Network pharmacology identifies the inhibitory effect of Yiqiyangyinquyu prescription on salivary gland inflammation in Sjögren's syndrome.

This study aimed to explore the mode of action of Yiqiyangyinquyu prescription (YP) against Sjögren's syndrome (SS) by combining network pharmacology with molecular docking techniques. YP's active components and target proteins were identified using the BATMAN-traditional Chinese medicine database. Concurrently, targets associated with SS were extracted from databases, including Genecards, Online Mendelian Inheritance in Man, and Therapeutic Target Database. The standard targets were then imported into the STRING database to construct a protein-protein interaction network. We then conducted gene ontology and Kyoto encyclopedia of genes and genomes enrichment analyses, which were succeeded by molecular docking studies to validate core active components and key targets. Finally, in vitro experiments and molecular dynamics simulation were conducted to substantiate the therapeutic efficacy of YP in treating SS. A total of 206 intersection targets and 46 active compounds were identified. Gene ontology analysis unveiled that YP targets were primarily enriched in cellular responses to chemical stress, inflammation, and cell proliferation. Key enriched signaling pathways encompassed the interleukin 17, hypoxia-inducible factor-1, tumor necrosis factor (TNF-α), and advanced glycation end products-receptor for AGEs (AGE-RAGE) signaling pathways. Molecular docking results demonstrated high-affinity between neotanshinone C, tanshiquinone B, miltionone I, TNF-α, interleukin 1 beta (IL-1ß), and interleukin 6 (IL-6). Noteworthy, TNF-α, considered the most important gene in YP against SS, binds to YP most stably, which was further validated by molecular dynamics simulation. In vitro experiments confirmed YP's capacity to reduce TNF-α, IL-1ß, and IL-6 expression, effectively alleviating SS-related inflammation. YP demonstrated a significant anti-inflammatory effect by suppressing inflammatory cytokines (TNF-α, IL-6, and IL-1ß), providing experimental evidence for its clinical application in treating SS.

Optimal design of impeller for self-priming pump based on orthogonal method.

In order to improve the efficiency of the self-priming pump in the outdoor emergency rescue mobile pump truck, this paper took the key energy conversion component-impeller as the target and used the orthogonal experimental design method to optimize its hydraulic performance. Firstly the numerical calculations were compared with the experimental results to confirm the reliability of the calculation method. Then, L9 (34) orthogonal design was applied to investigate the influence of the impeller diameter, the blade outlet width, the blade wrap angle and the number of blades on the hydraulic performance of the self-priming pump. Through range analysis, the order of influence of each influencing factor on the head and efficiency of the self-priming pump was determined, and finally obtained the optimal parameter combination scheme. The results show that the optimized self-priming pump exceeds the head of the prototype pump at all flow conditions, and the efficiency curve at high flow conditions is significantly improved and has a wide high efficiency zone.

Genome-wide DNA methylation sequencing reveals epigenetic features and potential biomarkers of Sjögren syndrome.

AIM: Sjögren syndrome (SS) is a slowly progressive, inflammatory, autoimmune disease. The aim of this study was to construct the DNA methylation profiles of whole blood of SS patients and healthy controls (HC), and to explore the role of differentially methylated genes in the pathogenesis of the disease. METHODS: Whole-genome bisulfite sequencing was performed on three SS patients and four HC. The biological function of genes associated with differentially methylated regions (DMRs) was investigated using Gene Ontology functional analysis and Kyoto Encyclopedia of Genes and Genomes pathway analysis, using network-based key driver analysis (KDA) to find KDA genes. In clinical samples of SS patients and controls, the expression levels of KDA genes were validated by quantitative real-time polymerase chain reaction and immunohistochemical analysis. Moreover, the diagnostic value of KDA genes for SS was confirmed using receiver operating characteristic curves. RESULTS: We identified 322 DMRs, annotated as 162 associated genes. Six genes were selected via the number of networks of KDA genes. Differential expression of genes such as human leukocyte antigen (HLA) class I, ADAR, and OAS2 was observed in patients' peripheral blood mononuclear cells and the minor salivary glands, which can be used as potential diagnostic biomarkers for SS. CONCLUSION: Clinical sample validation suggested that HLA class I, ADAR, and OAS2 might play a role in the development of SS. Our study shows epigenetic regulatory mechanisms and potential disease markers associated with SS, which in turn will enable us to identify new therapeutic targets.

