Photoresponsive metal-organic framework with combined photodynamic therapy and hypoxia-activated chemotherapy for the targeted treatment of rheumatoid arthritis.

Activated M1-type macrophages, which produce inflammatory factors that exacerbate rheumatoid arthritis (RA), represent crucial target cells for inhibiting the disease process. In this study, we developed a novel photoresponsive targeted drug delivery system (TPNPs-HA) that can effectively deliver the hypoxia-activated prodrug tirapazamine (TPZ) specifically to activated macrophages. After administration, this metal-organic framework, PCN-224, constructed uing the photosensitizer porphyrin, exhibits the ability to generate excessive toxic reactive oxygen species (ROS) when exposed to near-infrared light. Additionally, the oxygen-consumed hypoxic environment further activates the chemotherapeutic effect of TPZ, thus creating a synergistic combination of photodynamic therapy (PDT) and hypoxia-activated chemotherapy (HaCT) to promote the elimination of activated M1-type macrophages. The results highlight the significantly potential of this photoresponsive nano-delivery system in providing substantial relief for RA. Furthermore, these findings support its effectiveness in inhibiting the disease process of RA, thereby offering new possibilities for the development of precise and accurate strategies for RA.

Effects of Cannabidiol on Parkinson's Disease in a Transgenic Mouse Model by Gut-Brain Metabolic Analysis.

Parkinson's disease (PD) is a common neurodegenerative disease characterized by a disorder of the dopaminergic system in the midbrain, causing classical PD motor symptoms. The therapeutic effect of cannabidiol (CBD) on PD has been a research frontier in recent years. However, the pathogenesis of PD and the therapeutic mechanism of cannabinoid remain unclear. To further study the causes of PD and the effect of CBD on PD, we exposed the PD transgenic mouse model to CBD and then estimated the motorial and postural coordination through a modified swim test. Afterwards, the mechanism was investigated via the histopathology of substantia nigra and the gut-brain metabolic analysis in the approach of UHPLC-TOF-MS. The results showed that CBD significantly improved motor deficits of PD model and protected the substantia nigra area. The metabolic function of fatty acid biosynthesis, arginine biosynthesis/metabolism, butanoate (ketone body) metabolism, ß-alanine metabolism, and pantothenate/CoA biosynthesis was highlighted in the pathological and therapeutic process along the gut-brain axis. In conclusion, CBD could attenuate PD via the neuroprotective effect on the midbrain. The attenuation of the central nervous system in turn improved motor performance of PD, which might be partially induced by the metabolic interaction between the gut-brain. In view of gut-brain metabolomics, the mechanism of PD pathogenesis and the effect of CBD on PD are highly related to the biosynthesis and metabolism of energy and essential substance.

Capsaicin ameliorates renal fibrosis by inhibiting TGF-ß1-Smad2/3 signaling.

BACKGROUND AND PURPOSE: Chronic kidney disease (CKD), characterized by renal fibrosis, is a global refractory disease with few effective therapeutic strategies. It has been reported that capsaicin exerts many pharmacological effects including liver and cardiac fibrosis. However, whether capsaicin plays a therapeutic role in renal fibrosis remains unclear. METHODS: We investigated antifibrotic effects of capsaicin in two mouse renal fibrosis models as follows: C57BL/6J mice were subjected to unilateral ureteral obstruction (UUO) and fed with an adenine-rich diet. We uncovered and verified the mechanisms of capsaicin in human proximal tubular epithelial cells (HK2). We mainly used histochemistry, immunohistochemistry and immunofluorescence staining, western blot assay, biochemical examination and other tools to examine the effects of capsaicin on renal fibrosis and the underlying mechanisms. RESULTS: Capsaicin treatment significantly alleviated fibronectin and collagen depositions in the tubulointerstitium of the injured kidneys from UUO and adenine-fed mice. Meanwhile, capsaicin treatment obviously reduced α-SMA expression. Moreover, capsaicin treatment dramatically protected against the phenotypic alteration of tubular epithelial cells by increasing E-cadherin expression and decreasing vimentin expression during renal fibrosis. Mechanistically, capsaicin treatment effectively suppressed α-SMA and vimentin expressions but promoted E-cadherin expression in HK2 cells mainly through the inhibition of TGF-ß1-Smad2/3 signaling. CONCLUSION: Capsaicin significantly ameliorated renal fibrosis possibly by retarding the activation of myofibroblasts and protecting against the phenotypic alteration of tubular epithelial cells mainly through the inhibition of TGF-ß1-Smad2/3 signaling. Thus, our findings may provide a new insight into the clinical application of capsaicin in renal fibrosis.

