Accumulating clinical and epidemiological evidence indicates a close relationship between diabetes mellitus and dementia. The ginsenoside compound K (CK) has been reported to ameliorate diabetes ...mellitus and confer protection to the central nervous system. In this study, we investigated whether CK could improve memory impairment and cognitive dysfunction in diabetic db/db mice. Firstly, we found that CK treatments significantly improved behavioral impairment and cognitive dysfunction based on Morris water maze, Y-maze, and fear conditioning tests. Besides, CK decreased the fasting glucose level, increased lipid metabolism, and ameliorated glucose tolerance, insulin sensitivity, and dyslipidemia in diabetic db/db mice. In addition, CK treatments alleviated oxidative stress and inhibited the inflammatory response in hippocampal tissue. Further investigations showed that CK treatments inhibited the NLRP3 inflammasome pathway, as evidenced by the declined expression of TXNIP, NLRP3 inflammasomes, ASC, cleaved caspase-1, and mature IL-1β in hippocampal tissues. Moreover, CK treatments alleviated ER stress via down-regulating the level of BiP, CHOP, p-PERK, p-IRE1α and ATF6 in the hippocampus of db/db mice. These results suggest that CK improves memory and cognitive dysfunction, possibly by ameliorating glucose tolerance, insulin sensitivity, and dyslipidemia, suppressing oxidative stress and inflammatory response and modulating the NLRP3 inflammasome pathway and ER stress.
Abstract
Backgrounds
Surgical resection and adjunct chemotherapy or radio-therapy has been applied for the therapy of superficial malignant tumor in clinics. Whereas, there are still some problems ...limit its clinical use, such as severe pains and side effect. Thus, it is urgent need to develop effective, minimally invasive and low toxicity therapy stagey for superficial malignant tumor. Topical drug administration such as microneedle patches shows the advantages of reduced systemic toxicity and nimble application and, as a result, a great potential to treat superficial tumors.
Methods
In this study, microneedle (MN) patches were fabricated to deliver photosensitizer IR820 and chemotherapy agent cisplatin (CDDP) for synergistic chemo-photodynamic therapy against breast cancer.
Results
The MN could be completely inserted into the skin and the compounds carrying tips could be embedded within the target issue for locoregional cancer treatment. The photodynamic therapeutic effects can be precisely controlled and switched on and off on demand simply by adjusting laser. The used base material vinylpyrrolidone—vinyl acetate copolymer (PVPVA) is soluble in both ethanol and water, facilitating the load of both water-soluble and water-insoluble drugs.
Conclusions
Thus, the developed MN patch offers an effective, user-friendly, controllable and low-toxicity option for patients requiring long-term and repeated cancer treatments.
•NE alleviates memory and cognitive dysfunctions in diabetic db/db mice.•NE suppresses oxidative stress and inflammatory response in the hippocampus of diabetic mice.•NE inhibits the NLRP3 ...inflammasome pathway in the hippocampus of diabetic mice.•NE attenuates the ER stress in the hippocampus of diabetic mice.
Accumulating clinical and epidemiological evidence indicates a close relationship between diabetes mellitus and dysfunction in memory and cognition. Neferine (NE) is a unique bis-benzylisoquinoline alkaloid derived from the seed embryo of Nelumbo nucifera (Lotus), an herbal medicine with a long history of use in used in China. NE has been reported to ameliorate diabetes mellitus and exert considerable protective effects on the central nervous system. Thus, this study aimed to investigate the effects of NE on memory and cognitive dysfunction in db/db mouse model of diabetes. First, we found that NE treatments significantly ameliorated behavioral impairment and cognitive dysfunction in the Morris water maze, Y-maze, and fear conditioning test in db/db mice. Additionally, in these diabetic mice, NE decreased fasting glucose and insulin resistance while promoting lipid metabolism. Furthermore, NE treatments alleviated oxidative stress and inhibited inflammatory responses in the hippocampus. Further investigations showed that NE suppressed the NOD-like receptor protein 3 (NLRP3) inflammasome pathway via down-regulating the levels of thioredoxin-interacting protein (TXNIP), NLRP3 inflammasomes, apoptosis-associated speck-like protein containing a CARD (ASC), and mature interleukin-1β (IL-1β) in the hippocampus. Moreover, NE alleviated endoplasmic-reticulum (ER) stress via down-regulating the levels of immunoglobulin heavy-chain-binding protein (GRP78), C/EBP homologous protein (CHOP), proteins kinase R-like endoplasmic reticulum kinase (PERK), inositol-requiring enzyme 1 (IRE1), and activating transcription factor 6 (ATF6) in the hippocampus. In conclusion, these results suggest that NE ameliorated memory and cognitive dysfunction, possibly through modulating the NLRP3 inflammasome pathways and alleviating ER stress.