The association between admission serum albumin and preoperative deep venous thrombosis in geriatrics hip fracture: a retrospective study of 1819 patients with age ≥ 65 years.

OBJECTIVE: This study evaluated the association between serum albumin levels and preoperative deep vein thrombosis (DVT) in geriatric hip fractures. METHODS: Older adult patients with hip fractures were screened between January 2015 and September 2019. The demographic and clinical characteristics of the patients were collected. Multivariate binary logistic regression and generalized additive model were used to identify the linear and nonlinear association between albumin levels and preoperative DVT. Analyses were performed using EmpowerStats and the R software. RESULTS: A total of 1819 patients were included in this study. The average age was 79.37 ± 6.88 years. There were 550 males and 1269 females. The preoperative albumin was 38.19 ± 4.07 g/L. There were 580 (31.89%) preoperative DVTs. Multivariate binary logistic regression showed that albumin level was associated with preoperative DVT (odds ratio [OR] = 0.94, 95% confidence interval [CI]: 0.91-0.97, P = 0.0002) after adjusting for confounding factors. The fully adjusted model showed a DVT risk decrease of 6% when albumin concentration increased by one g/L after controlling for confounding factors. In addition, the trend test and propensity score matching also showed a stable linear correlation between albumin level and preoperative DVT. CONCLUSION: Serum albumin is associated with preoperative DVT in geriatric patients with hip fractures, and it could be considered a predictor for the risk of DVT. REGISTRATION ID: ChiCTR2200057323.

Loss of C3a and C5a receptors promotes adipocyte browning and attenuates diet-induced obesity via activating inosine/A2aR pathway.

Complement activation is thought to underline the pathologic progression of obesity-related metabolic disorders; however, its role in adaptive thermogenesis has scarcely been explored. Here, we identify complement C3a receptor (C3aR) and C5a receptor (C5aR) as critical switches to control adipocyte browning and energy balance in male mice. Loss of C3aR and C5aR in combination, more than individually, increases cold-induced adipocyte browning and attenuates diet-induced obesity in male mice. Mechanistically, loss of C3aR and C5aR increases regulatory T cell (Treg) accumulation in the subcutaneous white adipose tissue during cold exposure or high-fat diet. Activated Tregs produce adenosine, which is converted to inosine by adipocyte-derived adenosine deaminases. Inosine promotes adipocyte browning in a manner dependent on activating adenosine A2a receptor. These data reveal a regulatory mechanism of complement in controlling adaptive thermogenesis and suggest that targeting the C3aR/C5aR pathways may represent a therapeutic strategy in treating obesity-related metabolic diseases.

The Association between the Hematocrit at Admission and Preoperative Deep Venous Thrombosis in Hip Fractures in Older People: A Retrospective Analysis.

Hematocrit, a commonly used hematological indicator, is a simple and easily applicable test. As a marker of anisocytosis and anemia, it indicates the percentage of blood cells per unit volume of whole blood. This study aimed to evaluate the association between the level of the hematocrit at admission and preoperative deep vein thrombosis (DVT) in hip fractures of older people. We collected the demographic and clinical characteristics of patients with geriatric hip fractures between 1 January 2015, and 30 September 2019, at the largest trauma center in northwestern China. Doppler ultrasonography was used to diagnose DVT. The correlation between hematocrit levels at admission and preoperative DVT was assessed using linear and nonlinear multivariate logistic regression, according to the adjusted model. All analyzes were performed using EmpowerStats and R software. In total, 1840 patients were included in this study, of which 587 patients (32%) had preoperative DVT. The mean hematocrit level was 34.44 ± 5.64 vol%. Linear multivariate logistic regression models showed that admission hematocrit levels were associated with preoperative DVT (OR = 0.97, 95% CI: 0.95−0.99; p = 0.0019) after adjustment for confounding factors. However, the linear association was unstable, and nonlinearity was identified. An admission hematocrit level of 33.5 vol% was an inflection point for the prediction. Admission hematocrit levels <33.5 vol% were not associated with preoperative DVT (OR = 1.00, 95% CI: 0.97−1.04, p = 0.8230), whereas admission hematocrit levels >33.5 vol% were associated with preoperative DVT (OR = 0.94, 95% CI: 25 0.91−0.97, p = 0.0006). Hematocrit levels at admission were nonlinearly associated with preoperative DVT, and hematocrit at admission was a risk factor for preoperative DVT. However, the severity of a low hematocrit was not associated with preoperative DVT when the hematocrit was <33.5 vol%.

