Fangchinoline inhibits growth and biofilm of Candida albicans by inducing ROS overproduction.

Infections caused by Candida species, especially Candida albicans, threaten the public health and create economic burden. Shortage of antifungals and emergence of drug resistance call for new antifungal therapies while natural products were attractive sources for developing new drugs. In our study, fangchinoline, a bis-benzylisoquinoline alkaloid from Chinese herb Stephania tetrandra S. Moore, exerted antifungal effects on planktonic growth of several Candida species including C. albicans, with MIC no more than 50 µg/mL. In addition, results from microscopic, MTT and XTT reduction assays showed that fangchinoline had inhibitory activities against the multiple virulence factors of C. albicans, such as adhesion, hyphal growth and biofilm formation. Furthermore, this compound could also suppress the metabolic activity of preformed C. albicans biofilms. PI staining, followed by confocal laser scanning microscope (CLSM) analysis showed that fangchinoline can elevate permeability of cell membrane. DCFH-DA staining suggested its anti-Candida mechanism also involved overproduction of intracellular ROS, which was further confirmed by N-acetyl-cysteine rescue tests. Moreover, fangchinoline showed synergy with three antifungal drugs (amphotericin B, fluconazole and caspofungin), further indicating its potential use in treating C. albicans infections. Therefore, these results indicated that fangchinoline could be a potential candidate for developing anti-Candida therapies.

Antifungal and anti-biofilm activities of patchouli alcohol against Candida albicans.

The opportunistic fungal pathogen Candida albicans could cause severe clinical outcomes which could be exacerbated by the scarcity of antifungals. The capacity of C. albicans to form biofilms on medical devices that are hard to eradicate, further deepen the need to develop antifungal agents. In this study, we, for the first time, showed that patchouli alcohol (PA) can inhibit the growth of multiple C. albicans strains, as well as four other Candida species, with MICs of 64 µg/mL and MFCs from 64 to 128 µg/mL. The biofilm formation and development, adhesion, yeast-to-hyphal transition and extracellular polysaccharide of C. albicans can be inhibited by PA in a concentration-dependent manner. Confocal microscopy analyses of cells treated with PA showed that PA can increase the membrane permeability and intracellular reactive oxygen species (ROS) production. In C. elegans, PA did not influence the survival below 64 µg/mL. In this study PA demonstrated antifungal and antibiofilm activity against C. albicans and our results showed the potential of developing PA to fight Candida infections.

Using Pharmacokinetic-Pharmacodynamic Modeling to Study the Main Active Substances of the Anticancer Effect in Mice from Panax ginseng-Ophiopogon japonicus.

Ginseng Radix et Rhizoma Rubra (Panax ginseng C.A. Mey, Hongshen, in Chinese) and Ophiopogonis Radix (Ophiopogon japonicus (L.f) Ker-Gawl., Maidong, in Chinese) are traditional Chinese herbal pairs, which were clinically employed to enhance the immune system of cancer patients. This study employed the pharmacokinetic and pharmacodynamic (PK-PD) spectrum-effect association model to investigate the antitumor active substances of P. ginseng and O. japonicus (PG-OJ). The metabolic processes of 20 major bioactive components were analyzed using Ultra-Performance Liquid Chromatography-Mass Spectrometry/Mass Spectrometry (UPLC-MS/MS) in the lung tissue of tumor-bearing mice treated with PG-OJ. The ELISA method was employed to detect the levels of TGF-ß1, TNF-α, and IFN-γ in the lung tissue of mice at various time points, and to analyze their changes after drug administration. The results showed that all components presented a multiple peaks absorption pattern within 0.083 to 24 h post-drug administration. The tumor inhibition rate of tumor and repair rate of IFN-γ, TNF-α, and TGF-ß1 all increased, indicating a positive therapeutic effect of PG-OJ on A549 tumor-bearing mice. Finally, a PK-PD model based on the GBDT algorithm was developed for the first time to speculate that Methylophiopogonanone A, Methylophiopogonanone B, Ginsenoside Rb1, and Notoginsenoside R1 are the main active components in PG-OJ for lung cancer treatment.

Alkyl-Substituted N,S-Embedded Heterocycloarenes with a Planar Aromatic Configuration for Hosting Fullerenes and Organic Field-Effect Transistors.

