvHD) and chronic GvHD was 29.2% and 16.7%, respectively. We conclude that HSCT can be a curative option for patients with IBMFS. Modification of the conditioning regimen based on the type of disease may lead to encouraging long-term outcomes. [ABSTRACT FROM AUTHOR]

Attention-deficit hyperactivity disorder (ADHD) and substance use disorders (SUDs) may have common etiologies. ADHD is more prevalent in patients with substance use disorders, and this pattern is consistent across different substances of abuse. Individuals with SUDs and ADHD exhibit significant variations in their clinical presentations. The developmental trajectory of ADHD to SUDs is complex: ADHD symptoms appear first in some patients but not in others. Many patients present with a heterogeneous collection of psychiatric and substance use co-morbidities, and these symptoms change over time. ADHD symptom severity is also highly variable, and more severe ADHD symptoms worsen co-morbid SUDs and complicate treatment. New longitudinal studies with innovative methods in high-risk populations and in community-based samples may clarify issues related to patient-treatment matching. When closely monitored, psychostimulant and other adjunct medications can be safely used to treat ADHD in this population, and such treatment may also improve outcome of SUDs. In particular, emerging evidence suggests individual-level tailoring ("precision medicine") approaches may represent a key pathway to improve clinical outcome. [ABSTRACT FROM AUTHOR]

Conventional radiographs play an important role as a first line imaging modality in the assessment for suspected hip fractures in the majority of trauma centres. The routinely performed radiographic projections in our emergency department for patients with clinically suspected hip fractures include antero-posterior (AP) and cross-table lateral views of the affected hip. Certain clinical scenarios which include the presence of significant pain of the injured lower limb, a large patient habitus, as well as pre-existing patient morbidity which would limit the range of motion of the lower limbs, for example the presence of prior joint replacement surgery or lower limb contractures, may however preclude proper positioning of the patient to obtain an optimal cross-table lateral view of the affected hip. The objective of this study is to investigate whether a modified axiolateral hip projection would be a feasible alternative to the cross-table lateral projection in the initial radiographic assessment of suspected cases of hip fracture. [ABSTRACT FROM AUTHOR]

Amounting evidences demonstrated that Rho/Rho-associated kinase (ROCK) might be a novel target for the therapy of Parkinson's disease (PD). Recently, we synthesized L-F001 and revealed it was a potent ROCK inhibitor with multifunctional effects. Here we investigated the effects of L-F001 in PD models. We found that L-F001 potently attenuated 6-OHDA-induced cytotoxicity in PC12 cells and significantly decreased intracellular reactive oxygen species (ROS), prevented the 6-OHDA-induced decline of mitochondrial membrane potential and intracellular GSH levels. In addition, L-F001 increased Akt and GSK-3beta phosphorylation and induced the nuclear Nrf2 and HO-1 expression in a time- and concentration-dependent manner. Moreover, L-F001 restored the levels of p-Akt and p-GSK-3beta (Ser9) as well as HO-1 expression reduced by 6-OHDA. Those effects were blocked by the specific PI3K inhibitor, LY294002, indicating the involvement of Akt/GSK-3beta pathway in the neuroprotective effect of L-F001. In addition, L-F001 significantly attenuated the tyrosinehydroxylase immunoreactive cell loss in 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine (MPTP)-induced mice PD model. Together, our findings suggest that L-F001 prevents 6-OHDA-induced cell death through activating Akt/GSK-3beta and Nrf2/HO-1 signaling pathway and attenuates MPTP-induced dopaminergic neuron toxicity in mice. L-F001 might be a promising drug candidate for PD. [ABSTRACT FROM AUTHOR]

