PPARG is a potential target of Tanshinone IIA in prostate cancer treatment: a combination study of molecular docking and dynamic simulation based on transcriptomic bioinformatics.

Tanshinone IIA is a lipophilic organic compound from the root of Danshen (Salvia miltiorrhiza) and is one of the most well-known Tanshinone molecules by pharmacologists. In recent years, in addition to effects of anti-cardiovascular and neurological diseases, Tanshinone IIA has also shown some degrees of anti-prostate cancer potential. Although they do have some studies focusing on the molecular mechanism of Tanshinone IIA's anti-prostate cancer effects, a further understanding on the transcriptomic and structural level is still lacking. In this study, transcriptomic sequencing technology and computer technology were employed to illustrate the effects of Tanshinone IIA on prostate cancer through bioinformatic analysis and molecular dynamics simulation, and PPARG was considered to be one of the targets for Tanshinone IIA according to docking scoring and dynamic calculation. Our study provides a novel direction to further understand the mechanism of the effects of Tanshinone IIA on prostate cancer, and further molecular biological studies need to be carried on to further investigate the molecular mechanism of Tanshinone IIA's anti-prostate cancer effect through PPARG.

Electrical stimulation therapy for pain and related symptoms in multiple sclerosis: A systematic review and meta-analysis.

BACKGROUND: The effectiveness of electrical stimulation therapy (EST) for pain, depression, fatigue, disability, and quality of life in multiple sclerosis (MS) remains uncertain. This study aims to analyze and discuss the efficacy of various EST treatments in alleviating pain among MS patients. METHODS: The primary search was conducted using PubMed, Web of Science, Cochrane Library, Embase, and the Cumulative Index of Nursing and Allied Health Literature databases until September 25, 2023. Randomized controlled trials (RCTs) including patients with MS pain receiving EST compared with other therapies were included. Pain intensity, quality of life, and neuropsychiatric symptoms were reported. The mean difference (MD) with 95 % confidence intervals (CIs) was estimated separately for outcomes to understand the mean effect size. RESULTS: Ten RCTs containing 315 participants were included. The pooled data from 8 trials including 267 participants showed that the EST was superior in alleviating pain (MD = -1.75, 95 % CI -2.85--0.64, P = 0.002, I2=73 %) evaluated by the visual analog scale. In subgroup analysis, medium-term EST treatment showed the highest effect size compared to short-term and long-term treatment (MDmedium-term = -2.17, 95 % CI -3.51--0.84, P = 0.001, I2 = 0 %). However, no significant differences were found in terms of pain-related quality of life, depression, fatigue, and pain-related disability. No adverse events related to EST were reported. A high risk of bias was identified in three of the ten included studies. CONCLUSIONS: EST is effective and safe for alleviating pain in MS, but it should be noted that limited sample sizes and methodological issues were present in the included studies. More robust assessment criteria and high-quality RCTs are required for patients with MS. TRIAL REGISTRATION: CRD42023406787. (https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=406787).

[Exploration and consideration on establishing a core outcome set of Traditional Chinese Medicine clinical trials in distal radius fracture].

There are inconsistencies in treatment outcomes, measurement instruments, and criteria for assessing clinical effectiveness in studies related to distal radius fractures (DRF), resulting in potential biases and failing to provide high-quality clinical evidence. To address these challenges, international researchers have reached a consensus on developing the core outcome indicator set for distal radius fractures(COS-DRF). However, it's important to note that the existing COS-DRF framework could not reflect the unique characteristics of Traditional Chinese Medicine (TCM) treatment. Currently, there are no established standards for treatment outcomes and measurement instruments specific to TCM clinical research, nor has a COS-DRF been established for TCM clinical studies in China. In light of these gaps, our research team aims to construct a core set of treatment outcomes for TCM clinical research on distal radius fractures. This involves compiling a comprehensive list of treatment outcomes and measurement instruments, initially derived from a thorough literature review and expert consensus, which will then undergo further refinement and updates based on real-world clinical experiences, incorporating feedback from 2 to 3 rounds of expert consensus or Delphi questionnaire surveys. Our goal is to establish a COS-DRF or CMS-DRF that aligns with the principles and practices of TCM, and provide high-quality evidence for clinical practice.

Deep eutectic solvent combined with ultrasound technology: A promising integrated extraction strategy for anthocyanins and polyphenols from blueberry pomace.