Cycloarenes and heterocycloarenes display unique physical structures and hold great potential as organic semiconductors. However, the synthesis of (hetero)cycloarenes remains a big challenge, and there are limited reports on their applications. Herein, a series of nitrogen- and sulfur-codoped cycloarenes NS-Octulene-n (n = 2, 3, 4) with branched alkyl substituents containing linear spacer groups from C2 to C4 have been conveniently synthesized. Compared with their isoelectronic analogues Octulene and S-Octulene, both having a saddle-shaped configuration, the coincorporation of two nitrogen atoms and two sulfur atoms leads to a fully coplanar aromatic backbone structure. Each of these three planar heterocycloarenes acts as a supramolecular host for encapsulation of both fullerenes C60 and C70 with a stronger donor-acceptor interaction for the complexation between the heterocycloarene and C70 due to the unique molecular geometry and defined cavity. Meanwhile, the electron-rich nitrogen atoms also slightly increase the energies of both highest occupied molecular orbital (HOMO) and lowest unoccupied molecular orbital (LUMO) in this series of planar heterocycloarenes, indicating that they can be used as p-type semiconductors. Most importantly, benefitting from the planar π-conjugated backbone structure accompanied by excellent crystallinity and ordered molecular packing, as well as upon the engineering of the alkyl chain branching position, thin-film field-effect transistors of NS-Octulene-3 with moderate alkyl branching point exhibit the maximum hole mobility of 0.86 cm2 V-1 s-1, which is the highest for (hetero)cycloarene-based organic semiconductors. This study will shed new light on designing novel high-performance macrocyclic polycyclic aromatic hydrocarbon (PAH) semiconductors.

Single Atom Catalysts with Out-of-Plane Coordination Structure on Conjugated Covalent Organic Frameworks.

Adjusting the local coordination environment of single-atom electrocatalysts is a viable way to improve catalytic performance. The diversity of coordination geometric structures is limited to the traditional in-plane configuration, with only a little consideration paid to out-of-plane configurations due to the lack of suitable carriers and fabrication methods. This study reports out-of-plane coordination of Co-based single-atom catalysts mediated by the conjugated bipyridine-rich covalent organic framework (COF). The bipyridine nitrogen on the COF layer backbone of these catalysts serves as the linker center for cobalt sites anchoring, while the complementary moieties are coordinated at the other side of the Co metal and reside beyond the COF backbone plane, thus yielding out-of-plane coordination. The electrochemical experiments and density functional theory calculations reveal that catalysts with multiple out-of-plane coordinations exhibit different electrocatalytic oxygen evolution activities and catalytic pathways. The out-of-plane coordination enabled by COFs provides a strategy for designing single-atom electrocatalysts, expanding the application of COFs in the field of electrocatalysis.

The combination of ginger and zinc supplement could improve lead-induced reproductive dysfunction by inhibiting apoptosis mediated by oxidative damage and inflammation.

Due to the growing industry and industrialization of many urban communities, one of the dangers that threaten human life is long-term exposure to heavy metals such as lead. Lead contamination can have a detrimental effect on fertility. On the other hand, the combination of ginger and zinc supplements can be a powerful sexual enhancer. Despite extensive studies on the effect of ginger and zinc on reproduction, the effects of the combination of ginger and zinc supplement on lead-induced reproductive dysfunction are not fully understood. Sixty-four adult male rats were allocated into control, lead acetate (10 mg/kg), ginger (250 mg/kg), ginger-lead group, zinc (120 mg/kg) group, zinc-lead group, ginger-zinc group and ginger-zinc-lead group. The drugs were administrated by gavage for 4 weeks. The concentration of LH, FSH, testosterone, TNF-α, IL-1ß, antioxidant enzyme activity, MDA, spermatogenesis, and sperm parameters were measured. The expression of NF-kB, Nrf2, Bcl2, BAX, and Cas-3 was evaluated. The histopathological assessment was also detected. Lead significantly could induce inflammation, apoptosis, and oxidative damage in testis tissue, and decrease hormonal levels, spermatogenesis, and sperm parameters compared to the control group (p < 0.05). While in reverse manner ginger, zinc, and their combination significantly improved all of them compared to the lead group (p < 0.05). These results were also supported by histological findings. It can be concluded that ginger, zinc, and their combination could prevent lead-induced reproductive dysfunction by inhibiting apoptosis mediated by oxidative damage and inflammation and improve reproductive performance.