Characterization of the Components and Pharmacological Effects of Mountain-Cultivated Ginseng and Garden Ginseng Based on the Integrative Pharmacology Strategy.

Panax ginseng C. A. Mey (PGCAM) is a herbaceous perennial belonging to the Araliaceae family, mainly including Mountain-Cultivated Ginseng (MCG) and Garden Ginseng (GG) on the market. We aimed to establish a rapid, accurate and effective method to distinguish 15-year-old MCG and GG using ultra-performance liquid chromatography-quadrupole time-of-flight-tandem mass spectrometry (UPLC-QTOF-MS/MS), and also explored the pharmacological mechanisms of the main components using the Integrative Pharmacology-based Network Computational Research Platform of Traditional Chinese Medicine (TCMIP V2.0; http://www.tcmip.cn/). Altogether, 23 potential quality markers were characterized to distinguish 15-year-old MCG and GG, including ginsenosides Ra2, Rg1, and Ra1, and malonyl-ginsenoside Ra3, etc. The contents of 19 constituents (mainly protopanaxadiol-type) were higher in MCG compared with that in GG, and four constituents (mainly carbohydrate compounds) were higher in GG. The 105 putative targets corresponding to 23 potential quality markers were mainly involved in 30 pathways, which could be divided into 10 models, such as immune regulation, systems (metabolic, nervous, cardiovascular, reproductive), blood-pressure regulation, as well as antitumor, antiaging, antibacterial and anti-inflammatory effects. Furthermore, the potential quality markers of MCG and GG could inhibit the proliferation of breast cancer by regulating the mRNA expression of PSA, S6K, MDM2, and P53 genes by acting on AR, MTOR, PI3K and other targets. The Integrative Pharmacology Strategy may provide an efficient way to identify chemical constituents and explore the pharmacological actions of TCM formulations.

hiPSC-Derived Cardiac Tissue for Disease Modeling and Drug Discovery.

Relevant, predictive normal, or disease model systems are of vital importance for drug development. The difference between nonhuman models and humans could contribute to clinical trial failures despite ideal nonhuman results. As a potential substitute for animal models, human induced pluripotent stem cell (hiPSC)-derived cardiomyocytes (CMs) provide a powerful tool for drug toxicity screening, modeling cardiovascular diseases, and drug discovery. Here, we review recent hiPSC-CM disease models and discuss the features of hiPSC-CMs, including subtype and maturation and the tissue engineering technologies for drug assessment. Updates from the international multisite collaborators/administrations for development of novel drug discovery paradigms are also summarized.

Current Advances and Limitations of Deep Learning in Anticancer Drug Sensitivity Prediction.

Anticancer drug screening can accelerate drug discovery to save the lives of cancer patients, but cancer heterogeneity makes this screening challenging. The prediction of anticancer drug sensitivity is useful for anticancer drug development and the identification of biomarkers of drug sensitivity. Deep learning, as a branch of machine learning, is an important aspect of in silico research. Its outstanding computational performance means that it has been used for many biomedical purposes, such as medical image interpretation, biological sequence analysis, and drug discovery. Several studies have predicted anticancer drug sensitivity based on deep learning algorithms. The field of deep learning has made progress regarding model performance and multi-omics data integration. However, deep learning is limited by the number of studies performed and data sources available, so it is not perfect as a pre-clinical approach for use in the anticancer drug screening process. Improving the performance of deep learning models is a pressing issue for researchers. In this review, we introduce the research of anticancer drug sensitivity prediction and the use of deep learning in this research area. To provide a reference for future research, we also review some common data sources and machine learning methods. Lastly, we discuss the advantages and disadvantages of deep learning, as well as the limitations and future perspectives regarding this approach.