To avoid wasting blueberry pomace resources, deep eutectic solvents (DESs) were combined with ultrasound technology to establish an efficient green method for the recovery of anthocyanins and polyphenols from plant-derived by-products. Choline chloride:1,4-butanediol (molar ratio of 1:3) was chosen as the optimal solvent based on the screening of eight solvents and single-factor experiments. Response surface methodology was applied to optimize the extraction parameters: water content, 29%; extraction temperature, 63 °C; liquid-solid ratio, 36:1 (v/w). The yields of total anthocyanins and total polyphenols from the optimized extraction were 11.40 ± 0.14 mg cyanidin-3-glucoside equiv./g and 41.56 ± 0.17 mg gallic acid equiv./g, respectively, which were both significantly better than the yields achieved with 70% ethanol. The purified anthocyanins showed excellent inhibition of α-glucosidase (IC50 = 16.57 µg/mL). The physicochemical parameters of DES suggest that it can be used for the extraction of bioactive substances.

Molecular Targets of Shenqi Dihuang, A Traditional Chinese Herbal Medicine, and Its Potential Role in Renal Cell Carcinoma Therapy.

Chinese herbal medicine (CHM), which includes herbal slices and proprietary products, is widely used in China. Shenqi Dihuang (SQDH) is a traditional Chinese medicine (TCM) formula with ingredients that affect tumor growth. Despite recent advances in prognosis, patients with renal cell carcinoma (RCC) cannot currently receive curative treatment. The present study aimed to explore the potential target genes closely associated with SQDH. The gene expression data for SQDH and RCC were obtained from the TCMSP and TCGA databases. The SQDH-based prognostic prediction model reveals a strong correlation between RCC and SQDH. In addition, the immune cell infiltration analysis indicated that SQDH might be associated with the immune response of RCC patients. Based on this, we successfully built the prognostic prediction model using SQDH-related genes. The results demonstrated that CCND1 and NR3C2 are closely associated with the prognosis of RCC patients. Finally, the pathways enrichment analysis revealed that response to oxidative stress, cyclin binding, programmed cell death, and immune response are the most enriched pathways in CCND1. Furthermore, transcription regulator activity, regulation of cell population proliferation, and cyclin binding are closely associated with the NR3C2.

Efficient and genotype independent maize transformation using pollen transfected by DNA-coated magnetic nanoparticles.

Current gene delivery methods for maize are limited to specific genotypes and depend on time-consuming and labor-intensive tissue culture techniques. Here, we report a new method to transfect maize that is culture-free and genotype independent. To enhance efficiency of DNA entry and maintain high pollen viability of 32%-55%, transfection was performed at cool temperature using pollen pretreated to open the germination aperture (40%-55%). Magnetic nanoparticles (MNPs) coated with DNA encoding either red fluorescent protein (RFP), ß-glucuronidase gene (GUS), enhanced green fluorescent protein (EGFP) or bialaphos resistance (bar) was delivered into pollen grains, and female florets of maize inbred lines were pollinated. Red fluorescence was detected in 22% transfected pollen grains, and GUS stained 55% embryos at 18 d after pollination. Green fluorescence was detected in both silk filaments and immature kernels. The T1 generation of six inbred lines showed considerable EGFP or GUS transcripts (29%-74%) quantitated by polymerase chain reaction, and 5%-16% of the T1 seedlings showed immunologically active EGFP or GUS protein. Moreover, 1.41% of the bar transfected T1 plants were glufosinate resistant, and heritable bar gene was integrated into the maize genome effectively as verified by DNA hybridization. These results demonstrate that exogenous DNA could be delivered efficiently into elite maize inbred lines recalcitrant to tissue culture-mediated transformation and expressed normally through our genotype-independent pollen transfection system.

Probiotics Can Further Reduce Waist Circumference in Adults with Morbid Obesity after Bariatric Surgery: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

Whether probiotics could be used as an adjunct to bariatric surgery is controversial. This meta-analysis aimed to evaluate the effects of probiotics on body weight, body mass index (BMI), percentage of the excess weight loss (%EWL), waist circumference (WC), and C-reactive protein (CRP) in adults with obesity after bariatric surgery (BS). PUBMED, EMBASE, and the Cochrane Central Registry of Controlled Trials were searched from the earliest record to March 2020. All randomized controlled trials (RCTs) on the effects of probiotics in adults with obesity after bariatric surgery were analyzed according to the eligibility criteria. Four RCTs, including 172 participants, were analyzed. There was a statistically significant difference in probiotics in the reduction of waist circumference at 12 months after bariatric surgery. However, probiotics were not effective in weight, BMI, %EWL, WC, and CRP both within 3 months and at 12 months postoperation. Probiotics aid adults with morbid obesity in achieving further waist circumference improvement after BS, with no significant effect on weight, BMI, %EWL, and CRP. More quality clinical studies are needed to confirm the efficacy and safety of probiotics, and address a number of practical issues before the routine clinical use of probiotics in adults with obesity undergoing BS.

