Rapamycin Ameliorates Cognitive Impairments and Alzheimer's Disease-Like Pathology with Restoring Mitochondrial Abnormality in the Hippocampus of Streptozotocin-Induced Diabetic Mice.

Alzheimer's disease (AD) and diabetes mellitus (DM) share common pathophysiological findings, in particular, the mammalian target of rapamycin (mTOR) has been strongly implied to link to AD, while it also plays a key role in the insulin signaling pathway. However, the mechanism of how DM and AD is coupled remains elusive. In the present study, we found that streptozotocin (STZ)-induced DM mice significantly increased the levels P-mTOR Ser2448, P-p70S6K Thr389, P-tau Ser356 and Aß levels (Aß oligomer/monomer), as well as the levels of Drp1 and p-Drp1 S616 (mitochondrial fission proteins) are increased, whereas no change was found in the expression of Opa1, Mfn1 and Mfn2 (mitochondrial fusion proteins) compared with control mice. Moreover, the expression of 4-HNE and 8-OHdG showed an aberrant increase in the hippocampus of STZ-induced DM mice that is associated with a decreased capacity of spatial memory and a loss of synapses. Rapamycin, an inhibitor of mTOR, rescued the STZ-induced increases in mTOR/p70S6K activities, tau phosphorylation and Aß levels, as well as mitochondria abnormality and cognitive impairment in mice. These findings imply that rapamycin prevents cognitive impairment and protects hippocampus neurons from AD-like pathology and mitochondrial abnormality, and also that rapamycin treatment could normalize these STZ-induced alterations by decreasing hippocampus mTOR/p70S6K hyperactivity.

Mangiferin prevents the impairment of mitochondrial dynamics and an increase in oxidative stress caused by excessive fluoride in SH-SY5Y cells.

Previous studies both invivo and in vitro have revealed that high levels of fluoride cause neurotoxicity. Mangiferin has been reported to possess antioxidant, antiapoptotic, and anti-inflammatory properties. The present study was designed to characterize the mechanisms by which mangiferin protects against NaF-induced neurotoxicity. Increased levels of proapoptotic Bax, Caspase-3, Caspase-9, and cleaved-caspase 3, as well as a decreased level of antiapoptotic Bcl-2 induced by fluoride in human neuroblastoma SH-SY5Y cells, these effects were prevented by pretreatment of mangiferin. In addition, mangiferin attenuated the enhancement of p-JNK, reductions of Nrf2 and HO-1, and increased level of the mitochondrial fission proteins Drp1 caused by fluoride. Moreover, oxidative stress, as reflected in the levels of reactive oxygen species, 8-hydroxy-2'-deoxyguanosine, and 4-hydroxynonenal, was elevated by fluoride and these effects were again ameliorated by mangiferin. In conclusion, protection by mangiferin against fluoride-induced neurotoxicity involves normalizing the impaired mitochondrial apoptotic pathway and dynamics and reducing oxidative stress via inactivation of the JNK and activation of the Nrf2/HO-1 pathways.

Emodin protected against synaptic impairment and oxidative stress induced by fluoride in SH-SY5Y cells by modulating ERK1/2/Nrf2/HO-1 pathway.

Excessive fluoride exposure contributes to neurotoxic effects. Emodin exhibits antioxidative functions in the central nervous system (CNS); however, its neuroprotective mechanism against fluoride remains to be elucidated. Our aim was to explore the neuroprotective efficacy and the possible mechanisms of emodin. In our study, synaptic proteins and oxidative stress damage were examined after human neuroblastoma SH-SY5Y cells were treated with high doses of NaF for 24 hours. Moreover, pretreatment with emodin was used to shed light on the neuroprotective effects in NaF-induced toxicity in SH-SY5Y cells. We found that NaF significantly lowered the protein expressions of SNAP 25, synaptophysin and PSD 95 in SH-SY5Y cells. In addition, NaF exposure increased the protein expression of p-ERK1/2 and decreased the protein expressions of Nrf2 and HO-1, as well as facilitated increasing ROS, 4-hydroxynonenal (4-HNE), and 8-Hydroxy-2'-deoxyguanosine (8-OHdG). Pretreatment with emodin significantly recovered these alterations caused by NaF. These data implied that the neuroprotective effects of emodin and pointed to the promising utilization for protecting against neurotoxicity induced by fluoride.