[Effects of long-term rainfall addition on the morphological characteristics and point pattern of desert plants]. / é•¿æœŸæ¨¡æ‹Ÿå¢žé›¨å¯¹è’æ¼ æ¤ç‰©å½¢æ€ç‰¹å¾åŠç©ºé—´åˆ†å¸ƒæ ¼å±€çš„å½±å“.

Studying the effects of rainfall change on morphological characteristics, spatial pattern and spatial correlation of desert dominant plants could help to predict the response of desert ecosystem to global climate change. We conducted a 10-year simulated rainfall addition experiment and examined the morphological characteristics, spatial pattern and spatial correlation of typical desert plant species, Nitraria tangutorum and Artemisia ordosica, under long-term simulated rainfall enhancement conditions in Ulanbuh desert, using Programita software, Ripley's K function, and Monte Carlo method. The results showed that there were significant differences in the number, height, average crown and base diameter of the desert plants under different treatments. The number, height, average crown and base diameter of N. tangutorum and A. ordosica were significantly larger than CK, all of which increased with the amount of rainfall. When the amount of rainfall addition was less than 72 mm, the branch of N. tangutorum showed cluster distribution. When it was larger than 72 mm, it showed a tendency to decrease the aggregation intensity with rainfall increasing. The spatial distribution of A. ordosica population was characterized by random distribution-cluster distribution-random distribution pattern with rainfall increasing. In terms of spatial association, branch of N. tangutorum and A. ordosica showed negative correlation under control, but no correlation or positive correlation with rainfall increasing. When the amount of rainfall increased to 144 mm, the spatial association between two species changed from negative to positive. Under the scenario of increasing rainfall, soil moisture was improved, which would lead to a positive correlation between species and be more conducive to the coexistence and growth of N. tangutorum and A. ordosica.

Discovery of 4-Methylquinazoline Based PI3K Inhibitors for the Potential Treatment of Idiopathic Pulmonary Fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal lung disease, and its molecular pathogenesis remains poorly understood. Recently, emerging evidence demonstrates that the PI3K signaling transduction pathway is linked to the pathology of IPF. In this work, we rationally designed a new series of 4-methylquinazoline derivatives as highly potent PI3K inhibitors that significantly suppress the phosphorylation of the main PI3K downstream effectors and displays marked antiproliferative activity in mouse MLg2908 lung fibroblasts. In a bleomycin-induced mouse pulmonary fibrosis model, 5d from the series improved mouse lung function and slowed the progression of pulmonary fibrosis. Overall, this work promises a therapeutic potential for PI3K inhibitors to treat IPF.

Recycling of cooking oil fume condensate for the production of rhamnolipids by Pseudomonas aeruginosa WB505.

Rhamnolipids (RLs) are anionic biosurfactants with great application potential. This study explored the possibility of producing RLs from cooking oil fume condensates (COFCs) collected from range hoods. A mutant of Pseudomonas aeruginosa AB93066 was obtained and used to produce RLs from COFCs as a substrate. RL yields in a 7-L fermenter reached 12.3 g/L, and MALDI-TOF MS showed that Rha2-C10-C10 and Rha-C10-C10 are the most abundant (39.6% and 26.4%, respectively) RL components. The critical micellar concentration (CMC) of the RLs was 45.0 mg/L and the surface tension of water decreased from 60.5 to 25.3 mN/m. Using six kinds of common hydrocarbons as indices, the emulsification coefficients of the RLs obtained were found to exceed 60%; in particular, the emulsification coefficient for benzene was 80.3%. COFCs provide an inexpensive alternative as a substrate for RL production, and the synthetic process is relatively harmless and economical.

[Varieties textual research on "Bangjian": traditional Tibetan medicine including blue, black and variegated flowers].