Nobiletin inhibits breast cancer cell migration and invasion by suppressing the IL-6-induced ERK-STAT and JNK-c-JUN pathways.

BACKGROUND: Breast cancer is one of the most common cancers in women, affecting more than 2 million women worldwide annually. However, effective treatments for breast cancer are limited. Nobiletin is a flavonoid present in the dried mature pericarp of mandarin orange (Citrus reticulata Blanco), which is used to prepare Citri Renetulatae Pericarpium and can inhibit tumour growth and progression according to modern pharmacological studies. However, whether nobiletin exhibits an antimetastatic role in breast cancer and its potential mechanism need to be further investigated. PURPOSE: This study aims to evaluate the inhibitory effect of nobiletin on breast cancer and to elucidate potential mechanisms against invasion and migration. METHODS: Cell viability was determined by cell counting kit-8 and colony formation assays. Wound healing and Boyden chamber assays detected cancer cell migration and invasion capabilities. Immunoblotting and qPCR were applied to determine the protein and mRNA expression levels of extracellular signal-regulated kinases (ERK) and the c-Jun N-terminal kinase (JNK) signalling pathways. Molecular docking was used to assess the degree of nobiletin binding to phosphatidylinositol 3-kinase (PI3K). Xenografts and liver metastases were constructed in BALB/c nude mice to evaluate the anticancer effect of nobiletin in vivo. H&E staining and immunohistochemistry were used to detect proliferation and the expression of related proteins. RESULTS: Nobiletin induced cell death in a concentration- and time-dependent manner and possessed anti-invasion and anti-migration effects on MCF-7 and T47D cells by suppressing the interleukin-6-induced ERK and JNK signalling pathways. In addition, nobiletin docked with the binding site of PI3K, and the binding score was -8.0 kcal/mol. Furthermore, the inhibition of breast cancer growth and metastasis by nobiletin was demonstrated by constructing xenografts and liver metastases in vivo. CONCLUSION: Nobiletin inhibited liver metastasis of breast cancer by downregulating the ERK-STAT and JNK-c-JUN pathways, and its safety and efficacy were verified, indicating the potential of nobiletin as an anticancer agent.

Cyclophilin D-induced mitochondrial impairment confers axonal injury after intracerebral hemorrhage in mice.

The mitochondrial permeability transition pore is a nonspecific transmembrane channel. Inhibition of mitochondrial permeability transition pore opening has been shown to alleviate mitochondrial swelling, calcium overload, and axonal degeneration. Cyclophilin D is an important component of the mitochondrial permeability transition pore. Whether cyclophilin D participates in mitochondrial impairment and axonal injury after intracerebral hemorrhage is not clear. In this study, we established mouse models of intracerebral hemorrhage in vivo by injection of autologous blood and oxyhemoglobin into the striatum in Thy1-YFP mice, in which pyramidal neurons and axons express yellow fluorescent protein. We also simulated intracerebral hemorrhage in vitro in PC12 cells using oxyhemoglobin. We found that axonal degeneration in the early stage of intracerebral hemorrhage depended on mitochondrial swelling induced by cyclophilin D activation and mitochondrial permeability transition pore opening. We further investigated the mechanism underlying the role of cyclophilin D in mouse models and PC12 cell models of intracerebral hemorrhage. We found that both cyclosporin A inhibition and short hairpin RNA interference of cyclophilin D reduced mitochondrial permeability transition pore opening and mitochondrial injury. In addition, inhibition of cyclophilin D and mitochondrial permeability transition pore opening protected corticospinal tract integrity and alleviated motor dysfunction caused by intracerebral hemorrhage. Our findings suggest that cyclophilin D is used as a key mediator of axonal degeneration after intracerebral hemorrhage; inhibition of cyclophilin D expression can protect mitochondrial structure and function and further alleviate corticospinal tract injury and motor dysfunction after intracerebral hemorrhage. Our findings provide a therapeutic target for preventing axonal degeneration of white matter injury and subsequent functional impairment in central nervous diseases.

