Hybrid Membrane-Coated Nanoparticles for Precise Targeting and Synergistic Therapy in Alzheimer's Disease.

The blood brain barrier (BBB) limits the application of most therapeutic drugs for neurological diseases (NDs). Hybrid cell membrane-coated nanoparticles derived from different cell types can mimic the surface properties and functionalities of the source cells, further enhancing their targeting precision and therapeutic efficacy. Neuroinflammation has been increasingly recognized as a critical factor in the pathogenesis of various NDs, especially Alzheimer's disease (AD). In this study, a novel cell membrane coating is designed by hybridizing the membrane from platelets and chemokine (C-C motif) receptor 2 (CCR2) cells are overexpressed to cross the BBB and target neuroinflammatory lesions. Past unsuccessful endeavors in AD drug development underscore the challenge of achieving favorable outcomes when utilizing single-mechanism drugs.Two drugs with different mechanisms of actions into liposomes are successfully loaded to realize multitargeting treatment. In a transgenic mouse model for familial AD (5xFAD), the administration of these drug-loaded hybrid cell membrane liposomes results in a significant reduction in amyloid plaque deposition, neuroinflammation, and cognitive impairments. Collectively, the hybrid cell membrane-coated nanomaterials offer new opportunities for precise drug delivery and disease-specific targeting, which represent a versatile platform for targeted therapy in AD.

Microglial Activation, Tau Pathology, and Neurodegeneration Biomarkers Predict Longitudinal Cognitive Decline in Alzheimer's Disease Continuum.

Purpose: Biomarkers used for predicting longitudinal cognitive change in Alzheimer's disease (AD) continuum are still elusive. Tau pathology, neuroinflammation, and neurodegeneration are the leading candidate predictors. We aimed to determine these three aspects of biomarkers in cerebrospinal fluid (CSF) and plasma to predict longitudinal cognition status using Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort. Patients and Methods: A total of 430 subjects including, 96 cognitive normal (CN) with amyloid ß (Aß)-negative, 54 CN with Aß-positive, 195 mild cognitive impairment (MCI) with Aß-positive, and 85 AD with amyloid-positive (Aß-positive are identified by CSF Aß42/Aß40 < 0.138). Aß burden was evaluated by CSF and plasma Aß42/Aß40 ratio; tau pathology was evaluated by CSF and plasma phosphorylated-tau (p-tau181); microglial activation was measured by CSF soluble TREM2 (sTREM2) and progranulin (PGRN); neurodegeneration was measured by CSF and plasma t-tau and structural magnetic resonance imaging (MRI); cognition was examined annually over the subsequent 8 years using the Alzheimer's Disease Assessment Scale Cognition 13-item scale (ADAS13) and Mini-Mental State Exam (MMSE). Linear mixed-effects models (LME) were applied to assess the correlation between biomarkers and longitudinal cognition decline, as well as their effect size on the prediction of longitudinal cognitive decline. Results: Baseline CSF Aß42/Aß40 ratio was decreased in MCI and AD compared to CN, while CSF p-tau181 and t-tau increased. Baseline CSF sTREM2 and PGRN did not show any differences in MCI and AD compared to CN. Baseline brain volumes (including the hippocampal, entorhinal, middle temporal lobe, and whole-brain) decreased in MCI and AD groups. For the longitudinal study, there were significant interaction effects of CSF p-tau181 × time, plasma p-tau181 × time, CSF sTREM2 × time, and brain volumes × time, indicating CSF, and plasma p-tau181, CSF sTREM2, and brain volumes could predict longitudinal cognition deterioration rate. CSF sTREM2, CSF, and plasma p-tau181 had similar medium prediction effects, while brain volumes showed stronger effects in predicting cognition decline. Conclusion: Our study reported that baseline CSF sTREM2, CSF, and plasma p-tau181, as well as structural MRI, could predict longitudinal cognitive decline in subjects with positive AD pathology. Plasma p-tau181 can be used as a relatively noninvasive reliable biomarker for AD longitudinal cognition decline prediction.

Preparation and bioavailability of sustained-release doxofylline pellets in beagle dogs.

The objective of this study was to develop doxofylline-loaded sustained-release pellets coated with Eudragit NE30D alone (F1) or blend of Eudragit RL30D/RS30D (F2) and further evaluate their in vitro release and in vivo absorption in beagle dogs. Doxofylline-loaded cores with a drug loading of 70% (w/w) were prepared by layering drug-MCC powder onto seed cores in a centrifugal granulator and then coating them with different kinds of polymethacrylates in a bottom-spray fluidized bed coater. Dissolution behaviour of these formulations was studied in vitro under various pH conditions (from pH 1.2 to pH 7.4) to evaluate the effect of pH on drug release profiles. It was found that F2 produced a better release profile than F1 did and two different release mechanisms were assumed for F1 and F2, respectively. The relative bioavailability of the sustained-release pellets was studied in six beagle dogs after oral administration in a fast state using a commercially available immediate release tablet as a reference. Coated with Eudragit NE30D and a blend of Eudragit RL30D/RS30D (1:12), at 5% and 8% coating level, respectively, the pellets acquired perfect sustained-release properties and good relative bioavailability, with small fluctuation of drug concentration in plasma. But combined use of mixed Eudragit RL30D/RS30D polymers with proper features as coating materials produced a longer T(max), a lower C(max) and a little higher bioavailability compared to F1 (coated with Eudragit NE30D alone). The C(max), T(max) and relative bioavailability of F1 and F2 coated pellets were 15.16 microg/ml, 4.17 h, 97.69% and 11.41 microg/ml, 5 h, 101.59%, respectively. Also a good linear correlation between in vivo absorption and in vitro release was established for F1 and F2, so from the dissolution test, formulations in vivo absorption can be properly predicted.

