MASI: microbiota-active substance interactions database.

Xenobiotic and host active substances interact with gut microbiota to influence human health and therapeutics. Dietary, pharmaceutical, herbal and environmental substances are modified by microbiota with altered bioavailabilities, bioactivities and toxic effects. Xenobiotics also affect microbiota with health implications. Knowledge of these microbiota and active substance interactions is important for understanding microbiota-regulated functions and therapeutics. Established microbiota databases provide useful information about the microbiota-disease associations, diet and drug interventions, and microbiota modulation of drugs. However, there is insufficient information on the active substances modified by microbiota and the abundance of gut bacteria in humans. Only ∼7% drugs are covered by the established databases. To complement these databases, we developed MASI, Microbiota-Active Substance Interactions database, for providing the information about the microbiota alteration of various substances, substance alteration of microbiota, and the abundance of gut bacteria in humans. These include 1,051 pharmaceutical, 103 dietary, 119 herbal, 46 probiotic, 142 environmental substances interacting with 806 microbiota species linked to 56 diseases and 784 microbiota-disease associations. MASI covers 11 215 bacteria-pharmaceutical, 914 bacteria-herbal, 309 bacteria-dietary, 753 bacteria-environmental substance interactions and the abundance profiles of 259 bacteria species in 3465 patients and 5334 healthy individuals. MASI is freely accessible at http://www.aiddlab.com/MASI.

CircFOXP1/FOXP1 promotes osteogenic differentiation in adipose-derived mesenchymal stem cells and bone regeneration in osteoporosis via miR-33a-5p.

Osteoporosis (OP) is defined by bone mass loss and structural bone deterioration. Currently, there are no effective therapies for OP treatment. Circular RNAs (circRNAs) have been reported to have an important function in stem cell osteogenesis and to be associated with OP. Most circRNA roles in OP remain unclear. In the present study, we employed circRNA microarray to investigate circRNA expression patterns in OP and non-OP patient bone tissues. The circRNA-miRNA-mRNA interaction was predicted using bioinformatic analysis and confirmed by RNA FISH, RIP and dual-luciferase reporter assays. ARS and ALP staining was used to detect the degree of osteogenic differentiation in human adipose-derived mesenchymal stem cells (hASCs) in vitro. In vivo osteogenesis in hASCs encapsulated in collagen-based hydrogels was tested with heterotopic bone formation assay in nude mice. Our research found that circFOXP1 was significantly down-regulated in OP patient bone tissues and functioned like a miRNA sponge targeting miR-33a-5p to increase FOXP1 expression. In vivo and in vitro analyses showed that circFOXP1 enhances hASC osteogenesis by sponging miR-33a-5p. Conversely, miR-33a-5p inhibits osteogenesis by targeting FOXP1 3'-UTR and down-regulating FOXP1 expression. These results determined that circFOXP1 binding to miR-33a-5p promotes hASC osteogenic differentiation by targeting FOXP1. Therefore, circFOXP7ay prevent OP and can be used as a candidate OP therapeutic target.

Chronic treatment with baicalein alleviates behavioural disorders and improves cerebral blood flow via reverting metabolic abnormalities in a J20 transgenic mouse model of Alzheimer's disease.

Baicalein (BE) has both antioxidant and anti-inflammatory effects. It has also been reported able to improve cerebral blood circulation in brain ischemic injury. However, its chronic efficacy and metabolomics in Alzheimer's disease (AD) remain unknown. In this study, BE at 80 mg/kg was administrated through the oral route in J20 AD transgenic mice aged from aged 4 months to aged 10 months. Metabolic- and neurobehavioural phenotyping was done before and after 6 months' treatment to evaluate the drug efficacy and the relevant mechanisms. Meanwhile, molecular docking was used to study the binding affinity of BE and poly (ADP-ribose) polymerase-1 (PARP-1) which is related to neuronal injury. The open field test showed that BE could suppress hyperactivity in J20 mice and increase the frequency of the target quadrant crossing in the Morris Water Maze test. More importantly, BE restored cerebral blood flow back to the normal level after the chronic treatment. A 1H NMR-based metabolomics study showed that BE treatment could restore the tricarboxylic acid cycle in plasma. And such a treatment could suppress oxidative stress, inhibit neuroinflammation, alleviate mitochondrial dysfunction, improve neurotransmission, and restore amino homeostasis via starch and sucrose metabolism and glycolipid metabolism in the cortex and hippocampus, which could affect the behavioural and cerebral blood flow. These findings showed that BE is a potential therapeutic agent for AD.