Analysis of the Protective Effects of Rosa roxburghii-Fermented Juice on Lipopolysaccharide-Induced Acute Lung Injury in Mice through Network Pharmacology and Metabolomics.

Acute lung injury, a fatal condition characterized by a high mortality rate, necessitates urgent exploration of treatment modalities. Utilizing UHPLS-Q-Exactive Orbitrap/MS, our study scrutinized the active constituents present in Rosa roxburghii-fermented juice (RRFJ) while also assessing its protective efficacy against LPS-induced ALI in mice through lung histopathological analysis, cytokine profiling, and oxidative stress assessment. The protective mechanism of RRFJ against ALI in mice was elucidated utilizing metabolomics, network pharmacology, and molecular docking methodologies. Our experimental findings demonstrate that RRFJ markedly ameliorates pathological injuries in ALI-afflicted mice, mitigates systemic inflammation and oxidative stress, enhances energy metabolism, and restores dysregulated amino acid and arachidonic acid metabolic pathways. This study indicates that RRFJ can serve as a functional food for adjuvant treatment of ALI.

Simultaneous determination of choline, L-carnitine, betaine, trimethylamine, trimethylamine N-oxide, and creatinine in plasma, liver, and feces of hyperlipidemic rats by UHPLC-MS/MS.

BACKGROUND: Due to the close correlation between choline, L-carnitine, betaine and their intestinal microbial metabolites, including trimethylamine (TMA) and trimethylamine N-oxide (TMAO), and creatinine, there has been an increasing interest in the study of these compounds in vivo. METHODS: In this study, a rapid stable isotope dilution (SID)-UHPLC-MS/MS method was developed for the simultaneous determination of choline, L-carnitine, betaine, TMA, TMAO and creatinine in plasma, liver and feces of rats. The method was validated using quality control (QC) samples spiked at low, medium and high levels. Second, we applied the method to quantify the effects of Rosa Roxburghii Tratt juice (RRTJ) on plasma, liver, and fecal levels of choline, L-carnitine, betaine, TMA, TMAO, and creatinine in high-fat diet-induced hyperlipidemic rats, demonstrating the utility of the method. RESULTS: The limits of detection (LOD) were 0.04-0.027 µM and the limits of quantification (LOQ) were 0.009-0.094 µM. The linear ranges for each metabolite in plasma were choline1.50-96 µM; L-carnitine: 2-128 µM; betaine: 3-192 µM; TMA: 0.01-40.96 µM; TMAO: 0.06-61.44 µM and creatinine: 1-64 µM (R2 ≥ 0.9954). The linear ranges for each metabolite in liver were Choline: 12-768 µM; L-carnitine: 1.5-96 µM; betaine: 10-640 µM; TMA: 0.5-32 µM; TMAO: 0.02-81.92 µM and creatinine: 0.2-204.8 µM (R2 ≥ 0.9938). The linear ranges for each metabolite in feces were choline: 1.5-96 µM; L-carnitine: 0.01-40.96 µM; Betaine: 1.5-96 µM; TMA: 1-64 µM; TMAO: 0.02-81.92 µM and Creatinine: 0.02-81.92 µM (R2 ≥ 0.998). The intra-day and inter-day coefficients of variation were < 8 % for all analytes. The samples were stabilized after multiple freeze-thaw cycles (3 freeze-thaw cycles), 24 h at room temperature, 24 h at 4 °C and 20 days at -80 °C. The samples were stable. The average recovery was 89 %-99 %. This method was used to quantify TMAO and its related metabolites and creatinine levels in hyperlipidemic rats. The results showed that high-fat diet led to the disorder of TMAO and its related metabolites and creatinine in rats, which was effectively improved after the intervention of Rosa Roxburghii Tratt juice（RRTJ）. CONCLUSIONS: A method for the determination of choline, L-carnitine, betaine, TMA, TMAO and creatinine in plasma, liver and feces samples was established, which is simple, time-saving, high precision, accuracy and recovery.

