Seco-cyclic phorbol derivatives and their anti-HIV-1 activities.

Phorbol esters are recognized for their dual role as anti-HIV-1 agents and as activators of protein kinase C (PKC). The efficacy of phorbol esters in binding with PKC is attributed to the presence of oxygen groups at positions C20, C3/C4, and C9 of phorbol. Concurrently, the lipids located at positions C12/C13 are essential for both the anti-HIV-1 activity and the formation of the PKC-ligand complex. The influence of the cyclopropane ring at positions C13 and C14 in phorbol derivatives on their anti-HIV-1 activity requires further exploration. This research entailed the hydrolysis of phorbol, producing seco-cyclic phorbol derivatives. The anti-HIV-1 efficacy of these derivatives was assessed, and the affinity constant (Kd) for PKC-δ protein of selected seco-cyclic phorbol derivatives was determined through isothermal titration calorimetry. The findings suggest that the chemical modification of cyclopropanols could affect both the anti-HIV-1 activity and the PKC binding affinity. Remarkably, compound S11, with an EC50 of 0.27 µmol·L-1 and a CC50 of 153.92 µmol·L-1, demonstrated a potent inhibitory effect on the intermediate products of HIV-1 reverse transcription (ssDNA and 2LTR), likely acting at the viral entry stage, yet showed no affinity for the PKC-δ protein. These results position compound S11 as a potential candidate for further preclinical investigation and for studies aimed at elucidating the pharmacological mechanism underlying its anti-HIV-1 activity.

In Vitro and In Vivo Anti-Cancer Activity of Lasiokaurin in a Triple-Negative Breast Cancer Model.

Due to its intricate heterogeneity, high invasiveness, and poor prognosis, triple-negative breast cancer (TNBC) stands out as the most formidable subtype of breast cancer. At present, chemotherapy remains the prevailing treatment modality for TNBC, primarily due to its lack of estrogen receptors (ERs), progesterone receptors (PRs), and human epidermal growth receptor 2 (HER2). However, clinical chemotherapy for TNBC is marked by its limited efficacy and a pronounced incidence of adverse effects. Consequently, there is a pressing need for novel drugs to treat TNBC. Given the rich repository of diverse natural compounds in traditional Chinese medicine, identifying potential anti-TNBC agents is a viable strategy. This study investigated lasiokaurin (LAS), a natural diterpenoid abundantly present in Isodon plants, revealing its significant anti-TNBC activity both in vitro and in vivo. Notably, LAS treatment induced cell cycle arrest, apoptosis, and DNA damage in TNBC cells, while concurrently inhibiting cell metastasis. In addition, LAS effectively inhibited the activation of the phosphatidylinositol-3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/Akt/mTOR) pathway and signal transducer and activator of transcription 3 (STAT3), thus establishing its potential for multitarget therapy against TNBC. Furthermore, LAS demonstrated its ability to reduce tumor growth in a xenograft mouse model without exerting detrimental effects on the body weight or vital organs, confirming its safe applicability for TNBC treatment. Overall, this study shows that LAS is a potent candidate for treating TNBC.

Integration of network pharmacology, transcriptomics and molecular docking reveals two novel hypoglycemic components in snow chrysanthemum.

Our previous studies uncovered the glucose-lowering properties of snow chrysanthemum tea, however, the active ingredients and underlying mechanisms were yet to be uncovered. Flavonoids are the most active and abundant components in snow chrysanthemum tea. In this study, we treated leptin-deficient diabetic ob/ob or high-fat diet (HFD)-induced C57BL/6 J obese mice with or without total flavonoids of snow chrysanthemum (TFSC) for 14 weeks. Results indicated that TFSC ameliorated dyslipidemia and fatty liver, thereby reducing hyperlipidemia. Further mechanism experiments, including RNA-seq and experimental validation, revealed TFSC improved glycolipid metabolism primarily by activating the AMPK/Sirt1/PPARγ pathway. Additionally, by integrating UPLC, network pharmacology, transcriptomics, and experimental validation, we identified two novel hypoglycemic compounds, sulfuretin and leptosidin, in TFSC. Treatment with 12.5 µmol/L sulfuretin obviously stimulated cellular glucose consumption, and sulfuretin (3.125, 6.25 and 12.5 µmol/L) significantly mitigated glucose uptake damage and reliably facilitated glucose consumption in insulin-resistant HepG2 cells. Remarkably, sulfuretin interacted with the ligand-binding pocket of PPARγ via three hydrogen bond interactions with the residues LYS-367, GLN-286 and TYR-477. Furthermore, a concentration of 12.5 µmol/L sulfuretin effectively upregulated the expression of PPARγ, exhibiting a comparable potency to a renowned PPARγ agonist at 20 µmol/L. Taken together, our findings have identified two new hypoglycemic compounds and revealed their mechanisms, which significantly expands people's understanding of the active components in snow chrysanthemum that have hypoglycemic effects.