Purpose: Noninvasive imaging of treatment-induced necrosis is important to distinguish early responders from patients resistant to the treatment plan, enabling the tailored-made therapeutic intervention. The purpose of this study was to explore the feasibility of [99mTc]EDDA-HYNIC-2C-rhein for early assessment of tumor response to treatment.Procedures: In vitro necrosis avidity of [99mTc]EDDA-HYNIC-2C-rhein was evaluated in human lung cancer A549 cells treated with hyperthermia. Single photon emission-computed tomography/X-ray-computed tomography (SPECT/CT) imaging was performed in rats bearing subcutaneous W256 tumor treated with combretastatin A-4 disodium phosphate (CA4P) and rats bearing orthotopic liver W256 tumor treated with a single microwave ablation. All rats were euthanized immediately after the imaging session for biodistribution and histology studies. The mechanism of necrosis avidity for the tracer was further explored by in vivo blocking experiment and in vitro histochemistry and fluorescence staining.Results: The uptake of [99mTc]EDDA-HYNIC-2C-rhein in necrotic cells was significantly higher than that in viable cells (p < 0.05). SPECT/CT imaging showed that an obvious "hot spot" was observed in the CA4P-treated tumor while not in the control tumor at 5 h after tracer injection. Ex vivo γ-counting revealed that the uptake of [99mTc]EDDA-HYNIC-2C-rhein in tumor was increased 3.5-fold in rats treated with CA4P compared with rats treated with vehicle. Autoradiography and corresponding H&E staining suggested that the higher overall radiotracer uptake in the treated tumors was attributed to the increased necrosis. Blocking with unlabeled HYNIC-2C-rhein demonstrated the specific binding of the radiotracer to necrotic tissues. The perfect match of autoradiograph and histochemistry staining and PI fluorescence staining revealed that necrosis avidity of the tracer may be attributable to intercalation with exposed DNA in necrotic tissues.Conclusion: [99mTc]EDDA-HYNIC-2C-rhein can image necrosis induced by anticancer therapy and holds potential for early assessment of treatment response. [ABSTRACT FROM AUTHOR]

Objective: This study aims to explore the feasibility of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) and blood oxygen level-dependent magnetic resonance imaging (BOLD-MRI) in assessing vessel function and tumour aggressiveness during anti-angiogenesis treatment. Materials and methods: A colon cancer xenograft model was established in BALB/C nude mice with the HCT116 cell line. Sixteen mice were randomly divided into Group A and Group B, which were treated with saline or bevacizumab by intraperitoneal injection on the 1st, 4th, 7th, 10th and 13th days and underwent DCE-MRI and BOLD-MRI examinations before and on the 3rd, 6th, 9th, 12th and 15th days after treatment. Group C was treated with oxaliplatin monotherapy, and Group D was treated with bevacizumab and oxaliplatin as a point of comparison for therapeutic effects. The pathological examinations included HE, HIF-1α, fibronectin and TUNEL staining, as well as α-SMA and CD31 double staining. One-way analysis of variance and correlation analysis were the main methods used for statistical analysis. Results: Group D manifested the highest tumour inhibition rate and smallest tumour volume on day 15, followed by Group C, Group B and Group A. Ktrans (F = 81.386, P < 0.001), Kep (F = 45.901, P < 0.001), Ve (F = 384.290, P < 0.001) and R2* values (F = 89.323, P < 0.001) showed meaningful trends with time in Group B but not Group A. The Ktrans values and tumour vessel maturity index (VMI) were higher than baseline values 3–12 days after bevacizumab treatment. The CD31 positive staining rate and VMI had the strongest correlations with Ktrans values, followed by AUC180, Ve and Kep values. The R2* value positively correlated with the positive staining rates of HIF-1α and fibronectin. Conclusion: Intermittent application of low-dose anti-angiogenic inhibitor treatment may help improve the effect of chemotherapy by reducing hypoxia-related treatment resistance and improving drug delivery. DCE-MRI is useful for evaluating vessel maturity and vascular normalization, while BOLD-MRI may help to predict tumour hypoxia and metastatic potential after anti-vascular treatment. [ABSTRACT FROM AUTHOR]

Pregnant patients with β-thalassemia are more likely to have progressive anemia which expose them to risk of adverse pregnancy outcomes, blood transfusion, and iron overload. Results from our previous study indicated that Colla corii asini (CCA, E'jiao), a natural ingredient of traditional Chinese medicine, could significantly increase hemoglobin level of pregnant women with β- thalassemia, but the underlying molecular mechanism was unclear. Thus, we applied high-throughput transcriptome sequencing to study the transcriptomic change before and after the CCA treatment. Twenty eligible pregnant women were recruited and randomized to either the CCA treatment group or the blank control group in a 3:1 ratio. Patients in the treatment group orally received daily 15 g CCA powder for 4 weeks. We analyzed the therapeutic effect indexes and the transcriptomic change in subjects' peripheral blood before and after treatment. We found that β CD 41-42(-TTCT)/βA was the main genotype of the subjects. The regulatory impact of CCA treatment became more evident among the subjects of genotype β CD 41-42(-TTCT)/βA. Gene ontogenesis analysis revealed that the top five molecular functions of differentially expressed genes were involved in membrane functionality and cellular structure. We further identified two consistent upregulated genes ZNF471 and THOC5 in the effective treatment group, which were engaged in Kruppel-associated box (KRAB) domain-containing zinc-finger protein pathway and THOC5 pathway, respectively. Based on our current findings, we hypothesize that the anti-anemia effect of CCA on pregnant women with β-thalassemia might be related to translation regulation of spectrin synthesis, membrane stability, and eventually prolonged the life span of erythrocytes. [ABSTRACT FROM AUTHOR]