The Application of Citrus folium in Breast Cancer and the Mechanism of Its Main Component Nobiletin: A Systematic Review.

Citrus folium and its main ingredient nobiletin (NOB) have received widespread attention in recent years due to their antitumor effects. The antitumor effect of Citrus folium is related to the traditional use, mainly in its Chinese medicinal properties of soothing the liver and promoting qi, resolving phlegm, and dispelling stagnation. Some studies have proved that Citrus folium and NOB are more effective for triple-negative breast cancer (TNBC), which is related to the syndrome of stagnation of liver qi. From the perspective of modern biomedical research, NOB has anticancer effects. Its potential molecular mechanisms include inhibition of the cell cycle, induction of apoptosis, and inhibition of angiogenesis, invasion, and migration. Citrus folium and NOB can also reduce the side effects of chemotherapy drugs and reverse multidrug resistance (MDR). However, more research studies are needed to clarify the underlying mechanisms. The modern evidence of Citrus folium and NOB in breast cancer treatment has a strong connection with the traditional concepts and laws of applying Citrus folium in Chinese medicine (CM). As a low-toxic anticancer drug candidate, NOB and its structural changes, Citrus folium, and compound prescriptions will attract scientists to use advanced technologies such as genomics, proteomics, and metabolomics to study its potential anticancer effects and mechanisms. On the contrary, there are relatively few studies on the anticancer effects of Citrus folium and NOB in vivo. The clinical application of Citrus folium and NOB as new cancer treatment drugs requires in vivo verification and further anticancer mechanism research. This review aims to provide reference for the treatment of breast cancer by Chinese medicine.

An organic NIR-II nanofluorophore with aggregation-induced emission characteristics for in vivo fluorescence imaging.

Background: In vivo fluorescence imaging in the second near-infrared (NIR-II, 1000-1700 nm) window using organic fluorophores has great advantages, but generally suffers from a relatively low fluorescence quantum yield (mostly less than 2%). In this study, organic nanoparticles (L1013 NPs) with a high fluorescence quantum yield (9.9%) were systhesized for in vivo imaging. Methods: A molecule (BTPPA) with donor-acceptor-donor structure and aggregation-induced emission enabling moieties was prepared. BTPPA molecules were then encapsulated into nanoparticles (L1013 NPs) using a nanoprecipitation method. The L1013 NPs were intravenously injected into the mice (including normal, stroke and tumor models) for vascular and tumor imaging. Results: L1013 NPs excited at 808 nm exhibit NIR-II emission with a peak at 1013 nm and an emission tail extending to 1400 nm. They have a quantum yield of 9.9% and also show excellent photo/colloidal stabilities and negligible in vitro and in vivo toxicity. We use L1013 NPs for noninvasive real-time visualization of mouse hindlimb and cerebral vessels (including stroke pathology) under a very low power density (4.6-40 mW cm‒2) and short exposure time (40-100 ms). Moreover, L1013 NPs are able to localize tumor pathology, with a tumor-to-normal tissue ratio of 11.7±1.3, which is unusually high for NIR-II fluorescent imaging through passive targeting strategy. Conclusion: L1013 NPs demonstrate the potential for a range of clinical applications, especially for tumor surgery.

A method for combining multiple-units readout of optogenetic control with natural stimulation-evoked eyeblink conditioning in freely-moving mice.

