Increased GHS-R1a expression in the hippocampus impairs memory encoding and contributes to AD-associated memory deficits.

Growth hormone secretagogue receptor 1a (GHS-R1a), also known as the ghrelin receptor, is an important nutrient sensor and metabolic regulator in both humans and rodents. Increased GHS-R1a expression is observed in the hippocampus of both Alzheimer's disease (AD) patients and AD model mice. However, the causal relationship between GHS-R1a elevation in the hippocampus and AD memory deficits remains uncertain. Here, we find that increasing GHS-R1a expression in dCA1 pyramidal neurons impairs hippocampus-dependent memory formation, which is abolished by local administration of the endogenous antagonist LEAP2. GHS-R1a elevation in dCA1 pyramidal neurons suppresses excitability and blocks memory allocation in these neurons. Chemogenetic activation of those high GHS-R1a neurons during training rescues GHS-R1a overexpression-induced memory impairment. Moreover, we demonstrate that increasing GHS-R1a expression in dCA1 pyramidal neurons hampers these neurons' ability to encode spatial memory and reduces engram size in the dCA1 region. Finally, we show that GHS-R1a deletion mitigates spatial memory deficits in APP/PS1 mice with increased GHS-R1a expression in the hippocampus. Our findings reveal a negative, causal relationship between hippocampal GHS-R1a expression and memory encoding, and suggest that blocking the abnormal increase in GHS-R1a activity/expression may be a promising approach to improve memory and treat cognitive decline in AD.

Inorganic carbon utilization strategies of plateau aquatic plants in response to native habitats.

Aquatic plants are a crucial component of the aquatic ecosystem in the Tibetan Plateau region. Researching the adaptability of plateau aquatic plants in photosynthesis to the plateau environment can enhance understanding of the operational mechanisms of plateau ecosystems, thereby providing a scientific basis for the protection and management of plateau aquatic ecosystems. This study presents an investigation of photosynthetic inorganic carbon utilization strategies and photosynthetic efficiency of 17 aquatic plants under natural growing conditions in Niyang River basin on the Tibetan Plateau. In pH-drift experiments, 10 of 17 species were able to utilize HCO3-, and environmental factors like water pH were shown to have a significant effect on the ability of the tested species to utilize HCO3-. Titratable acidity in the leaves of Stuckenia filiformis, Zannichellia palustris, Batrachium bungei, and Myriophyllum spicatum showed significant diurnal fluctuations at certain sampling sites, indicating the presence of CAM. In B. bungei, water pH positively correlated with CAM activity, while CO2 concentration negatively correlated with CAM activity. The chlorophyll fluorescence analysis revealed that aquatic plants inhabiting the Tibetan Plateau exhibited photosynthetic adaptations. In conclusion, the aquatic plants on the Tibetan Plateau employ diverse strategies for utilizing inorganic carbon during photosynthesis, exhibiting their flexible adaptability to the native high-altitude habitats of the Tibetan Plateau.

Lysine-Polydopamine Nanocrystals Loaded with the Codrug Abemaciclib-Flurbiprofen for Oral Treatment of Cancer.