"Bangjian" were traditional Tibetan medicine-flowers from Gentianaceae, which were widely used and had a long medicinal history for the function of detoxifying, curing heat symptoms and treating the laryngitis. The Tibetan compound preparation endowed SFDA approval number always used Bangjian aas the main raw materials for relieving cough, asthma and treating respiratory diseases such as acute and chronic bronchitis. Its commodity medicinal materials were also sold in Qinghai, Sichuan, Tibet and other local medicinal materials market and local specialty marke. However, when recorded by literatures of Tibetan medicine, Bangjian were often classified into white, blue and black or white, blue and variegated according to color of flowers, leading to disordered varieties. In this paper, different Bangjian including their original plants and the main application varieties were studied and authenticated by textual research, wild specimen collection, investigation and collection of samples from Tibetan hospitals，Tibetan pharmaceutical factories and medical material markets. Results showed that Bangjian-including blue, black and variegated flowers were originated from 14 species and 3 varietas according to literatures, and the main application varieties mainly come from Ser. Ornatae of Sect. Monopodiae, such as Gentiana veitchiorum for the most, G. sino-ornata as well as G. lawrencei var. farreri. Suggestion about establishing the quality standard of Bangjian was gived, which provided reference in reasonable use and scientific research for Bangjian, and also had practical value for its clinical use and development.

Sinomenine Attenuates Angiotensin II-Induced Autophagy via Inhibition of P47-Phox Translocation to the Membrane and Influences Reactive Oxygen Species Generation in Podocytes.

BACKGROUND/AIMS: Sinomenine, a pure alkaloid extracted from the Chinese medicinal plant Sinomenium acutum, and sinomenine hydrochloride (SN) has been successfully used for the therapy of rheumatoid arthritis (RA) and kidney diseases. Autophagy is a cytoprotective mechanism used by podocytes and other cells to alleviate the effects of oxidative stress, and angiotensin II (Ang II) significantly promotes podocyte autophagy. However, excessive autophagy may lead to cell death and podocyte depletion. The present study evaluated the effect of SN in podocytes induced by Ang II. METHODS: Podocytes were pretreated with graded concentrations (10(-8) M ∼ 10(-4) M) of SN and then stimulated with Ang II. The LC3B protein and the p47-phox membrane fraction were measured by Western blot. Autolysosomes were assessed by transmission electron microscopy. FACS was used to quantify the ROS produced by podocytes. The translocation of p47-phox to the membrane was investigated by immunofluorescence. RESULTS: The 10(-8) M ∼ 10(-4) M of SN alone did not effect ROS generation or podocyte autophagy. The 10(-8) M and 10(-6) M SN attenuated Ang II-induced autophagy in podocytes. Furthermore, SN decreased the level of ROS generation in Ang II-induced podocytes via inhibition of NOX subunit p47-phox translocation to the membrane. CONCLUSION: The appropriate concentration of SN attenuated Ang II-induced podocyte autophagy through ROS generation, at least in part, by regulating NOX subunit p47-phox translocation to the membrane.

Characterization of Mycobacterium Abscessus Subtypes in Shanghai of China: Drug Sensitivity and Bacterial Epidemicity as well as Clinical Manifestations.

The aim of the study was to investigate the epidemic characteristics of Mycobacterium abscessus in Shanghai.Fifty-five strains from 55 M. abscessus pulmonary disease patients were isolated. Drug sensitivity was measured by a broth microdilution method. Subtypes of M. abscessus were identified by DNA sequencing. Multilocus sequence typing (MLST), mining spanning tree (MST), and pulsed-field gel electrophoresis (PFGE) were used to analyze sequence types (ST) and clonal complexes (CC). Clinical manifestations were assessed by CT imaging.We identified 42 A isolates, 11 M, and 2 B-subtypes. A and M were highly sensitive to tigecycline and amikacin (97.6-100%). The A-type easily developed drug resistance against clarithromycin. Both types were highly resistance to sulfonamides, moxifloxacin, doxycycline, imipenem, and tobramycin. MLST analysis identified 41 STs including 32 new STs. The MST algorithm distributed 55 isolates into 12 separate CC. The PFGE analysis exhibited 53 distinct restriction patterns and the M-type was closely clustered according to their ST and CC numbers. CT imaging showed that tree-in-bud and patch shadow were commonly observed in M-type, whereas pulmonary cavities were often found in A-type infection patients (P < 0.001).ST1 in A and ST23 in M-type were the main epidemic strains in Shanghai. The M-type appeared to be prone to epidemic nosocomial transmission.