Fluorescence Analysis of Circulating Exosomes for Breast Cancer Diagnosis Using a Sensor Array and Deep Learning.

Emerging liquid biopsy methods for investigating biomarkers in bodily fluids such as blood, saliva, or urine can be used to perform noninvasive cancer detection. However, the complexity and heterogeneity of exosomes require improved methods to achieve the desired sensitivity and accuracy. Herein, we report our study on developing a breast cancer liquid biopsy system, including a fluorescence sensor array and deep learning (DL) tool AggMapNet. In particular, we used a 12-unit sensor array composed of conjugated polyelectrolytes, fluorophore-labeled peptides, and monosaccharides or glycans to collect fluorescence signals from cells and exosomes. Linear discriminant analysis (LDA) processed the fluorescence spectral data of cells and cell-derived exosomes, demonstrating successful discrimination between normal and different cancerous cells and 100% accurate classification of different BC cells. For heterogeneous plasma-derived exosome analysis, CNN-based DL tool AggMapNet was applied to transform the unordered fluorescence spectra into feature maps (Fmaps), which gave a straightforward visual demonstration of the difference between healthy donors and BC patients with 100% prediction accuracy. Our work indicates that our fluorescent sensor array and DL model can be used as a promising noninvasive method for BC diagnosis.

[Clinical oberservation on rotator cuff suture threader and strapping suture in meniscus tear under arthroscopy].

OBJECTIVE: To explore clinical effect of arthroscopic meniscus tear strapping suture by rotator cuff suture threader. METHODS: Forty patients with meniscus tear injury admitted from July 2015 to May 2019, including 27 males and 13 females, aged from 20 to 55 years old with an average of (36.0±1.4) years old. Menisci laceration was sutured with rotator cuff suture thread under arthroscopy. Postoperative complication was observed, Lysholm knee joint score before and after operation at 12 months were used to evaluate clinical effects, visual analogue scale (VAS) and range of knee flexion and extension were applied to evaluate recovery of pain and function. RESULTS: All patients were followed up from 12 to 15 months with an average of (12.6±0.7) months.No complication such as joint effusion, suture failure occurred. Two patients occurred mild pain after activity without clinical physical abnormality, and 1 patient manifested moderate pain with joint space tenderness, the other rest without abnormal. Lysholm knee joint score was increased from (49.55±1.21) preoperatively to (98.95±0.42) at 12 months after operation, VAS score decreased from (5.18±0.78)preoperatively to (1.03±0.77) at 12 months after operation, and range of knee joint flexion and extension activity increased from (50.63±9.20)°preoperatively to (130.38±4.99)°after operation, and there were statistical differences in Lysholm knee joint score, VAS and range of knee joint flexion and extension activity (P< 0.05). CONCLUSION: Arthroscopic strapping suture by rotator cuff suture threading device applies to most meniscus injuries, including medial meniscus posterior horn tears, lateral meniscus body tears and lateral meniscus posterior horn tears. This technique meets the need of full-internal meniscus suture without specialmeniscus suture, and has advantages of convenient operation, less complications and good postoperative function.

Functional effects of berberine in modulating mitochondrial dysfunction and inflammatory response in the respective amyloidogenic cells and activated microglial cells - In vitro models simulating Alzheimer's disease pathology.