Crystal Engineering of Angular-Shaped Heteroarenes Based on Cyclopenta[b]thiopyran for Controlling the Charge Carrier Mobility.

Cyclopenta[b]thiopyran, isomeric to benzo[b]thiophene while isoelectronic to azulene, is involved as a building block to construct soluble organic semiconductors for field-effect transistors. Two series of angular-shaped heteroarenes based on cyclopenta[b]thiopyran, that is, Cn-SS (n = 4, 6, 8, 10) with different linear alkyl groups and C8-SS-Clm (m = 2, 3, 4) with chlorides substituted at different positions, have been straightforward synthesized. The obtained seven S-heteroarenes exhibit intriguing and similar photophysical and electrochemical properties, such as near-infrared absorption and high-energy levels of the highest occupied molecular orbitals. Nevertheless, the S-heteroarenes with identical π-conjugated skeletons demonstrate completely different molecular packing structures, which is proofed to be the key determinate factor for the charge carrier mobilities. Upon the engineering of the pendant alkyl lengths, the highest hole mobility in the Cn-SS series is achieved for C8-SS (1.1 cm2 V-1 s-1) with moderate alkyl length. The further incorporation of chlorides on C8-SS results in the shortened intermolecular H···S contacts and the interplane distances. Most interestingly, when chlorine-containing chloroform and chlorobenzene are used as crystallization solvents, single crystals of C8-SS-Clm with different packing structures are produced owing to the intermolecular interactions among the solute and solvent molecules. Upon further engineering of the chlorination position and the crystallization solvent, the maximum hole mobility in the ambient air improves to 2.7 cm2 V-1 s-1 for C8-SS-Cl2 crystallized from chlorobenzene, suggesting that the introduction of the accessible chlorides is a feasible pathway to engineering the crystal structures and controlling the charge transport characteristics.

A Review of Recent Research on the Role of MicroRNAs in Renal Cancer.

Renal cell carcinoma (RCC) is a most common type of urologic neoplasms; it accounts for 3% of malignant tumors, with high rates of relapse and mortality. The most common types of renal cancer are clear cell carcinoma (ccRCC), papillary renal cell carcinoma (pRCC), and chromophobe renal carcinoma (chRCC), which account for 90%, 6-15%, and 2-5%, respectively, of all renal malignancies. Although surgical resection, chemotherapy, and radiotherapy are the most common treatment method for those diseases, their effects remain dissatisfactory. Furthermore, recent research shows that the treatment efficacy of checkpoint inhibitors in advanced RCC patients is widely variable. Hence, patients urgently need a new molecular biomarker for early diagnosis and evaluating the prognosis of RCC. MicroRNAs (miRNAs) belong to a family of short, non-coding RNAs that are highly conserved, have long half-life evolution, and post-transcriptionally regulate gene expression; they have been predicted to play crucial roles in tumor metastasis, invasion, angiogenesis, proliferation, apoptosis, epithelial-mesenchymal transition, differentiation, metabolism, cancer occurrence, and treatment resistance. Although some previous papers demonstrated that miRNAs play vital roles in renal cancer, such as pathogenesis, diagnosis, and prognosis, the roles of miRNAs in kidney cancer are still unclear. Therefore, we reviewed studies indexed in PubMed from 2017 to 2020, and found several studies suggesting that there are more than 82 miRNAs involved in renal cancers. The present review describes the current status of miRNAs in RCC and their roles in progression, diagnosis, therapy targeting, and prognosis of RCC.

[Phenylpropanoids from Zanthoxylum species and their pharmacological activities: a review].

Phenylpropanoids are one of the major chemical constituents in Zanthoxylum species. They include simple phenylpropanoids, coumarins, and lignans and possess anti-tumor, anti-inflammatory, anti-platelet aggregation, anti-bacterial, anti-viral, insecticidal, and antifeedant activities. This review summarizes the chemical constituents and pharmacological activities from the Zanthoxylum plants in hopes of providing reference for the research and application of phenylpropanoids from this genus.

Bone marrow mesenchymal stem cells enhance autophagy and help protect cells under hypoxic and retinal detachment conditions.