Purpose: Oral mucositis is a common side effect of radiochemotherapy and may adversely affect the patients' quality of life (QoL). Honey application may reduce the mucositis grade in patients. Here, we conducted a meta-analysis of randomized controlled trials (RCTs) to evaluate the prophylactic and therapeutic effects of honey on radiochemotherapy-induced oral mucositis.Methods: Publications on RCTs were extracted from the PubMed, Embase, CINAHL, and Cochrane Library databases. The primary outcomes were mucositis grades and pain scores. Secondary outcomes were the recovery time and QoL. The study was registered with PROSPERO (number CRD42018108486).Results: Nineteen RCTs, involving 1276 patients, were reviewed. Honey considerably mitigated oral mucositis in both prophylactic and therapeutic phases. In the prophylactic phase, intolerable mucositis development was significantly prevented in the honey-treated group (RR = 0.18, 95% confidence interval [CI] = 0.09 to 0.41). Patients treated with honey showed significant decrease in pain scores in the first month of treatment (weighted mean difference [WMD] = - 3.25, 95% CI = - 4.41 to - 2.09) and at the end of the treatment (WMD = - 2.32, 95% CI = - 4.47 to - 0.18).Conclusion: Honey, which is relatively cheap and easily available, prevented mucositis and effectively mitigate mucositis in patients after radiochemotherapy. Moreover, it significantly reduced the mucositis grade and engendered a fast and painless healing process. Therefore, honey use during and after radiochemotherapy is recommended for mucositis prevention and treatment. [ABSTRACT FROM AUTHOR]

Purpose: The aim of this research was to design dexamethasone palmitate (DP) loaded sialic acid modified liposomes, with the eventual goal of using peripheral blood neutrophils (PBNs) that carried drug-loaded liposomes to improve the therapeutic capacity for rheumatoid arthritis (RA). Methods: A sialic acid – cholesterol conjugate (SA-CH) was synthesized and anchored on the surface of liposomal dexamethasone palmitate (DP-SAL). The physicochemical characteristics and in vitro cytotoxicity of liposomes were evaluated. Flow cytometry and confocal laser scanning microscopy were utilized to investigate the accumulation of liposomes in PBNs. The adjuvant-induced arthritis was adopted to investigate the targeting ability and anti-inflammatory effect of DP loaded liposomes. Results: Both DP-CL and DP-SAL existed an average size less than 200 nm with remarkably high encapsulation efficiencies more than 90%. In vitro and in vivo experiments manifested SA-modified liposomes provided a reinforced accumulation of DP in PBNs. As well, DP-SAL displayed a greater degree of accumulation in the joints and a stronger anti-inflammatory effect in terms of RA suppression. Conclusions: SA-modified liposomal DP was a promising candidate for RA-targeting treatment through the neutrophil-mediated drug delivery system. [ABSTRACT FROM AUTHOR]

10β,17β-dihydroxyestra-1,4-dien-3-one (DHED) which is a brain-selective prodrug of 17β-estradiol has been reported to improve the cognitive function in Alzheimer's disease (AD) mice model. However, little is known about the potential mechanism for cognitive improvement. In the present study, we used AD mice to investigate the effects and mechanisms of DHED treatment. Female Tg2576 transgenic AD mice were ovariectomized and then treated by implanting Alzet osmotic minipumps containing DHED or vehicle subcutaneously for 8 weeks. Consistent with previous report, DHED treatment ameliorated cognitive function of AD mice with decreasing Aβ levels in the hippocampus. Besides, we also found DHED treatment could reduce oxidative and inflammatory stress and the level of p-tau. The mechanisms underlying the cognitive function improvement may be linked with estrogen receptor (ER)-klf5-NF-κB pathway, demonstrated by decreased expression of klf5 and the secretion of inflammatory cytokines. However, the effects of DHED treatment could be reversed when ERα was inhibited by ICI182780. Taken together, our findings uncovered a new mechanism for DHED to improve the cognitive function of AD mice and may provide a viable therapy to treat AD. [ABSTRACT FROM AUTHOR]