Rhizoma Curcumae is a popular type of traditional Chinese medicine whose essential oils are widely used in the treatment of cancer in China. This review aims to systematically summarize and analyze ...the anti-cancer properties of terpenoids, the main components of essential oils in Rhizoma Curcumae, and thus enable the development of new anti-cancer drugs.
Information on the recent progress of anti-cancer studies on terpenoids isolated from Rhizoma Curcumae, including β-elemene, δ-elemene, furanodiene, furanodienone, curcumol, and germacrone, was gathered and analyzed.
Among these terpenoids, β-elemene is the most widely studied, whereas δ-elemene, furanodiene, furanodienone, curcumol, and germacrone have just recently attracted the attention of researchers. The anti-cancer effects of these terpenoids are related to the retardation of cell cycle arrest, the induction of apoptosis, and the inhibition of metastasis or tissue invasion, among others.
Most studies have focused on the in vitro data, and in vivo data is urgently needed. Further insight into the anti-cancer activity and the molecular basis of these compounds, combined with efforts in pharmaceutical chemistry and/or pharmaceutics, will potentially enable the development of new anti-cancer agents.
Display omitted
Kazinol B (KB), an isoprenylated flavan derived from Broussonetia kazinoki Sieb. (Moraceae) root, has long been used in folk medicine.
This study examines the protective effects of KB and its ...underlying mechanisms in hypoxia and reoxygenation (H/R)-induced cardiac injury in H9c2 rat cardiac myoblasts.
H9c2 cells were incubated with various concentrations of KB (0, 0.3, 1, 3, 10 and 30 μM) for 2 h and then subjected to H/R insults. The protective effects of KB and its underlying mechanisms were explored.
KB significantly elevated cell viability (1 μM, 1.21-fold; 3 μM, 1.36-fold, and 10 μM, 1.47-fold) and suppressed LDH release (1 μM, 0.77-fold; 3 μM, 0.68-fold, and 10 μM, 0.59-fold) in H/R-induced H9c2 cells. Further, 10 μM KB blocked apoptotic cascades, as shown by the Annexin-V/PI (0.41-fold), DNA fragmentation (0.51-fold), caspase-3 (0.52-fold), PARP activation (0.27-fold) and Bax/Bcl-2 expression (0.28-fold) assays. KB (10 μM) downregulated reactive oxygen species production (0.51-fold) and lipid peroxidation (0.48-fold); it upregulated the activities of GSH-Px (2.08-fold) and SOD (1.72-fold). KB (10 μM) induced Nrf2 nuclear accumulation (1.94-fold) and increased ARE promoter activity (2.15-fold), HO-1 expression (3.07-fold), AKT (3.07-fold) and AMPK (3.07-fold) phosphorylation. Nrf2 knockdown via using Nrf2 siRNA abrogated KB-mediated protective effects against H/R insults. Moreover, pharmacological inhibitors of AKT and AMPK also abrogated KB-induced Nrf2 activation and its protective function.
KB prevented H/R-induced cardiomyocyte injury via modulating the AKT and AMPK-mediated Nrf2 induction. KB might be a promising drug candidate for managing ischemic cardiac disorders.
Due to the unexpected side effects of the iodinated contrast agents, novel contrast agents for X-ray computed tomography (CT) imaging are urgently needed. Nanoparticles made by heavy metal elements ...are often employed, such as gold and bismuth. These nanoparticles have the advantages of long in vivo circulation time and tumor targeted ability. However, due to the long residence time in vivo, these nanoparticles may bring unexpected toxicity and, the preparation methods of these nanoparticles are complicated and time-consuming.
In this investigation, a small molecular bismuth chelate using diethylenetriaminepentaacetic acid (DPTA) as the chelating agent was proposed to be an ideal CT contrast agent.
The preparation method is easy and cost-effective. Moreover, the bismuth agent show better CT imaging for kidney than iohexol in the aspect of improved CT values. Up to 500 µM, the bismuth agent show negligible toxicity to L02 cells and negligible hemolysis. And, the bismuth agent did not induce detectable morphology changes to the main organs of the mice after intravenously repeated administration at a high dose of 250 mg/kg. The pharmacokinetics of the bismuth agent follows the first-order elimination kinetics and, it has a short half-life time of 0.602 h. The rapid clearance from the body promised its excellent biocompatibility.
This bismuth agent may serve as a potential candidate for developing novel contrast agent for CT imaging in clinical applications.
Optical radiation can cause permanent damage to the color of Chinese traditional paintings, which have extremely high responsivity in the museum illumination. In order to obtain quantitative ...influence laws of artificial illumination on inorganic pigments in Chinese traditional paintings and provide basis for choosing light sources, a long periodic illumination experiment was carried out to examine how prolonged exposure of three light sources (tungsten halogen, metal halide and white light emitting diodes), frequently‐used in museums, affect the chromaticity of five inorganic pigments azurite (blue), cinnabar (red), orpiment (yellow), ancient graphite (black), clam shell powder (white), commonly used in Chinese traditional paintings. Through the experiment, we found that the illumination causes a color change to inorganic pigments, and the degree of which is related to the photochemical stability of pigments and the high energy shortwave radiation in the light source spectrum. We also obtain the color change laws of the five pigments and the quantitative relationships of color damage for different painting types. These results can provide data basis for related research on Chinese traditional painting illumination and choice basis for light sources in museum lighting designs.