Our study aimed to evaluate the protective role and mechanisms of bone marrow mesenchymal stem cells (BMSCs) in hypoxic photoreceptors and experimental retinal detachment. The cellular morphology, viability, apoptosis and autophagy of hypoxic 661w cells and cells cocultured with BMSCs were analysed. In retinal detachment model, BMSCs were intraocularly transplanted, and then, the retinal morphology, outer nuclear layer (ONL) thickness and rhodopsin expression were studied as well as apoptosis and autophagy of the retinal cells. The hypoxia-induced apoptosis of 661w cells obviously increased together with autophagy levels increasing and peaking at 8 hours after hypoxia. Upon coculturing with BMSCs, hypoxic 661w cells had a better morphology and fewer apoptosis. After autophagy was inhibited, the apoptotic 661w cells under the hypoxia increased, and the cell viability was reduced, even in the presence of transplanted BMSCs. In retina-detached eyes transplanted with BMSCs, the retinal ONL thickness was closer to that of the normal retina. After transplantation, apoptosis decreased significantly and retinal autophagy was activated in the BMSC-treated retinas. Increased autophagy in the early stage could facilitate the survival of 661w cells under hypoxic stress. Coculturing with BMSCs protects 661w cells from hypoxic damage, possibly due to autophagy activation. In retinal detachment models, BMSC transplantation can significantly reduce photoreceptor cell death and preserve retinal structure. The capacity of BMSCs to reduce retinal cell apoptosis and to initiate autophagy shortly after transplantation may facilitate the survival of retinal cells in the low-oxygen and nutrition-restricted milieu after retinal detachment.

microRNA-199a-5p regulates epithelial-to-mesenchymal transition in diabetic cataract by targeting SP1 gene.

BACKGROUND: As a common ocular complication of diabetes mellitus, diabetic cataract is becoming a leading cause of visual impairment. The progression of diabetic cataract progression involves epithelial-to-mesenchymal transition (EMT), the precise role of which remains to be investigated. As microRNAs (miRNAs) are suggested to be involved in the pathogenesis of many diseases, identification of aberrantly expressed miRNAs in diabetic lens epithelial cells (LECs) and their targets may provide insights into our understanding of diabetic cataract and potential therapeutic targets. METHODS: Diabetic cataract capsules and LECs exposed to high glucose (25 mmol/L, 1-5 days) were used to mimic the model. Quantitative RT-PCR was performed to evaluate the differential expression of miRNA. Dual luciferase reporter assay was used to identify the binding target of miR-199a-5p. The expression of EMT-associated proteins was determined by immunofluorescence and Western blot analysis. RESULTS: Our results showed the differential expression of miR-9, -16, -22, -199a and -204. MiR-199a was downregulated in diabetic cataract capsule and hyperglycemia-conditioned human LECs. Specific protein 1 could be directly targeted and regulated by miR-199a in LECs and inhibit EMT in diabetic LECs. CONCLUSION: Our findings implied miR-199a could be a therapeutic target by regulating SP1 directly to affect EMT in diabetic cataract and provided novel insights into the pathogenesis of diabetic cataract.

Fungal keratitis: Pathogenesis, diagnosis and prevention.

As a kind of serious, potentially sight-threatening corneal infections with poor prognosis, fungal keratitis can bring a heavy economic burden to patients and seriously affect the quality of life, especially those in developing countries where fungal keratitis is more prevalent. Typical clinical features include immune rings, satellite lesions, pseudopods, hypha moss, hypopyon and endothelial plaques. The ideal therapeutic effects could not be achieved by current treatments for many reasons. Therefore, under the current status, understanding the pathogenesis, early diagnosis and prevention strategies might be of great importance. Here, in this review, we discuss the recent progresses that may advance our understanding of pathogenesis, early diagnosis and prevention of fungal keratitis.

Prevalence and risk factors for postoperative delirium in patients with colorectal carcinoma: a systematic review and meta-analysis.