The voltage-gated sodium channel NaV1.7, encoded by the gene SCN9A, is located in peripheral neurons and plays an important role in epileptogenesis. Previous studies have identified an increasing number of SCN9A mutations in patients with variable epilepsy phenotypes. Phenotypes of SCN9A mutations include febrile seizures (FS), genetic epilepsy with febrile seizures plus (GEFS+), and Dravet syndrome (DS), which pose challenges in clinical treatment. Here, we identified a heterozygous SCN9A mutation (c.980G > A chr2:167149868 p.G327E) from two twin sisters with Rolandic epilepsy by whole-exome sequencing. The patient became seizure free with a combination of levetiracetam and clonazepam. Identification of this mutation is also helpful for advancing our understanding of the role of SCN9A in epilepsy and provides deeper insights for SCN9A mutations associated with broad clinical spectrum of seizures. [ABSTRACT FROM AUTHOR]

Objectives: To evaluate the characteristics of Bletilla striata microspheres (BSMs) and its effects as an embolic agent in a rabbit model. Methods: BSMs were prepared with an emulsification-cool condensation-chemical cross-linking method. The characteristics of BSMs in vitro were observed. Embolization experiments were performed in renal artery of rabbit and in a rabbit liver VX2 carcinoma model. Seventy-two New Zealand rabbits were divided into 2 groups, and the right renal artery was embolized with BSMs (200 μm in diameter) in the experimental group and with polyvinyl alcohol (PVA) of the same size in the control group. The pathological findings were examined with hematoxylin-eosin and Masson stainings. Liver and renal functions were tested before and after embolization. VX2 tumor was transplanted in 15 New Zealand rabbits, which were randomly divided into 3 groups (n=5). Group A were treated with saline, group B with a mixture of doxorubicin and lipiodol, and group C with hepatic arterial infusion of BSMs (200 μm in diameter). Tumor growth rate was evaluated by magnetic resonance imaging scan. Apoptosis-related factors (bax, bcl-2) and tumor vascular endothelial cell growth factor (VEGF) were evaluated through immunohistochemical staining. Results: The characteristics of BSMs in vitro were in full compliance with the requirements for use in interventional procedures. In the renal artery embolization experiment, after BSMs intervention, it was more difficult to form collateral circulation than that with PVAs, and the kidney manifested atrophy and calcification. There were no significant difference of liver and renal functions in rabbits between groups. In the liver VX2 carcinoma embolization experiment, compared with group A, the growth rate of VX2 liver tumor and Bcl-2 levels was reduced, while apoptosis index, Bax, and VEGF were increased in group B (P<0.05). There were no significant difference between groups B and C (P>0.05). Conclusions: The characteristics of BSMs in vitro and in vivo meet the requirements for its use as an embolic agent in interventional approaches. [ABSTRACT FROM AUTHOR]

Peritoneal fibrosis (PF) is a major cause of ultrafiltration failure in patients receiving long-term peritoneal dialysis (PD), and effective prevention and treatment strategies are urgently needed. The dimethylamino Michael adduct of a natural product-derived micheliolide (MCL), dimethylaminomicheliolide (DMAMCL), is a new lead compound with the advantages of high stability, low toxicity, and sustainable release of MCL. This study aimed to investigate the protective effect of DMAMCL against PD-related PF and the mechanisms involved. In this study, we found that DMAMCL significantly decreased PD-induced extracellular matrix (ECM) deposition in a mouse model of PD, and that delayed DMAMCL administration halted the progression of PF in an established PD model. In addition, rapamycin administration induced autophagy and significantly ameliorated PF. The protective effect of DMAMCL against PF was weakened when co-administered with DMAMCL and 3-methyladenine. Inducing autophagy by rapamycin decreased transforming growth factor-β1–induced ECM accumulation in vitro. MCL promoted autophagy and inhibited ECM deposition. The anti-fibrotic effect of MCL was eliminated when knocking down ATG7 by siRNA. Taken together, DMAMCL might prevent against PF through activating autophagy. The anti-fibrotic effect of DMAMCL may be a new candidate for the treatment in patients with PD-related PF. Key messages: Dimethylaminomicheliolide, the pro-drug of micheliolide, protects against peritoneal fibrosis in a mouse peritoneal dialysis model. Micheliolide inhibits TGF-β1-induced extracellular matrix accumulation in vitro. Autophagy plays a protective role against peritoneal fibrosis. The antifibrogenic effect of dimethylaminomicheliolide may be due to the activation of autophagy. [ABSTRACT FROM AUTHOR]