The impact of nurse-led nonpharmacological multidisciplinary holistic nursing care on fatigue patients receiving hemodialysis: a randomized, parallel-group, controlled trial.

BACKGROUND: Fatigue is a symptom characterized by an elevated prevalence in patients undergoing hemodialysis, which may cause extreme mental and muscular debilitation, significantly influencing social interaction, life quality and well-being. However, the significance of fatigue to patients undergoing hemodialysis has not been recognized yet, and prevention and management of fatigue in this population have not been thoroughly investigated. Additionally, previous studies mainly focused on muscular fatigue, while mental fatigue has been seldom discussed. This study aims to investigate the interaction between nurses and multidisciplinary of nonpharmacological integrated care interventions (NICIs) and assess the impact of fatigue on patients undergoing hemodialysis. METHODS: The integrative nonpharmacological care interventions in this study included walking, motivational interviewing (MI) and health education regarding behavioral self-management. A single-center randomized controlled trial was conducted in the dialysis center of the nephrological department in a tertiary affiliated hospital of medical university from January to June 2019. A total of 118 patients were selected and randomly divided into the intervention group (IG) and the control group (CG). Four patients dropped out during the study, and 114 patients were enrolled for the eventual analysis. The 60 patients in the IG received routine nursing combined with integrated care interventions, while the 54 patients in the CG received routine nursing only. This study lasted for six months. RESULTS: The experimental group exhibited significant reductions of overall fatigue (2.26 vs. 0.48), mental fatigue (1.41 vs. 0.54), muscular fatigue (2.13 vs. 0.75), and some biochemical indicators (e.g., serum urea) (P<0.05), compared with the CG. CONCLUSIONS: Nurses and multidisciplinary teams have been demonstrated to play a key role and interplay function in chronic disease management. Hence, the nurse-led multidisciplinary NICIs significantly alleviated total fatigue (muscular fatigue and mental fatigue) and improved other parameters. TRIAL REGISTRATION: ChiCTR-IOR-16008621 (March 18, 2016).

The Effect of Nonpharmacological Integrated Care Protocols on Patients with Fatigue Undergoing Hemodialysis: A Randomized Controlled Trial.

This study was designed to investigate the effects of nonpharmacological integrated care protocols on fatigue in patients with hemodialysis. This parallel randomized controlled trial was conducted on patients undergoing hemodialysis from May to October 2020 at the Dialysis Center of the Fifth Affiliated Hospital of Zunyi Medical University. The patients were randomized into an intervention group (accepting nonpharmacological integrated care protocols and standard care) or a control group (accepting standard care only) using a computer-generated random number. The nonpharmacological holistic care intervention used in this study involved a well-rounded multidisciplinary team that worked together to improve dietary compliance, medication adherence, and self-management to improve patients' care and promote self-management. From the 120 evaluated patients, 116 cases were eligible and analyzed. The results showed that patients from the intervention group had obviously reduced overall fatigue, mental fatigue, and muscular fatigue relative to the control group. The nonpharmacological integrated care protocols were interactive and promotive to each other. Meanwhile, the role and function of nurses in the management of chronic disease were demonstrated to be crucial.

Novel active compounds and the anti-diabetic mechanism of mulberry leaves.