OBJECTIVE: Postoperative delirium (POD) is a common, but severe complication in elderly patients undergoing surgery for colorectal cancer, but the prevalence and potential risk factors for POD were not well established. Therefore, a meta-analysis was preformed to clarify the prevalence and risk factors of POD in patients undergoing surgery for colorectal cancer. METHODS: PubMed, Embase, and the Cochrane Library were systematically searched on August 2019. Studies were included if they reported the prevalence and risk factors of POD in patients undergoing colorectal cancer surgery. The guidelines for critically appraising studies of prevalence or incidence of a health problem were used to assess the quality of included studies. Pooled odds ratios (ORs) for individual risk factors were estimated using the Mantel-Haenszel methods in random effect model. Sensitive analyses based on different inclusion criteria were conducted to explore whether the current meta-analysis was enough credible and robust. RESULTS: Seventeen studies totaling 4472 patients undergoing colorectal cancer surgery were included. The pooled prevalence of POD is 14% (95% CI = 12-17%). Twelve significant risk factors were identified in pooled analysis including older age (OR = 1.10), sex (OR = 1.87), history of psychiatric disease (OR = 6.47), comorbidities (OR = 2.17), prognostic nutritional index (OR = 1.12), physical status (OR = 1.27), American Society of Anesthesiologists Score (ASA Scores) (OR = 1.65), history of alcohol abuse (OR = 2.23), postoperative pain management (OR = 1.91), perioperative blood transfusion (OR = 2.37), cognitive status (OR = 1.91), and lower serum level of albumin (OR = 0.58). CONCLUSIONS: POD is a frequent complication in patients undergoing surgery with colorectal cancer. Several risk factors including history of psychiatric disease, transfusion, comorbidities, male gender, and old age were significant predictors for POD.

Transparent Conductive Supramolecular Hydrogels with Stimuli-Responsive Properties for On-Demand Dissolvable Diabetic Foot Wound Dressings.

Diabetic foot ulcers (DFU) remain a very considerable health care burden, and their treatment is difficult. Hydrogel-based wound dressings are appealing to provide an optimal environment for wound repair. However, the currently available hydrogel dressings still need surgical or mechanical debridement from the wound, causing reinjury of the newly formed tissues, wound infection, delayed healing time, and personal suffering. Additionally, to meet people's increasing demand, hydrogel wound dressings with improved performance and multifunctionality are urgently required. Here, a new multifunctional supramolecular hydrogel for on-demand dissolvable diabetic foot wound dressings is designed and constructed. Based on multihydrogen bonds between hydrophilic polymers, the resultant supramolecular hydrogels present controlled and excellent properties, such as good transparency, antibacterial ability, conductive, and self-healing properties. Thus, the supramolecular hydrogels improve the new tissue formation and provide a significant therapeutic effect on DFU by inducing angiogenesis, enhancing collagen deposition, preventing bacterial infection, and controlling wound infection. Remarkably, the resultant hydrogels also exhibit stimuli-responsive ability, which renders its capability to be dissolved on-demand, allowing for a facile DFU dressing removal. This multifunctional supramolecular hydrogel may provide a novel concept in the design of on-demand dissolvable wound dressings.

MiR-429 and MiR-143-3p Function as Diagnostic and Prognostic Markers for Osteosarcoma.

BACKGROUND: Osteosarcoma (OS) is a highly malignant mesenchymal tumor with a low survival rate and a high metastatic rate. Recently, microRNAs were reported to be potential diagnostic and prognostic markers in various cancers, including osteosarcoma. The present study aimed to determine the clinical values of miR-429 and miR-143-3p in OS concerning diagnosis and prognosis. METHODS: miR-429 and miR-143-3p expression in serum samples from OS patients and matched healthy controls were measured by a real-time quantitative polymerase chain reaction. The association with miR-429 or miR-143-3p and clinicopathological features were compared by Student's t-test. The diagnostic and prognostic values of miR-429 and miR-143-3p in OS were verified by ROC analysis and Kaplan-Meier survival assays. RESULTS: MiR-429 expression (0.3234 ± 0.0224) and miR-143-3p expression (0.7463 ± 0.0282) were significantly down-regulated in the serum from OS patients. Moreover, low miR-429 expression was remarkably associated with tumor size (p < 0.001), clinical-stage (p < 0.001), and distant metastasis (p < 0.001); low miR-143-3p expression was remarkably associated with tumor size (p = 0.0020), clinical-stage (p < 0.001), and distant metastasis (p < 0.001). Importantly, the area under the curves (AUC) of miR-429 and miR-143-3p were 0.9222 (95% CI: 0.8714 - 0.9730) and 0.8300 (95% CI: 0.7484 - 0.9116), respectively. The cutoff values were 1.0692 and 0.9913 with the highest specificity and sensitivity. The OS patients with lower miR-429 or miR-143-3p expressions survived shorter than those with higher miR-429 or miR-143-3p expressions (p = 0.0409 and 0.0421). CONCLUSIONS: Serum miR-429 and miR-143-3p may function as diagnostic and prognostic markers for OS.