Background: Intertrochanteric fragility fracture (IFF) treated with proximal femoral nail anti-rotation (PFNA) is associated with significant hidden blood loss and high blood transfusion rate. The purpose of the present study was to evaluate the efficacy and safety of tranexamic acid (TXA) in reducing blood loss in these patients. Materials and Methods: Consecutive eligible patients were recruited and randomly assigned to a TXA group or a control group. The TXA group received 15 mg/kg body weight of TXA intravenously 15 min before incision and the same dose 3 h later. The control group received 100 mL of saline intravenously 15 min before incision. The efficacy outcomes included the total perioperative blood loss, postoperative transfusion rate, postoperative hemoglobin level, and length of the hospital stay. The safety outcomes were the incidence of thrombotic events and the mortality rate within 6 weeks after surgery. Results: We had 44 patients in the TXA group and 46 patients in the control group for the final analysis. The TXA group had significantly lower total perioperative blood loss than the control group (384.5 ± 366.3 mL vs. 566.2 ± 361.5 mL; P < 0.020). Postoperative transfusion rate was 15.9% in the TXA group versus 36.9% in the control group (P = 0.024). Each group had one patient with postoperative deep venous thrombosis. In the control group, three patients had cerebral infarction, and one patient died within 6 weeks after the operation. Conclusion: Intravenous TXA is effective in reducing total perioperative blood loss and transfusion rate in IFF treated with PFNA. No increased risk of thrombotic events was observed with the use of TXA; however, this study was underpowered for detecting this outcome. Further research is necessary before TXA can be recommended for high-risk patients. [ABSTRACT FROM AUTHOR]

Several recently published clinical trials have shown tofacitinib to be effective in the treatment of autoimmune diseases. This drug is commonly prescribed either in a 5-mg or in a10-mg dosage twice daily. In this review, we aimed to systematically compare the adverse drug events which were observed with 5 mg versus 10 mg tofacitinib for the treatment of autoimmune diseases. MEDLINE, EMBASE, the Cochrane library, and www.ClinicalTrials.gov were searched (from March to April 2018) for suitable English publications (published before April 2018). The inclusion criteria were as follows: randomized controlled trials, autoimmune disorders (rheumatic arthritis, psoriatic arthritis, moderate to severe psoriasis, and ankylosing spondylitis), and comparison of adverse drug events associated with 5 mg versus 10 mg tofacitinib. This study had follow-up time periods of 3 months and ≥ 6 months. Statistical analysis was carried out by RevMan 5.3 whereby risk ratios (RRs) and 95% confidence intervals (CIs) were generated. A total number of 4287 participants were included (2144 versus 2143 participants who received 5 mg and 10 mg tofacitinib twice daily respectively). The results showed that at 3 months, similar risks of adverse drug events, serious adverse events, and adverse events leading to drug discontinuation were observed with 5 mg versus 10 mg tofacitinib (RR 1.04, 95% CI 0.98-1.10; P = 0.17, I2 = 0%; RR 1.06, 95% CI 0.77-1.48; P = 0.71, I2 = 0%; and RR 1.06, 95% CI 0.78-1.43; P = 0.73, I2 = 32%, respectively). The other outcomes including serious infection events, adjudicated herpes zoster infection, adjudicated opportunistic infection, mild and severe neutropenia, malignancies, and adjudicated major adverse cardiovascular events were also similarly manifested. However, a decreased level of hemoglobin significantly favored 5 mg tofacitinib (RR 1.75, 95% CI 1.19-2.58; P = 0.005, I2 = 49%). Even at a follow-up time period of ≥ 6 months, adverse drug events, serious adverse events, adverse drug events leading to drug discontinuation, and serious infection were still similarly observed. According to this current review, both dosages of tofacitinib were safe to use. Even if similar adverse drug events were observed with 5 mg versus 10 mg tofacitinib twice daily for the treatment of autoimmune disorders, anemia was more prominent with 10 mg tofacitinib at a 3 month follow-up. Nevertheless, future studies based on a larger population size with longer follow-up time periods should further be considered. [ABSTRACT FROM AUTHOR]