Rosa roxburghii fermented juice mitigates LPS-induced acute lung injury by modulation of intestinal flora and metabolites.

Acute lung injury (ALI) is a severe pulmonary condition with high mortality and morbidity, lacking effective pharmacotherapeutic options. Rosa roxburghii Tratt, a unique fruit from southwestern China, is valued for its rich nutritional content and functional properties. Fermentation is known to enhance the nutritional value, flavor, and shelf life of foods. In this study, we investigated the effects of fermented Rosa roxburghii juice (RRFJ) on gut microbiota, metabolites, and the levels of short-chain fatty acids in the intestines, as well as its impact on lung tissue and intestine tissue injury, inflammation, and oxidative stress in murine models. The results showed that RRFJ modulated gut microbiota and metabolites, increased short-chain fatty acid levels, and consequently reduced lung tissue injury, inflammation, and oxidative stress in mice with ALI. These findings suggest that RRFJ has the potential to serve as a functional dietary adjunct in the management of acute lung injury, providing a scientific basis for its therapeutic role.

Effects of antennal segments defects on blood-sucking behavior in Aedes albopictus.

After mating, female mosquitoes need a blood meal to promote the reproductive process. When mosquitoes bite infected people and animals, they become infected with germs such as viruses and parasites. Mosquitoes rely on many cues for host selection and localization, among which the trace chemical cues emitted by the host into the environment are considered to be the most important, and the sense of smell is the main way to perceive these trace chemical cues. However, the current understanding of the olfactory mechanism is not enough to meet the needs of mosquito control. Unlike previous studies that focused on the olfactory receptor recognition spectrum to reveal the olfactory mechanism of mosquito host localization. In this paper, based on the observation that mosquitoes with incomplete antennae still can locate the host and complete blood feeding in the laboratory, we proposed that there may be some protection or compensation mechanism in the 13 segments of antennae flagella, and only when the antennae are missing to a certain threshold will it affect the mosquito's ability to locate the host. Through rational-designed behavioral experiments, we found that the 6th and 7th flagellomeres on the Aedes albopictus antenna are important in the olfactory detection of host searching. This study preliminarily screened antennal segments important for host localization of Ae. albopictus, and provided a reference for subsequent cell biology and molecular biology studies on these segments. Meanwhile, the morphology and distribution of sensilla on each antenna flagellomere were also analyzed and discussed in this paper.

Emodin Protects SH-SY5Y Cells Against Zinc-Induced Synaptic Impairment and Oxidative Stress Through the ERK1/2 Pathway.

Zinc is an essential trace element important for the physiological function of the central nervous system. The abnormal accumulation of zinc inside neurons may induce mitochondrial dysfunction and oxidative stress, which contribute to many brain diseases. We hypothesized that natural anthraquinone derivative emodin can protect against neurotoxicity induced by pathological concentrations of zinc via the extracellular signal-regulated kinase 1/2 (ERK1/2) signaling pathway and alleviate oxidative stress and mitochondrial dysfunction. Human neuroblastoma (SH-SY5Y 26 cells) was treated with zinc sulfate and different concentrations of emodin, and changes in the levels of ETK1/2 expression, oxidative stress (DCFH-DA staining), mitochondrial function (JC-1 staining), lipid peroxidation (4-hydroxynonenal staining), and DNA oxidation (8-hydroxy-2-deoxyguanosine staining) were examined. Emodin ameliorated zinc-induced altered expression of levels of phosphorylated ERK1/2 (not total ETK1/2) and synaptic proteins (presynaptic SNAP 25, synaptophysin and postsynaptic PSD95) in SH-SY5Y cells. Moreover, emodin inhibited the generation of reactive oxygen species and oxidative stress and facilitated the collapse of mitochondrial membrane potential (ΔΨm) in SH-SY5Y cells. In conclusion, our results indicated that emodin exerts neuroprotective effects against zinc by normalizing synaptic impairment by decreasing the phosphorylation of ERK1/2, reducing reactive oxygen species and protecting mitochondrial function.