AIM: Berberine (BBR) is an alkaloid extracted from Coptidis Rhizoma, also known as Huang-Lian. Huang-Lian has been used extensively in traditional Chinese medicine for the treatment of various diseases, including diabetes and dementia. Because Alzheimer's disease (AD) is a complex disease that involves various pathophysiological changes, the diverse neuroprotective effects of BBR may be useful for improving the brain's energy state at an early stage of the disease. MAIN METHODS: We performed extracellular flux and 1H NMR-based metabolic profiling analyses to investigate the effects of BBR on metabolic processes in these cells. Pioglitazone (PIO), a peroxisome proliferator-activated receptor-γ (PPARγ) agonist has been studied extensively for the treatment of AD. We explored the combination dosing effects of BBR and PIO in vitro, then leveraged computational methods to explain the experimental finding. KEY FINDINGS: BBR demonstrates potential in modulating the mitochondrial bioenergetics and attenuating dysfunction of the primary energy and glutathione metabolism pathways in an AD cell model. It also suppresses basal respiration and reduces the production of pro-inflammatory cytokines in activated microglial cells. Both experimental and computational observations indicate that BBR and PIO have comparable binding affinities to the PPARγ protein, suggesting both drugs may have some overlapping effects for AD. SIGNIFICANCE: BBR exerts beneficial effects on disrupted metabolic processes in amyloidogenic cells and activated microglial cells, which are important for preventing or delaying early-stage disease progression. The choice of BBR or PIO for AD treatment depends on their respective pharmacokinetic profiles, delivery, efficacy and safety, and warrants further study.

High-Content Phenotypic Screen of a Focused TCAMS Drug Library Identifies Novel Disruptors of the Malaria Parasite Calcium Dynamics.

The search for new antimalarial drugs with unexplored mechanisms of action is currently one of the main objectives to combat the resistance already in the clinic. New drugs should target specific mechanisms that once initiated lead inevitably to the parasite's death and clearance and cause minimal toxicity to the host. One such new mode of action recently characterized is to target the parasite's calcium dynamics. Disruption of the calcium homeostasis is associated with compromised digestive vacuole membrane integrity and release of its contents, leading to programmed cell death-like features characterized by loss of mitochondrial membrane potential and DNA degradation. Intriguingly, chloroquine (CQ)-treated parasites were previously reported to exhibit such cellular features. Using a high-throughput phenotypic screen, we identified 158 physiological disruptors (hits) of parasite calcium distribution from a small subset of approximately 3000 compounds selected from the GSK TCAMS (Tres Cantos Anti-Malarial Set) compound library. These compounds were then extensively profiled for biological activity against various CQ- and artemisinin-resistant Plasmodium falciparum strains and stages. The hits were also examined for cytotoxicity, speed of antimalarial activity, and their possible inhibitory effects on heme crystallization. Overall, we identified three compounds, TCMDC-136230, -125431, and -125457, which were potent in inducing calcium redistribution but minimally inhibited heme crystallization. Molecular superimposition of the molecules by computational methods identified a common pharmacophore, with the best fit assigned to TCMDC-125457. There were low cytotoxicity or CQ cross-resistance issues for these three compounds. IC50 values of these three compounds were in the low micromolar range. In addition, TCMDC-125457 demonstrated high efficacy when pulsed in a single-dose combination with artesunate against tightly synchronized artemisinin-resistant ring-stage parasites. These results should add new drug options to the current armament of antimalarial drugs as well as provide promising starting points for development of drugs with non-classical modes of action.

[Finite element analysis of adolescent idiopathic scoliosis of PUMC II d2 surgical treatment with different fusion levels].

OBJECTIVE: To explore the best surgical fusion level for adolescent idiopathic scoliosis (AIS) of PUMC II d(2) with finite element model (FEM). METHODS: FEM (T(5)-S) of PUMC II d(2) idiopathic scoliosis was used to simulate upper thoracic curve, lower lumbar curve and double curve fusion manners. The pedicle of concave vertebral arch received 50, 100 and 150 N load respectively. Displacement of T(5) and T(11) on upper sagittal plane (displacement of Z axis positive value on upper sagittal plane, displacement of negative value on lower sagittal plane) and their different values were compared. T(5) displacement represented the outcomes of double curve orthopedics. T(11) displacement represented the outcomes of lower lumbar curve orthopedics. Their difference (T(5)-T(11)) represented the outcomes of upper thoracic curve orthopedics. Different fusion segments and displacement of T(5) and T(11) under different orthopedic forces were measured. RESULTS: In PUMC II d(2) lateral curvature, T(5) displacement on Z axis: fusion displacement of double curve was greater than the upper or lower curve alone (F = 8, P < 0.01). Difference of T(5)-T(11) displacement: double curve orthopedics > upper thoracic curve orthopedics alone > lower lumbar curve orthopedics alone (F = 8, P < 0.01). Displacement of T(11) on Z axis: double curve orthopedics > lower lumbar curve orthopedics alone > upper thoracic curve orthopedics alone (F = 8, P < 0.01). CONCLUSION: Fusing two curves achieves the best effect on the AIS of PUMC II d(2) in comparison with upper or lower curve fusion alone. Effects of 3 kinds of load on correction of upper thoracic curve: double curve orthopedics > upper thoracic curve orthopedics alone > lower lumbar curve orthopedics alone. Effect of 3 kinds of load on correction of lower lumbar curve orthopedics alone: double curve orthopedics > lower lumbar curve orthopedics alone > upper thoracic curve orthopedics alone. Three-dimensional finite element analysis is an effective method to analyze the biomechanics of scoliosis deformity correction and provides a virtually non-invasive verification manner. And it may optimize the surgical protocol.