Nonsteroidal anti-inflammatory drugs (NSAIDs) combined with chemotherapeutic agents for the treatment of colorectal cancer (CRC) are a promising therapeutic strategy. NSAIDs can effectively boost the antitumor efficacy of chemotherapeutic agents by inhibiting the synthesis of COX-2. However, hazardous side effects and barriers to oral drug absorption are the main challenges for combination therapy with chemotherapeutics and NSAIDs. To address these issues, a safe and effective lysine-polydopamine@abemaciclib-flurbiprofen (Flu) codrug nanocrystal (Lys-PDA@AF NCs) was designed. Abemaciclib (Abe), a novel and effective inhibitor of the CDK4/6 enzyme, and Flu were joined to prepare Abemaciclib-Flu codrug (AF) by amide bonds, and then the AF was made into nanocrystals. Lysine-modified polydopamine was selected as a shell to encapsulate nanocrystals to enhance intestinal adhesion and penetration and lengthen the duration time of drugs in vivo. Nuclear magnetic resonance, Fourier transform infrared, Massspectrometry, X-ray photoelectron spectroscopy, Transmission electron microscopy, and drug loading were used to evaluate the physicochemical characteristics of the nanocrystals. In our study, Abe and Flu were released to exert their synergistic effect when the amide bond of AF was broken and the amide bond was sensitive to cathepsin B which is overexpressed in most tumor tissues, thus increasing the selectivity of the drug to the tumor. The results showed that Lys-PDA@AF NCs had higher cytotoxicity for CRC cell with an IC50 of 4.86 µg/mL. Additionally, pharmacokinetics showed that Abe and Flu had similar absorption rates in the Lys-PDA@AF NCs group, improving the safety of combination therapy. Meanwhile, in vivo experiments showed that Lys-PDA@AF NCs had excellent antitumor effects and safety. Overall, it was anticipated that the created Lys-PDA@AF NCs would be a potential method for treating cancer.

Progress on network modeling and analysis of gut microecology: a review.

The gut microecological network is a complex microbial community within the human body that plays a key role in linking dietary nutrition and host physiology. To understand the complex relationships among microbes and their functions within this community, network analysis has emerged as a powerful tool. By representing the interactions between microbes and their associated omics data as a network, we can gain a comprehensive understanding of the ecological mechanisms that drive the human gut microbiota. In addition, the network-based approach provides a more intuitive analysis of the gut microbiota, simplifying the study of its complex dynamics and interdependencies. This review provides a comprehensive overview of the methods used to construct and analyze networks in the context of gut microecological background. We discuss various types of network modeling approaches, including co-occurrence networks, causal networks, dynamic networks, and multi-omics networks, and describe the analytical techniques used to identify important network properties. We also highlight the challenges and limitations of network modeling in this area, such as data scarcity and heterogeneity, and provide future research directions to overcome these limitations. By exploring these network-based methods, researchers can gain valuable insights into the intricate relationships and functional roles of microbial communities within the gut, ultimately advancing our understanding of the gut microbiota's impact on human health.

Glycyrrhetinic acid modified chlorambucil prodrug for hepatocellular carcinoma treatment based on DNA replication and tumor microenvironment.

Chlorambucil (CLB) is widely used in the treatment of solid tumors. However, CLB has poor water solubility, short half-life and side effects such as leucopenia and thrombocytopenia, in addition to the inhibition of tumor immune microenvironment. In our study, chlorambucil-chitosan (CLB-CS) prodrug micelles were successfully prepared, and glycyrrhetinic acid (GA) was selected, which could improve the immunosuppressive microenvironment and actively targeted liver cancer cells. At the tumor site, CLB blocked the cell cycle and promoted apoptosis. In addition, GA improved the tumor microenvironment by increasing the proportion of CD4+T and CD8+T cells at the tumor site, and promoting the differentiation of CD4+T cells into Th1 cells, thereby reducing the proportion of Treg and Th2 cell subsets, so as to offset the adverse factors of CLB against tumor immunity. By interfering with DNA replication and modulating the tumor microenvironment, GA/CLB-CS micelles enabled the effective treatment of liver cancer.

Solid-state molecular oxygen activation using ball milling and a piezoelectric material for aerobic oxidation of thiols.

The agitation of BaTiO3 via ball milling converts mechanical energy into electrical energy, leading to the reduction of molecular oxygen via a single electron transfer pathway analogous to the photocatalytic reaction. This mechanoredox strategy for the oxidative coupling of thiols could eliminate waste and develop a recyclable methodology to accomplish organic transformations in a greener fashion, exhibiting promising potential for large-scale chemical manufacturing.

A two-step precise targeting nanoplatform for tumor therapy via the alkyl radicals activated by the microenvironment of organelles.