In vitro effect of pachymic acid on the activity of Cytochrome P450 enzymes.

Pachymic acid is a wildly used traditional Chinese medicine with various pharmacological features. It also exists in many drugs which are wildly used in pediatric.The effect of pachymic acid on the activity of eight major CYP isoforms was investigated in human liver microsomes.The effects of pachymic acid on eight human liver CYP isoforms (i.e. 1A2, 3A4, 2A6, 2E1, 2D6, 2C9, 2C19 and 2C8) were investigated in vitro using human liver microsomes (HLMs), and the enzyme kinetic parameters were calculated.The activity of CP3A4, 2E1, and 2C9 was inhibited by pachymic acid in a concentration-dependent manner with IC50 values of 15.04, 27.95, and 24.22 µM, respectively. Pachymic acid is a non-competitive inhibitor of CYP3A4, with the Ki value of 6.47 µM. While the inhibition of CYP2E1 and 2C9 was performed in a competitive manner, with the Ki value of 11.96 and 10.94 µM, respectively. Moreover, the inhibition of CYP3A4 was in a time-dependent manner with the KI/Kinact value of 7.77/0.048 min-1 µM-1.The in vitro inhibitory effect of pachymic acid on the activity of CYP3A4, 2E1, and 2C9 indicated the potential drug-drug interaction with the drugs that metabolized by CYP3A4, 2E1, and 2C9. Further clinical and in vivo studies are needed to evaluate the significance of this interaction.

Binding of the polysaccharide from Acanthopanax giraldii Harms to toll-like receptor 4 activates macrophages.

ETHNOPHARMACOLOGICAL RELEVANCE: The traditional Chinese medicine, Acanthopanax giraldii Harms, is commonly used to treat arthralgia due to wind, cold and dampness, as well as weakness in the feet and knees. Its other reported effects include eliminating flatulence, strengthening muscles and bones, and delaying aging. The polysaccharides in A. giraldii Harms are the major bioactive substances that confer the herb's antioxidant properties as well as anticancer and antiviral effects. AIMS OF THE STUDY: To elucidate the underlying mechanism and signaling cascade involved in the homogeneous A. giraldii Harms polysaccharide II (AHP-II)-mediated immunomodulation of mice macrophages. MATERIALS AND METHODS: The phagocytosis of neutral red and the production of nitric oxide, interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α), were measured to determine AHP-II-induced macrophage activation. Confocal microscopy and flow cytometry were used to confirm the binding of AHP-II to macrophages. The involvement of Toll-like receptor (TLR) 4 in AHP-II-induced macrophage activation was demonstrated using antibody blocking and macrophages from C3H/HeJ TLR4-mutant mice. Western blotting was used to map AHP-II-induced downstream signaling pathways. RESULTS: AHP-II increased the phagocytosis of macrophages and the release of nitric oxide, IL-6 and TNF-α cytokines. Direct, saturable and reversible binding of AHP-II to macrophages was observed, while it can be inhibited by the anti-TLR4 antibody. In addition, the presence of the anti-TLR4 antibody inhibited AHP-II-induced macrophage IL-6 and TNF-α production in the peritoneal macrophages of C3H/HeJ mice. Moreover, AHP-II-TLR4-stimulated macrophages activate the downstream intracellular ERK and JNK/nuclear factor (NF)-κB signaling pathways. In addition, the AHP-II-mediated regulation of IL-6 and TNF-α production from macrophages was greatly affected by specific ERK, JNK and NF-κB inhibitors. CONCLUSION: Our study elucidated the immunomodulatory mechanism of AHP-II in macrophage activation and identified TLR4 as the main receptor coordinating AHP-II binding. Our findings suggest AHP-II may be used as a novel immunopotentiator for medical purposes.

Inhalation treatment of primary lung cancer using liposomal curcumin dry powder inhalers.