Sheng-mai-san reduces adriamycin-induced cardiomyopathy in rats.

The traditional Chinese medicine prescription "sheng-mai-san (SMS)" has been used for treating patients with coronary heart disease for a long time and was found to have antioxidative effects. Here, we applied adriamycin (doxorubicin, ADR), a highly effective anticancer agent, as an inducer to establish the animal model of dose-related cardiomyopathy due to inhibition of nucleic acid as well as protein synthesis, formation of free radicals, and lipid peroxidation. The objective of this study was to investigate the protective effects of SMS on adriamycin-induced cardiomyopathy. Wistar rats were divided into four groups: CONT (control), ADR, SMS, and ADR + SMS. ADR (cumulative dose, 15 mg/kg) was administered to rats in six equal intraperitoneal injections over a period of 2 weeks and SMS was administered via a feeding tube throughout the mouth once a day for 30 days (cumulative dose, 150 g/kg). At the end of the 5-week post-treatment period, the hearts of the rats were surgically removed for the study of synthesis rates of DNA, RNA and proteins. Besides myocardial antioxidants, lipid peroxidation and morphological ultrastructure were also evaluated. Three weeks after the treatment, cardiomyopathy and congestive heart failure were characterized according to assessment in ascites, congested liver, depressed cardiac function and myocardial cell damage. The results demonstrated that nucleic acid as well as protein synthesis was inhibited, while lipid peroxidation was increased. Myocardial glutathione peroxidase (GSHPx) activity was decreased and electron microscopic examination revealed myocardial lesion indicative of ADR-induced cardiomyopathy. In contrast, administration of SMS before and concurrent with ADR significantly attenuated the myocardial effects. It also lowered mortality as well as the amount of ascites. In addition, indexes in myocardial GSHPx, macromolecular biosynthesis and superoxide dismutase activities were increasing, with a concomitant decrease in lipid peroxidation and preserved myocardial ultrastructure. These results indicated that SMS may be partially protective against ADR-induced cardiomyopathy.

Panax ginseng reduces adriamycin-induced heart failure in rats.

The purpose of this study was to investigate the protective effects of Panax ginseng on adriamycin-induced heart failure. Wistar rats were divided into four groups: control, adriamycin, ginseng and adriamycin with ginseng. Adriamycin (cumulative dose, 15 mg/kg) was administered to rats in six equal intraperitoneal injections over a period of 2 weeks. Ginseng was administered via an oral feeding tube once a day for 30 days (cumulative dose, 150 g/kg). At the end of the 5 week post-treatment period, the hearts of the rats were used to study the synthesis rates of DNA, RNA and protein, myocardial antioxidants and lipid peroxidation. At the end of 3 weeks treatment, heart failure was characterized by ascites, congested liver and depressed cardiac function. Nucleic acid as well as protein synthesis was inhibited, lipid peroxidation was increased and myocardial glutathione peroxidase activity was decreased indicating adriamycin-induced heart failure. In contrast, the administration of ginseng, before and concurrent with adriamycin, significantly attenuated the myocardial effects, lowered the mortality as well as the amount of ascites, increased in myocardial glutathione peroxidase, macromolecular biosynthesis and superoxide dismutase activities, with a concomitant decrease in lipid peroxidation. These findings indicated that ginseng may be partially protective against adriamycin-induced heart failure.

Effects of Xuefu Zhuyu Tang and mitomycin C on liver tumors in mice.

BACKGROUND: Carcinogenesis, in traditional Chinese medicine, is defined as resulting from the accumulation of stagnant and toxic substances within the human body. Xuefu zhuyu tang (XZT) represents a group of herbs for 'destagnation'; and mitomycin C (MMC) is currently and widely used for cancer therapy. We investigated the combined effects of XZT and MMC on mice bearing liver tumors. METHODS: Mice bearing experimental liver tumors were divided into 4 groups, including tumor control, XZT-, MMC-, and combined-treatment groups. Several effects were observed in this study including survival rate, increase of life span, and mean survival time within 60 days after treatment. Survival rates and biosynthesis activities of tumor and liver cells were also evaluated. RESULTS: Oral administration of XZT, an intraperitoneal injection of MMC, and a combination of the two increased the mean survival time of tumor-bearing mice by 12.5, 14.1, and 17.2 days, respectively. These 3 treatments were cytotoxic to sarcoma-180-induced liver tumor cells. The synthesis rates of deoxyribonucleic acid (DNA), ribonucleic acid (RNA), and protein by tumor cells were all measurably inhibited by the combined treatment. CONCLUSION: XZT combined with MMC may be an effective modality in cancer therapy. The detailed mechanisms of these combinations in human liver neoplasms use to be further studied.