Rapamycin Attenuated Zinc-Induced Tau Phosphorylation and Oxidative Stress in Rats: Involvement of Dual mTOR/p70S6K and Nrf2/HO-1 Pathways.

Alzheimer's disease is pathologically characterized by abnormal accumulation of amyloid-beta plaques, neurofibrillary tangles, oxidative stress, neuroinflammation, and neurodegeneration. Metal dysregulation, including excessive zinc released by presynaptic neurons, plays an important role in tau pathology and oxidase activation. The activities of mammalian target of rapamycin (mTOR)/ribosomal S6 protein kinase (p70S6K) are elevated in the brains of patients with Alzheimer's disease. Zinc induces tau hyperphosphorylation via mTOR/P70S6K activation in vitro. However, the involvement of the mTOR/P70S6K pathway in zinc-induced oxidative stress, tau degeneration, and synaptic and cognitive impairment has not been fully elucidated in vivo. Here, we assessed the effect of pathological zinc concentrations in SH-SY5Y cells by using biochemical assays and immunofluorescence staining. Rats (n = 18, male) were laterally ventricularly injected with zinc, treated with rapamycin (intraperitoneal injection) for 1 week, and assessed using the Morris water maze. Evaluation of oxidative stress, tau phosphorylation, and synaptic impairment was performed using the hippocampal tissue of the rats by biochemical assays and immunofluorescence staining. The results from the Morris water maze showed that the capacity of spatial memory was impaired in zinc-treated rats. Zinc sulfate significantly increased the levels of P-mTOR Ser2448, P-p70S6K Thr389, and P-tau Ser356 and decreased the levels of nuclear factor erythroid 2-related factor-2 (Nrf2) and heme oxygenase-1 (HO-1) in SH-SY5Y cells and in zinc-treated rats compared with the control groups. Increased expression of reactive oxygen species was observed in zinc sulfate-induced SH-SY5Y cells and in the hippocampus of zinc-injected rats. Rapamycin, an inhibitor of mTOR, rescued zinc-induced increases in mTOR/p70S6K activation, tau phosphorylation, and oxidative stress, and Nrf2/HO-1 inactivation, cognitive impairment, and synaptic impairment reduced the expression of synapse-related proteins in zinc-injected rats. In conclusion, our findings imply that rapamycin prevents zinc-induced cognitive impairment and protects neurons from tau pathology, oxidative stress, and synaptic impairment by decreasing mTOR/p70S6K hyperactivity and increasing Nrf2/HO-1 activity.

Dichondra repens J.R.Forst. and G.Forst.: A Review of Its Traditional Uses, Chemistry, Pharmacology, Toxicology and Applications.

Ethnopharmacology relevance: Dichondra repens J.R.Forst. and G.Forst (DRF; Convolvulaceae, called Matijin in Chinese), has been traditionally used to treat jaundice, bacillary dysentery, urinary tract infection, edema, contusions, and strains and sprains based on traditional Chinese medicine (TCM) concepts. Aim of study: This paper intends to provide a comprehensive and critical analysis of research on DRF focusing on a relationship between traditional uses and pharmacological effects, evaluating the therapeutic potential of this plant. Methods: Relevant data on DRF were retrieved from available databases. Results: The heat-clearing and detoxifying, and removing the phlegm and turbid urine effects of DRF are linked to its anti-hepatitis B virus (HBV), anti-inflammatory, and hepatoprotective activities. Especially, the hepatoprotective effects of DRF are mainly based on anti-HBV activities of phenylalanine dipeptides Matijin-Su (MTS) and its derivatives derived from this plant. Further, a phase I anti-HBV clinical trial of a candidate compound named bentysrepinine (Y101, Chinese name Tifentai) has been completed. Also, anti-tumor, analgesic, and antibacterial properties have been reported in the extracts and compounds from DRF. Although pharmacy, pharmacodynamics, toxicology, and pharmacokinetics of bentysrepinine have been systemically reported, no studies have reported chemistry, safety, pharmacology of other compounds or extracts systemically. Conclusion: Phenylalanine dipeptide compounds are main components and MTS is a characteristic substance of DRF. The main pharmacological effect of DRF is anti-HBV activity, which is coherent with the traditional use of this plant in China. Except bentysrepinine, few studies have been conducted on toxicities of the extracts or compounds from DRF. Thus, it is still necessary to evaluate safety, chemistry, pharmacology of the extracts or compounds from DRF regarding the link between traditional uses and modern applications before the future clinical trials. Bacterial sepsis, cholecystitis and tumors may be prior therapeutic targets of this plant in the future.