With the in-depth research of organelles, the microenvironment characteristics of their own, such as the acid environment of lysosomes and the high temperature environment of mitochondria, could be used as a natural and powerful condition for tumor therapy. Based on this, we constructed a two-step precise targeting nanoplatform which can realize the drug release and drug action triggered by the microenvironment of lysosomes (endosomes) and mitochondria, respectively. To begin with, the mesoporous silica nanoparticles (MSNs) were modified with triphenylphosphonium (TPP) and loaded with 2,2'-azobis[2-(2-imidazolin-2-yl) propane] dihydrochloride (AIPH). Then, folic acid (FA) targeted pH-sensitive liposomes containing docetaxel (Lipo/DTX-FA) were prepared by thin-film dispersion method, and the core-shell AIPH/MSN-TPP@Lipo/DTX-FA nanoparticles were constructed by self-assembly during the hydration of the liposomes. When this nanoplatform entered into the tumor cells through FA receptor-mediated endocytosis, the pH-sensitive liposomes were destabilized in the lysosomes, resulting in the release of DTX and AIPH/MSN-TPP nanoparticles. After that, AIPH was delivered to mitochondria by AIPH/MSN-TPP, and the alkyl radicals produced by AIPH under the high temperature environment can cause oxidative damage to mitochondria. Not only that, the DTX could enhance the anti-tumor effect of AIPH by downregulating the expression of anti-apoptotic Bcl-2 protein. The in vitro and in vivo results demonstrate that this delivery system could induce apoptosis based on organelles' s own microenvironment, which provides a new approach for tumor therapy.

A Probiotic Spore-Based Oral Autonomous Nanoparticles Generator for Cancer Therapy.

Spores, the dormant life forms of probiotics, can germinate to metabolically active vegetative cells with the disintegration of their hydrophobic protein coat in the intestinal microenvironment, which provides the possibility for the formation of nanoparticles (NPs) in vivo. Inspired by the natural physiological process of spores, herein, an oral autonomous NPs generator is developed to overcome the spatially variable gastrointestinal tract environment and multibiological barriers. Spores modified with deoxycholic acid (DA) and loaded with chemotherapeutic drugs (doxorubicin and sorafenib, DOX/SOR) serve as an autonomous production line of NPs, which can efficaciously protect the drugs passing through the rugged environment of the stomach and furthermore can be transported to the intestinal environment and colonized rapidly. Subsequently, the DOX/SOR/Spore-DA NPs are produced by the autonomous NPs generator in the intestinal regions based on the disintegrated hydrophobic protein and the hydrophilic DA, and they can efficiently penetrate the epithelial cells via the bile acid pathway, increasing basolateral drug release. In vitro and in vivo studies confirm that this biological nanogenerator can autonomously produce substantial NPs in the intestine, providing a promising strategy for cancer therapy.

An oral drug delivery system with programmed drug release and imaging properties for orthotopic colon cancer therapy.

Oral drug delivery systems (ODDSs) have attracted considerable attention in relation to orthotopic colon cancer therapy due to certain popular advantages. Unfortunately, their clinical applications are generally limited by the side-effects caused by systemic drug exposure and poor real-time monitoring capabilities. Inspired by the characteristics of pH changes of the gastrointestinal tract (GIT) and specific enzymes secreted by the colonic microflora, we anchored polyacrylic acid (PAA) and chitosan (CS) on Gd3+-doped mesoporous hydroxyapatite nanoparticles (Gd-MHAp NPs) to realize programmed drug release and magnetic resonance imaging (MRI) at the tumor sites. In particular, the grafted PAA, as a pH-responsive switch, could effect controlled drug release in the colon. Further, CS is functionalized as the enzyme-sensitive moiety, which could be degraded by ß-glycosidase in the colon. Gadolinium is a paramagnetic lanthanide element used in chelates, working as a contrast medium agent for an MRI system. Interestingly, after oral administration, CS and PAA could protect the drug-loaded nanoparticles (NPs) against variable physiological conditions in the GIT, allowing the drug to reach the colon tumor sites, preventing premature drug release. Enhanced drug concentrations at the colon tumor sites were achieved via this programmed drug release, which subsequently ameliorated the therapeutic effect. In addition, encapsulating both chemotherapeutic (5-fluorouracil, 5-FU) and targeted therapy drug (gefitinib, Gef) within Gd-MHAp NPs produced a synergistic therapeutic effect. In summary, this study demonstrated that such a novel drug system (Gd-MHAp/5-FU/Gef/CS/PAA NPs) could protect, transport, and program drug release locally within the colonic environment; further, this system exhibited a worthwhile therapeutic effect, providing a promising novel treatment strategy for orthotopic colon cancer.