Lung cancer is the leading cause of cancer-related deaths. Traditional chemotherapy causes serious toxicity due to the wide bodily distribution of these drugs. Curcumin is a potential anticancer agent but its low water solubility, poor bioavailability and rapid metabolism significantly limits clinical applications. Here we developed a liposomal curcumin dry powder inhaler (LCD) for inhalation treatment of primary lung cancer. LCDs were obtained from curcumin liposomes after freeze-drying. The LCDs had a mass mean aerodynamic diameter of 5.81 µm and a fine particle fraction of 46.71%, suitable for pulmonary delivery. The uptake of curcumin liposomes by human lung cancer A549 cells was markedly greater and faster than that of free curcumin. The high cytotoxicity on A549 cells and the low cytotoxicity of curcumin liposomes on normal human bronchial BEAS-2B epithelial cells yielded a high selection index partly due to increased cell apoptosis. Curcumin powders, LCDs and gemcitabine were directly sprayed into the lungs of rats with lung cancer through the trachea. LCDs showed higher anticancer effects than the other two medications with regard to pathology and the expression of many cancer-related markers including VEGF, malondialdehyde, TNF-α, caspase-3 and BCL-2. LCDs are a promising medication for inhalation treatment of lung cancer with high therapeutic efficiency.

Pulmonary delivery of tea tree oil-ß-cyclodextrin inclusion complexes for the treatment of fungal and bacterial pneumonia.

OBJECTIVES: Bacterial pneumonia is a common cause of death worldwide. Tea tree oil (TTO) is a potent antimicrobial natural product, which is formulated in dry powder inhalers (DPIs) for the treatment of fungal and bacterial pneumonia. METHODS: Tea tree oil-ß-cyclodextrin inclusion complexes (TTO-ß-CD) were prepared and characterized. Aerodynamic properties of TTO-ß-CD powders were measured. The rat models of fungal (Candida albicans) and bacterial (Acinetobacter baumannii) pneumonia were prepared. Saline, TTO, TTO-ß-CD and the positive drug (fluconazole or penicillin) were directly delivered to the rat lungs. Pathological and biological assays were conducted. KEY FINDINGS: Tea tree oil-ß-CD powders had an appropriate aerodynamic diameter of 5.59 µm and the fine particle fraction of 51.22%, suitable for pulmonary delivery. TTO-ß-CD showed higher and similar antipneumonic effects on the rat models than fluconazole and penicillin, respectively. The effects of TTO-ß-CD were higher than TTO alone. The antipneumonic mechanisms involved blocking the recruitment of leucocytes and neutrophils, eliminating the microbes, downregulating pro-inflammatory cytokines (including tumour necrosis factor-α, interleukin-1ß and interleukin-6), suppressing cyclooxygenase 2 expression, and further reducing lung injury. CONCLUSIONS: Inhaled TTO-ß-CD powders have the advantages of portability, high stability, self-administration, high lung deposition and good antipneumonic effect. It is a promising DPI for the treatment of fungal and bacterial pneumonia.

Inhalable Andrographolide-ß-cyclodextrin Inclusion Complexes for Treatment of Staphylococcus aureus Pneumonia by Regulating Immune Responses.

Bacterial pneumonia is a serious disease with high mortality if no appropriate and immediate therapy is available. Andrographolide (AG) is an anti-inflammatory agent extracted from a traditional Chinese herb andrographis paniculata. Oral AG tablets and pills are clinically applied for treatment of upper respiratory tract infections. However, the low solubility and bioavailability of AG lead to high doses and long-term therapy. Here we developed an andrographolide-ß-cyclodextrin inclusion complex (AG-ß-CD) for inhalation therapy of Staphylococcus aureus pneumonia. AG-ß-CD was identified with X-ray diffraction and FT-IR. Surprisingly, both AG-ß-CD and AG showed little in vitro anti-S. aureus activity. However, pulmonary delivery of AG, AG-ß-CD, or penicillin had significant anti-S. aureus pneumonia effects. Leukocytes, neutrophils, white blood cells, total proteins, TNF-α, IL-6, NF-κB p65 expression, and bacterial colonies in the bronchoalveolar lavage fluids were detected. Pulmonary delivery of AG and AG-ß-CD led to bacterial inhibition and inflammation alleviation by regulating immune responses, while penicillin only killed bacteria without significant immune regulation. Moreover, the antipneumonia activity of AG-ß-CD was much higher than that of AG, probably resulting from locally accelerated AG dissolution due to ß-CD inclusion. The aerodynamic diameter of AG-ß-CD powders was 2.03 µm, suitable for pulmonary delivery. Inhalable AG-ß-CD is a promising antibacterial and anti-inflammatory medicine for the treatment of S. aureus pneumonia by regulating immune responses, and the effect is enhanced by ß-CD inclusion. AG and its formulations might be potent weapons against the resistant bacterial pneumonia due to their specific mechanism in the future.