IgA nephropathy with anti-neutrophil cytoplasmic antibody seropositivity.

BACKGROUND: There are few reports of IgA nephropathy (IgAN) with antineutrophil cytoplasmic antibody (ANCA)-associated glomerulonephritis. METHODS: The authors report the clinical and pathological findings in 14 patients with IgAN and ANCA seropositivity. RESULTS: These retrospective cases consisted of 4 men and 10 women with a mean age of 44.4 ± 12.7 years. ANCA-positivity was documented by EUROBlot kits and indirect immunofluorescence in all patients. The results of EUROBlot kits were positive in 14 patients (12 MPO-ANCA, 2 PR3-ANCA). Indirect immunofluorescence was positive in 14 patients (12 P-ANCA, 2 C-ANCA). Three of 14 IgAN with ANCA-positive patients showed severe clinical manifestations with crescents involving a mean of 56% glomeruli, including heavy proteinuria (mean 24-hour urine protein: 3.8 g/d), hematuria and acute renal failure (mean creatinine: 4.5 ± 3.7 mg/dL). The remaining 11 patients with no crescents showed various degrees of proteinuria (mean 24-hour urine protein: 2.4 ± 2.4 g/d), hematuria and serum creatinine levels (median creatinine: 0.9 (IQR, 0.5 - 1.4) mg/dL). The follow-up period for 10 patients had an average length of 14.0 ± 11.2 months. Among the three patients with crescents who had been treated with steroids and cyclophosphamide, one patient became dialysis dependent at the time of biopsy and remained on dialysis after treatment, another died of acute heart failure, and the last one showed improvement in renal function after treatment and did not develop end-stage renal disease (ESRD) 26 months after renal biopsy. The remaining 7 patients with no crescents were treated with steroids, cyclophosphamide, renin-angiotensin system inhibitors, and/or Traditional Chinese Medicine; 6 had stabilized or improved renal function and one progressed to ESRD with worsening renal function. CONCLUSIONS: These findings suggest not all ANCAs are involved in the pathology of IgAN. In patients with IgAN and ANCAs, identification of pathogenic vs. non-pathogenic ANCAs is recommended.

[Correlation Analysis Between Physicochemical Properties of Rhizosphere Soil and Appearance Characters of Codonopsis pilosula Root in Jiuzhaigou County].

OBJECTIVE: To study the physicochemical properties of rhizosphere soil and their influence on appearance characters of semi-natural cultivated Codonopsis pilosula root. METHODS: The comprehensive methods by combining outdoor investigating with indoor analyzing were applied. Rhizosphere soil samples and plant materials were collected from 35 collection points, the physicochemical properties of soil and the appearance characters of plant materials were investigated. RESULTS: The physical property of rhizosphere soil under semi-natural cultivated condition was good, the soil texture was coarse powder of loam, slightly alkaline. The cultivated layer contained abundant nutrient components, the average organic matter content of 35 soil samples was 60.66 g/kg,and 2.99 g/kg for total nitrogen, 115.46 mg/g for available nitrogen, 0.8 g/kg for total phosphorus, 6.43 mg/kg for available phosphorus, 23.69 g/kg for total potassium and 124.48 mg/kg for available potassium, respectively. The result of correlation analysis indicated that the physicochemical properties of rhizosphere soil had significant influence on the appearance characters of Codonopsis pilosula root. CONCLUSION: The semi-natural cultivated model can maintain the structure of soil and hold nutrient components, it is conducive to the growth of Codonopsis pilosula and the standardized production base establishment. To increase the yield of Codonopsis pilosula root, it is recommended to increase the application of nitrogen and phosphorus fertilizer.