A growing pool of transgenic mice expressing Cre-recombinases, together with Cre-dependent opsin viruses, provide good tools to manipulate specific neural circuits related to eyeblink conditioning (EBC). However, currently available methods do not enable to get fast and precise readout of optogenetic control when the freely-moving mice are receiving EBC training. In the current study, we describe a laser diode (LD)-optical fiber (OF)-Tetrode assembly that allows for simultaneous multiple units recording and optical stimulation. Since the numbers of various cables that require to be connected are minimized, the LD-OF-Tetrode assembly can be combined with CS-US delivery apparatus for revealing the effects of optical stimulation on EBC in freely- moving mice. Moreover, this combination of techniques can be utilized to optogenetically intervene in hippocampal neuronal activities during the post-conditioning sleep in a closed-loop manner. This novel device thus enhances our ability to explore how specific neuronal assembly contributes to associative motor memory in vivo.

Chondroitin sulfate proteoglycan represses neural stem/progenitor cells migration via PTPσ/α-actinin4 signaling pathway.

Neural stem/progenitor cells (NSPCs) are a promising candidate for the cell-replacement therapy after central nervous system (CNS) injury. However, the short of sufficient NSPCs migration and integration into the lesions is an essential challenge for cell-based therapy after CNS injury due to the disturbance of local environmental homeostasis. Chondroitin sulfate proteoglycan (CSPG) is obviously accumulated at the lesions and destroyed local homeostasis after CNS injury. The previous study has demonstrated that the CSPG is a dominating ingredient inhibiting axonal regrowth of newly born neurons after CNS injury. NSPCs, a strain of special neural subtypes, hold the capacity of leading processes formation to regulate NSPCs migration, which has the same mechanism as axonal regrowth. Hence, it is worth investigating the effect of CSPG on NSPCs migration and its underlying mechanism. Here, different concentration of CSPG was used to evaluate its effect on NSPCs migration. The results showed that the CSPG suppressed NSPCs migration in a dose-dependent manner from 10 to 80 µg/mL with phase-contrast microscopy after 24 hours. Meanwhile, transwell assays were performed to certify the above results. Our data indicated that the 40 µg/mL CSPG obviously suppressed NSPCs migration via decreasing filopodia formation using immunofluorescence staining. Furthermore, data indicated that the 40 µg/mL CSPG upregulated protein tyrosine phosphatase receptor σ (PTPσ) expression and decreased α-actinin4 (ACTN4) expression through immunofluorescence, reverse transcription polymerase chain reaction, and Western blot assays. While the inhibitory effect was attenuated using PTPσ-specific small interfering RNA. In addition, data demonstrated that the 40 µg/mL CSPG facilitated NSPCs differentiation into glial fibrillary acidic protein-positive cells and inhibited NSPCs directing into MAP2- and MBP-positive cells. Collectively, these data demonstrated that the CSPG suppressed NSPCs migration through PTPσ/ACTN4 signaling pathway. Meanwhile, CSPG facilitated NSPCs differentiation into astrocytes and inhibited NSPCs directing into neurons and oligodendrocytes.

Comparison of procedural sequences in same-day painless bidirectional endoscopy: Single-center, prospective, randomized study.

BACKGROUND AND AIM: To compare the efficacy and safety of esophagogastroduodenoscopy (EGD)-colonoscopy and colonoscopy-EGD sequences for patients subjected to same-day bidirectional endoscopy under remifentanil and propofol sedation. METHODS: A total of 209 eligible outpatients scheduled for diagnostic same-day bidirectional endoscopy between 16 February 2016 and 30 April 2016 were randomly assigned to the EGD-colonoscopy (n = 106) and colonoscopy-EGD (n = 103) sequence groups. Primary endpoint was total dose of propofol required for the procedure. Secondary endpoints included duration of endoscopy, patient satisfaction, adverse effects, endoscopy findings, and cardiopulmonary responses of the patients. RESULTS: Patients in the two groups were similar in terms of demographic and clinical data (P > 0.05). EGD-colonoscopy sequence group had lesser requirement of propofol for sedation (P < 0.05), faster recovery (P < 0.001), and lesser influence on mean arterial pressure (MAP) during the endoscopy (P < 0.05). Duration of EGD and colonoscopy, patient satisfaction, adverse effects, and pathological findings did not differ between the two groups. CONCLUSIONS: The EGD-colonoscopy sequence may be considered the preferred sequence for same-day bidirectional endoscopy as a result of less cardiovascular stress, lessened need for sedation with propofol, and faster recovery.