3D printing individualized heel cup for improving the self-reported pain of plantar fasciitis.

BACKGROUND: To explore the therapeutic effect and the biomechanical mechanism of 3D printing individualized heel cup in treating of plantar heel pain. METHODS: The clinical effect was evaluated by plantar pressure analysis and pain assessment in participants. Its biomechanical mechanism of protecting the plantar heel was explored using finite element simulation. RESULTS: The individualized heel cup could support and protect the osseous structure and soft tissue of plantar heel while walking and jogging, as well as significantly reduce the self-reported pain after being worn for 4 weeks. The nylon heel cup could alter the load concentration of the heel as well as decrease the load affected on plantar fascia and calcaneus bone. It also provided an obvious support for heel pad. CONCLUSION: To summarize, the 3D printed individualized heel cup can be used as an effective method for the treatment of plantar heel pain.

[Advances on chemical constituents of Tibetan Salvia genus].

Salvia is the largest genus of Labiatae family, and there are more than 1 000 species around the world. Our country is rich in the resources of Salvia plants. The plants of this genus contain multiple chemical components, including sesquiterpenoids, diterpenoids, triterpenoids and phenols, et al. In order to develop better Tibetan plants of Salvia genus, this article reviewed and summarized the constituents from Tibetan Salvia genus.

The Expression of CUGBP1 After Spinal Cord Injury in Rats.

CUG-binding protein 1, a member of the CELF (CUGBP and embryonic lethal abnormal vision-like factor) family of RNA-binding proteins, is shown to be multifunctional, regulating many posttranscriptional processes including alternative splicing, deadenylation, mRNA decay, and translation. Recently, CUGBP1 is found to represses p27 IRES activity and inhibits expression of endogenous p27 in cultured breast cancer cells. However, the roles of CUGBP1 in central nervous system injury remain unknown. In our study, we performed acute spinal cord injury (SCI) model in adult rats in order to research the expression changes of CUGBP1 in spinal cord. Western blot analysis showed a marked upregulation of CUGBP1 after SCI. Immunohistochemistry analysis revealed a wide distribution of CUGBP1 in the spinal cord. Double immunofluorescence staining indicated that CUGBP1 immunoreactivity was increased predominantly in neurons and astrocytes after SCI. Moreover, colocalization of CUGBP1/proliferating cell nuclear antigen (PCNA) was detected in GFAP positive cells. We also examined the expression profiles of p27, which was up-regulated after SCI. To further understand whether CUGBP1 plays a role in astrocyte proliferation, we applied LPS to induce astrocyte proliferation in vitro. Western blot analysis demonstrated that CUGBP1 expression was positively correlated with PCNA expression, and the p27 expression was negatively correlated with CUGBP1 expression following LPS stimulation. Our results suggest that CUGBP1 might be implicated in the pathophysiology of spinal cord after SCI.

Proteomics Analysis of Cellular Proteins Co-Immunoprecipitated with Nucleoprotein of Influenza A Virus (H7N9).

Avian influenza A viruses are serious veterinary pathogens that normally circulate among avian populations, causing substantial economic impacts. Some strains of avian influenza A viruses, such as H5N1, H9N2, and recently reported H7N9, have been occasionally found to adapt to humans from other species. In order to replicate efficiently in the new host, influenza viruses have to interact with a variety of host factors. In the present study, H7N9 nucleoprotein was transfected into human HEK293T cells, followed by immunoprecipitated and analyzed by proteomics approaches. A series of host proteins co-immunoprecipitated were identified with high confidence, some of which were found to be acetylated at their lysine residues. Bioinformatics analysis revealed that spliceosome might be the most relevant pathway involved in host response to nucleoprotein expression, increasing our emerging knowledge of host proteins that might be involved in influenza virus replication activities.