Predicting the Enzymatic Hydrolysis Half-lives of New Chemicals Using Support Vector Regression Models Based on Stepwise Feature Elimination.

The enzymatic hydrolysis of chemicals, which is important for in vitro drug metabolism assays, is an important indicator of drug stability profiles during drug discovery and development. Herein, we employed a stepwise feature elimination (SFE) method with nonlinear support vector machine regression (SVR) models to predict the in vitro half-lives in human plasma/blood of various esters. The SVR model was developed using public databases and literature-reported data on the half-lives of esters in human plasma/blood. In particular, the SFE method was developed to prevent over fitting and under fitting in the nonlinear model, and it provided a novel and efficient method of realizing feature combinations and selections to enhance the prediction accuracy. Our final developed model with 24 features effectively predicted an external validation set using the time-split method and presented reasonably good R2 values (0.6) and also predicted two completely independent validation datasets with R2 values of 0.62 and 0.54; thus, this model performed much better than other prediction models.

Arctigenin inhibits STAT3 and exhibits anticancer potential in human triple-negative breast cancer therapy.

Triple-negative breast cancers (TNBCs) are the most aggressive and hard-to-treat breast tumors with poor prognosis, and exploration for novel therapeutic drugs is impending. Arctigenin (Atn), a bioactive lignan isolated from seeds of Arctium lappa L, has been reported to inhibit many cancer types; however, the effect of Atn on TNBC remains unclear. In this study, we demonstrated that Atn decreased proliferation, and induced apoptosis in TNBC cells. Furthermore, we explored the underlying mechanism of Atn inhibition on TNBC cells. Computational docking and affinity assay showed that Atn bound to the SH2 domain of STAT3. Atn inhibited STAT3 binding to genomic DNA by disrupting hydrogen bond linking between DNA and STAT3. In addition, Atn augmented Taxotere®-induced TNBC cell cytotoxicity. TNBC xenograft tests also confirmed the antitumor effect of Atn in vivo. These characteristics render Atn as a promising candidate drug for further development and for designing new effective STAT3 inhibitors.

[Reverse fasciocutaneous flap pedicled with perforator branch of anterior medial malleolus artery for soft tissue defect on the dorsal side of foot].

OBJECTIVE: To report the therapeutic effect of reverse fasciocutaneous flap pedicled with perforator branch of anterior medial malleolus artery for soft tissue defect on the dorsal side of foot. METHODS: The perforator branch was located under the guidance of Doppler flowmeter. The flap was designed along the saphenous neurovascular axis. Then the flap was transferred reversely with the perforator branch as rotation point. RESULTS: From Feb. 2002 to Mar. 2008, 12 cases were treated and followed up for 6 - 18 months. All the flaps survived completely. The flap size ranged from 13.5 cm x 3.0 cm to 8 cm x 3 cm. The perforator branch located at 0.5 - 1.5 cm anterior-inferior to the medial malleolus. Both the cosmetic and functional results were satisfactory. CONCLUSIONS: The flap has a reliable blood supply and a flexible design. It is easily performed for soft tissue defect on the dorsal side of foot. It is a new type flap which combined neurocutaneous vascular flap with the perforator flap.