[Research on the Source Identification of Mine Water Inrush Based on LIF Technology and SIMCA Algorithm].

Rapid source identification of mine water inrush is of great significance for early warning and prevention in mine water hazard. According to the problem that traditional chemical methods to identify source takes a long time, put forward a method for rapid source identification of mine water inrush with laser induced fluorescence (LIF) technology and soft independent modeling of class analogy (SIMCA) algorithm. Laser induced fluorescence technology has the characteristics of fast analysis, high sensitivity and so on. With the laser assisted, fluorescence spectrums can be collected real-time by the fluorescence spectrometer. According to the fluorescence spectrums, the type of water samples can be identified. If the database is completed, it takes a few seconds for coal mine water source identification, so it is of great significance for early warning and post-disaster relief in coal mine water disaster. The experiment uses 405 nm laser emission laser into the 5 kinds of water inrush samples and get 100 groups of fluorescence spectrum, and then put all fluorescence spectrums into preprocessing. Use 15 group spectrums of each water inrush samples, a total of 75 group spectrums, as the prediction set, the rest of 25 groups spectrums as the test set. Using principal component analysis (PCA) to modeling the 5 kinds of water samples respectively, and then classify the water samples with SIMCA on the basis of the PCA model. It was found that the fluorescence spectrum are obvious different of different water inrush samples. The fluorescence spectrums after preprocessing of Gaussian-Filter, under the condition of the principal component number is 2 and the significant level α = 5%, the accuracy of prediction set and testing set are all 100% with the SIMCA to classify the water inrush samples.

Polyethylene Glycol Electrolyte Lavage Solution versus Colonic Hydrotherapy for Bowel Preparation before Colonoscopy: A Single Center, Randomized, and Controlled Study.

This single center, randomized, and controlled study aimed to compare the effectiveness and safety of polyethylene glycol electrolyte lavage (PEG-EL) solution and colonic hydrotherapy (CHT) for bowel preparation before colonoscopy. A total of 196 eligible outpatients scheduled for diagnostic colonoscopy were randomly assigned to the PEG-EL (n = 102) or CHT (n = 94) groups. Primary outcome measures included colonic cleanliness and adverse effects. Secondary outcome measures were patient satisfaction and preference, colonoscopic findings, ileocecal arrival rate, examiner satisfaction, and cecal intubation time. The results show that PEG-EL group was associated with significantly better colonic cleanliness than CHT group, fewer adverse effects, and increased examiner satisfaction. However, the CHT group had higher patient satisfaction and higher diverticulosis detection rates. Moreover, the results showed the same ileocecal arrival rate and patient preference between the two groups (P > 0.05). These findings indicate that PEG-EL is the preferred option in patients who followed the preparation instructions completely.

Dopamine inhibits neurons from the rat dorsal subcoeruleus nucleus through the activation of α2-adrenergic receptors.

Previous studies have revealed that the central dopaminergic system may participate in regulating sleep/wakefulness. In particular, rapid eye movement (REM) sleep behavior disorder (RBD) occurs in patients with Parkinson's disease (PD), highlighting the possible connection between dopamine and REM sleep-related neural structures. The dorsal subcoeruleus nucleus (SubCD) is a critical structure for the generation and maintenance of REM sleep. Thus, the present study investigated the modulatory effects of dopamine on SubCD neurons. Using whole-cell patch clamp recordings, we first observed that dopamine induced a hyperpolarization of the membrane potentials in SubCD neurons and thus inhibited their firing. We determined that a dose-dependent and tetrodotoxin-resistant postsynaptic outward current underpinned this inhibitory effect on SubCD neurons induced by dopamine. Finally, using pharmacological agents, we revealed that the dopamine-elicited outward current in SubCD neurons was mediated by α2-adrenergic receptors, but not by the dopamine receptors, including D1-like and D2-like receptors. These results suggest that the central dopaminergic system may play a role in the regulation of REM sleep through the effect of dopamine on SubCD neurons. The relationship between the loss of this effect and the RBD in PD is discussed.