Sulbactam-based therapy for Acinetobacter baumannii infection: a systematic review and meta-analysis

BACKGROUND: A number of studies have reported on the effectiveness of sulbactam-based therapies for Acinetobacter baumannii infection; however, there is little evidence that sulbactam-based therapies are more or less effective than alternative therapies. Unfortunately, there is a distinct lack of high quality data (i.e., from randomized controlled trials) available on this issue. Therefore, we conducted a systematic review and meta-analysis comparing the efficacy of sulbactam-based and non-sulbactam-based regimens in the treatment of A. baumannii infection. METHODS: We searched PubMed, MEDLINE, Biomedical Central, Google Scholar, the China National Knowledge Infrastructure, the Cochrane library, and the Directory of Open Access using the terms "sulbactam and baumannii" or "maxtam and baumannii". Randomized controlled trials, controlled clinical studies, and cohort studies were considered for inclusion. The primary outcome was the clinical response rate for sulbactam-based therapy vs comparator therapies. RESULTS: Four studies (1 prospective, 3 retrospective) were included in the metaanalysis. Sulbactam was given in combination with ampicillin, carbapenem, or cefoperazone (n = 112 participants). Comparator drugs included colistin, cephalosporins, anti-pseudomonas penicillins, fluoroquinolones, minocycline/doxycycline, aminoglycosides, tigecycline, polymyxin, imipenem/cilastatin, and combination therapy (n = 107 participants). The combined clinical response rate odds ratio did not significantly favor sulbactam-based therapy over comparator therapy (odds ratio = 1.054, 95% confidence interval = 0.550-2.019, p = 0.874), nor did any of the individual study odds ratios. CONCLUSIONS: The available evidence suggests that sulbactam-based therapy may be similarly efficacious to alternative antimicrobial therapies for the treatment of A. baumannii infection. Further research on this issue is warranted given the limited availability of data from high quality/randomized controlled trials.

Sulbactam-based therapy for Acinetobacter baumannii infection: a systematic review and meta-analysis.

BACKGROUND: A number of studies have reported on the effectiveness of sulbactam-based therapies for Acinetobacter baumannii infection; however, there is little evidence that sulbactam-based therapies are more or less effective than alternative therapies. Unfortunately, there is a distinct lack of high quality data (i.e., from randomized controlled trials) available on this issue. Therefore, we conducted a systematic review and meta-analysis comparing the efficacy of sulbactam-based and non-sulbactam-based regimens in the treatment of A. baumannii infection. METHODS: We searched PubMed, MEDLINE, Biomedical Central, Google Scholar, the China National Knowledge Infrastructure, the Cochrane library, and the Directory of Open Access using the terms "sulbactam and baumannii" or "maxtam and baumannii". Randomized controlled trials, controlled clinical studies, and cohort studies were considered for inclusion. The primary outcome was the clinical response rate for sulbactam-based therapy vs comparator therapies. RESULTS: Four studies (1 prospective, 3 retrospective) were included in the meta-analysis. Sulbactam was given in combination with ampicillin, carbapenem, or cefoperazone (n=112 participants). Comparator drugs included colistin, cephalosporins, anti-pseudomonas penicillins, fluoroquinolones, minocycline/doxycycline, aminoglycosides, tigecycline, polymyxin, imipenem/cilastatin, and combination therapy (n=107 participants). The combined clinical response rate odds ratio did not significantly favor sulbactam-based therapy over comparator therapy (odds ratio=1.054, 95% confidence interval=0.550-2.019, p=0.874), nor did any of the individual study odds ratios. CONCLUSIONS: The available evidence suggests that sulbactam-based therapy may be similarly efficacious to alternative antimicrobial therapies for the treatment of A. baumannii infection. Further research on this issue is warranted given the limited availability of data from high quality/randomized controlled trials.