Protamine-induced condensation of peptide nanofilaments into twisted bundles with controlled helical geometry.

Chiral self-assembly of peptides is of fundamental interest in the field of biology and material science. Protamine, an alkaline biomacromolecule which is ubiquitous in fish and mammalian, plays crucial roles in directing the helical twisting of DNA. Inspired by this, we reported a bioinspired pathway to direct the hierarchical chiral self-assembly of a short synthetic dipeptide. The peptide could self-assemble into negatively charged chiral micelles in water that spontaneously formed a nematic liquid crystalline phase. By incorporation with protamine, the micelles condensed with the protamine into large helical bundles with precisely controlled diameter. Furthermore, to simulate the intracellular environments, we investigated macromolecular crowding on the coassembly of peptide and protamine, which leads to the formation of much thinner helical structures. The results highlight the roles of highly charged biomacromolecules and macromolecular crowding on peptide self-assembly, which are beneficial for the practical applications of self-assembling peptides in biomedicine and sensing.

Effects of macromolecular crowding on alkaline phosphatase unfolding, conformation and stability.

The interior of the cell is tightly packed with various biological macromolecules, which affects physiological processes, especially protein folding process. To explore how macromolecular crowding may influence protein folding process, alkaline phosphatase (ALP) was chosen as a model protein, and the unfolding process of ALP induced by GdnHCl was studied in the presence of crowding agents such as PEG 4000, Dextran 70 and Ficoll 70. The effect of macromolecular crowding on the denatured state of ALP was directly probed by measuring enzyme activities, fluorescence spectroscopy and circular dichroism. From the results of circular dichroism, GdnHCl induced a biphasic change, suggesting that a three-state unfolding mechanism was involved in the denaturation process irrespective of the absence or presence of crowding agents. It was also found that crowding agents had a little impact on the unfolding process of ALP. The results of phase diagrams also demonstrated that the unfolding process of ALP induced by GdnHCl was three-state mechanism. Moreover, the results of fluorescence spectra demonstrated that with the increase of GdnHCl concentration, the structure of protein had changed, but existence of crowding agents can make protein structure more stable. Our results can provide valuable information for understanding the protein folding in vivo.

Stability of nitrofuran residues during honey processing and nitrofuran removal by macroporous adsorption resins.

There is increasing concern that the presence of antibiotics such as nitrofurans in animal-derived food products is harmful to human. This study originally assessed the effects of different honey processing steps on the stabilities of four nitrofuran metabolites (3-amino-2-oxazolidone, 1-aminohydantonin, semicarbazide and 3-amino-5-morpholinomethyl-2-oxazolidone). Macroporous adsorption resins (MARs) were evaluated for the removal of these residues. Nitrofuran metabolites were analysed by LC-MS/MS after each processing step. The results revealed that honey processing reduced nitrofuran metabolites in honey and the total loss was from 56.6% to 90.4%. Furthermore, LS-901 was the optimum MAR with adsorption rates of 69.9-91.8% for four metabolites. After removing nitrofuran metabolites, the honey could be safely used as winter feed for honeybees.