Proinflammatory M1 macrophages are critical for the progression of atherosclerosis. The Par3-like protein (Par3L) is a homolog of the Par3 family involved in cell polarity establishment. Par3L has ...been shown to maintain the stemness of mammary stem cells and promote the survival of colorectal cancer cells. In this study, we investigated the roles of the polar protein Par3L in M1 macrophage polarization and atherosclerosis. To induce atherosclerosis, Apoe
mice were fed with an atherosclerotic Western diet for 8 or 16 weeks. We showed that Par3L expression was significantly increased in human and mouse atherosclerotic plaques. In primary mouse macrophages, oxidized low-density lipoprotein (oxLDL, 50 μg/mL) time-dependently increased Par3L expression. In Apoe
mice, adenovirus-mediated Par3L overexpression aggravated atherosclerotic plaque formation accompanied by increased M1 macrophages in atherosclerotic plaques and bone marrow. In mouse bone marrow-derived macrophages (BMDMs) or peritoneal macrophages (PMs), we revealed that Par3L overexpression promoted LPS and IFNγ-induced M1 macrophage polarization by activating p65 and extracellular signal-regulated kinase (ERK) rather than p38 and JNK signaling. Our results uncover a previously unidentified role for the polarity protein Par3L in aggravating atherosclerosis and favoring M1 macrophage polarization, suggesting that Par3L may serve as a potential therapeutic target for atherosclerosis.
Stereotactic body radiotherapy harnesses improvements in technology to allow the completion of a course of external beam radiotherapy treatment for prostate cancer in the span of 4 to 5 treatment ...sessions. Although mounting short-term data support this approach, long-term outcomes have been sparsely reported.
To assess long-term outcomes after stereotactic body radiotherapy for low-risk and intermediate-risk prostate cancer.
This cohort study analyzed individual patient data from 2142 men enrolled in 10 single-institution phase 2 trials and 2 multi-institutional phase 2 trials of stereotactic body radiotherapy for low-risk and intermediate-risk prostate cancer between January 1, 2000, and December 31, 2012. Statistical analysis was performed based on follow-up from January 1, 2013, to May 1, 2018.
The cumulative incidence of biochemical recurrence was estimated using a competing risk framework. Physician-scored genitourinary and gastrointestinal toxic event outcomes were defined per each individual study, generally by Radiation Therapy Oncology Group or Common Terminology Criteria for Adverse Events scoring systems. After central review, cumulative incidences of late grade 3 or higher toxic events were estimated using a Kaplan-Meier method.
A total of 2142 men (mean SD age, 67.9 9.5 years) were eligible for analysis, of whom 1185 (55.3%) had low-risk disease, 692 (32.3%) had favorable intermediate-risk disease, and 265 (12.4%) had unfavorable intermediate-risk disease. The median follow-up period was 6.9 years (interquartile range, 4.9-8.1 years). Seven-year cumulative rates of biochemical recurrence were 4.5% (95% CI, 3.2%-5.8%) for low-risk disease, 8.6% (95% CI, 6.2%-11.0%) for favorable intermediate-risk disease, 14.9% (95% CI, 9.5%-20.2%) for unfavorable intermediate-risk disease, and 10.2% (95% CI, 8.0%-12.5%) for all intermediate-risk disease. The crude incidence of acute grade 3 or higher genitourinary toxic events was 0.60% (n = 13) and of gastrointestinal toxic events was 0.09% (n = 2), and the 7-year cumulative incidence of late grade 3 or higher genitourinary toxic events was 2.4% (95% CI, 1.8%-3.2%) and of late grade 3 or higher gastrointestinal toxic events was 0.4% (95% CI, 0.2%-0.8%).
In this study, stereotactic body radiotherapy for low-risk and intermediate-risk disease was associated with low rates of severe toxic events and high rates of biochemical control. These data suggest that stereotactic body radiotherapy is an appropriate definitive treatment modality for low-risk and intermediate-risk prostate cancer.
Bacteria have developed increasing resistance to currently used antimicrobial agents. New classes of antimicrobial drugs are urgently required to fight drug-resistant pathogens. Here, we designed and ...synthesized a series of calix4arene derivatives as antibacterial agents by biomimicking the structural properties and biological functions of antibacterial peptides. After introducing cationic hydrophilic moieties and preliminary structural optimization, we obtained a lead compound (
) that exhibited excellent antibacterial activity against Gram-positive bacteria, low toxicity toward mammalian cells and poor hemolytic activity. The antibacterial mechanism studies showed that compound
can destroy bacterial cell membrane directly, leading to bacterial death and a low tendency to develop bacterial resistance.
PDF