Mulberry (Morus alba L.) leaves have long been considered beneficial in traditional Chinese medicine to treat infectious and internal diseases. Recently studies have discovered that the mulberry leaf's total flavonoids (MLF) display excellent hypoglycemia properties. However, the active ingredients and their molecular mechanisms are still uncharacterized. In this study, we explored the hypoglycemic effects of MLF and mulberry leaf polysaccharides (MLP) on ob/ob mice, an animal model of type 2 diabetes mellitus (T2DM), compared with Ramulus Mori (Sangzhi) alkaloid (RMA). Network pharmacology was employed to identify the potential available targets and active compounds of MLF and RMA against hyperglycemia. Molecular docking, an insulin-resistant cell model and qPCR were employed to verify the antidiabetic activity of the critical compounds and the gene expression profiles of the top molecular targets. Here, the results showed that MLF and MLP improved glucose uptake in insulin-resistant hepatocytes. MLF, MLP and RMA alleviated insulin resistance and glucose intolerance in ob/ob mice. Unlike MLF and MLP, RMA administration did not influence the accumulation of intrahepatic lipids. Network pharmacology analysis revealed that morusin, kuwanon C and morusyunnansin L are the main active compounds of MLF and that they amend insulin resistance and glycemia via the PI3K- Akt signaling pathway, lipid and atherosclerosis pathways, and the AGE-RAGE signaling pathway. Moreover, 1-deoxynojirimycin (DNJ), fagomine (FA), and N-methyl-1-deoxynojirimycin are the primary active ingredients of RMA and target carbohydrate metabolism and regulate alpha-glucosidase activity to produce a potent anti-diabetic effect. The molecular docking results indicated that morusin, kuwanon C and morusyunnansin L are the critical bioactive compounds of MLF. They had high affinities with the key targets adenosine A1 receptor (ADORA1), AKT serine/threonine kinase 1 (AKT1), peroxisome proliferator-activated receptor gamma (PPARγ), and glycogen synthase kinase 3 beta (GSK3ß), which play crucial roles in the MLF-mediated glucose-lowering effect. Additionally, morusin plays a role in amending insulin resistance of hepatocytes by repressing the expression of the ADORA1 and PPARG genes. Our results shed light on the mechanism behind the glucose-lowering effects of MLF, suggesting that morusin, kuwanon C, and morusyunnansin L might be promising drug leads for the management of T2DM.

Exploring the Potential Mechanisms of Melilotus officinalis (L.) Pall. in Chronic Muscle Repair Patterns Using Single Cell Receptor-Ligand Marker Analysis and Molecular Dynamics Simulations.

Information regarding the function of Melilotus officinalis (L.) Pall. in skeletal muscles is still unknown. In this study, we explored the possible regulatory targets of M. (L.) Pall. that affects the repair patterns in chronic muscle injury. We analyzed the potential target genes and chemical composition of M. (L.) Pall. and constructed a "drug-component-disease target genes" network analysis. Five active ingredients and 87 corresponding targets were obtained. Muscle-tendon junction (MTJ) cells were used to perform receptor-ligand marker analysis using the CellphoneDB algorithm. Targets of M. (L.) Pall. were screened further for the cellular ligand-receptor protein action on MTJs. Enrichment analysis suggests that those protein-associated ligand receptors may be associated with a range of intercellular signaling pathways. Molecular docking validation was then performed. Five proteins (CCL2, VEGFA, MMP2, MET, and EGFR) may be regulated by the active ingredient luteolin and scoparone. Finally, molecular dynamics simulations revealed that luteolin can stably target binding to MMP2. M. (L.) Pall. influences skeletal muscle repair patterns by affecting the fibroblast interactions in the muscle-tendon junctions through the active ingredients luteolin and scoparone.

Green tea drinking habits and esophageal cancer in southern China: a case-control study.

AIM: To investigate effects of green tea drinking and its temperature on esophageal cancer development. METHODS: A 1:2 matched hospital-based case-control study including 150 cases and 300 controls was conducted in southern area of China from June 2004 to May 2010. A self-designed questionnaire was used to collect information on possible risk factors of esophageal cancer, and to assess the tea drinking habit and temperature. Conditional logistic regression was used to calculate odds ratios (ORs) and corresponding 95% confidence intervals (CIs). RESULTS: We find a significant protective effect of high consumption of green tea on esophageal cancer with low temperature tea (OR=0.79, 95%CI=0.29-0.97). However, drinking tea at a temperature of 70-79° and above 80° was related to greatly elevated risk of esophageal cancer with ORs of 2.21 (1.57-5.53) and 4.74 (2.67-10.51). An agreement was found between reported tea temperature and measured temperature (correlation coefficient =0.62). Further analysis indicated hot tea temperature to be associated with heavy risk of esophageal cancer in former and current smokers and current drinkers (former and current smokers: OR=8.91(1.91-16.77) and 7.33(2.23-12.46), respectively; former and current drinkers: OR=7.58(0.83-9.53) and 6.93(2.01-10.65)). CONCLUSION: In the South China context, drinking tea at high temperature significantly increases risk of esophageal cancer, especially in drinkers and smokers.