The phytochemistry, pharmacology and applications of Melicope pteleifolia: A review.

ETHNOPHARMACOLOGY RELEVANCE: The leaves, stems and roots of Melicope pteleifolia (Champ. ex Benth.) T.Hartley (MP; Rutaceae, called sanyaku in Chinese; syn.: Euodia lepta), have been used traditionally for the treatment of sore throat, rheumatism, eczema, dermatitis, bruises, and insect, rat, snake bites based on traditional Chinese medicine concepts. AIM OF THIS STUDY: This paper aims to provide a comprehensive and critical analysis of studies on MP and focusing on potential relationships between traditional uses and pharmacological effects, assessing the therapeutic potential as a medicine. MATERIALS AND METHODS: Relevant data on MP were retrieved using the keywords "Melicope pteleifolia", "pharmacology", "toxicity" and "applications" in databases including "Pubmed", "SciFinder", "Springer", "Elsevier", "Wiley", "Web of Science", "Google Scholar", "China Knowledge Resource Integrated databases (CNKI)", "PhD" and "MSc dissertations", and a hand-search. RESULTS AND DISCUSSION: The heat-clearing, dampness-removing and gallbladder-normalizing actions of MP have been linked to biomedical concepts like anti-inflammatory, antioxidant and hepatoprotective activities. The latter is potentially based on the presence of furaquinoline alkaloids, phenylpropanoids and flavonoids. Analgesic, antimicrobial and anti-tumor effects have also been reported. Currently limited evidence is available relating to potential toxicological risks especially of aqueous extracts with so far no reports signalling specific risks. Although some studies on the pharmacodynamics of MP have been reported, studies on action mechanisms of MP are still rare. CONCLUSIONS: In the future and prior to initiating clinical trials, the safety, in vitro and in vivo pharmacology, and mechanism of action of MP needs to be assessed, including a focus on the link between traditional uses and modern applications. In addition, phytochemical and biological studies need to conduct on flowers and fruits of MP. Furthermore, strict quality control measures are needed in the studies investigating any aspect of the pharmacology, chemistry and biology of MP.

Tau Protein and Zebrafish Models for Tau-Induced Neurodegeneration.

Tauopathies are a specific type of slow and progressive neurodegeneration, which involves intracellular deposition of fibrillar material composed of abnormal hyperphosphorylation of the microtubule associated protein (MAP) tau. Despite many years of intensive research, our understanding of the molecular events that lead to neurodegeneration is far from complete. No effective therapeutic treatments have been defined, and questions surround the validity and utility of existing animal models. It is an urgent need to develop a novel animal model to study the underlying neurodegenerative mechanisms of tauopathies. Zebrafish models of tauopathies could complement existing models by providing an in vivo platform for genetic and chemical screens in order to identify new therapeutic targets and compounds, meanwhile zebrafish models have permitted discovery of unique characteristics of these genes that could have been difficultly observed in other models. Novel transgenic zebrafish models expressing wild-type or mutant forms of human 4R-tau in neurons have recently been reported. These studies show disease-relevant changes including tau hyperphosphorylation, aggregation and somato-dendritic relocalization. This review highlights the availability of transgenic tau zebrafish models that allow more detailed biochemical studies of tau in the zebrafish CNS to characterize solubility, fibril morphology and further clarify phosphorylation proceedings. Furthermore, a deeper knowledge of the zebrafish brain and a better characterization of tau caused by alterations in neurodegenerative disorders are needed.