Aberration of social behavior and gut microbiota induced by cross-fostering implicating the gut-brain axis.

The gut microbiota and neurological development of neonatal mice are susceptible to environmental factors that may lead to altered behavior into adulthood. However, the role that changed gut microbiota and neurodevelopment early in life play in this needs to be clarified. In this study, by modeling early-life environmental changes by cross-fostering BALB/c mice, we revealed the effects of the environment during the critical period of postnatal development on adult social behavior and their relationship with the gut microbiota and the nervous system. The neural projections exist between the ascending colon and oxytocin neurons in the paraventricular nuclei (PVN), peripheral oxytocin levels and PVN neuron numbers decreased after cross-fostering, and sex-specific alteration in gut microbiota and its metabolites may be involved in social impairments and immune imbalances brought by cross-fostering via the gut-brain axis. Our findings also suggest that social cognitive impairment may result from a combination of PVN oxytocinergic neurons, gut microbiota, and metabolites.

Oxytocin neurons in the paraventricular nucleus and fear empathy among male mice.

BACKGROUND: Recent studies have identified empathy deficit as a core impairment and diagnostic criterion for people with autism spectrum disorders; however, the improvement of empathy focuses primarily on behavioural interventions without the target regulation. We sought to compare brain regions associated with empathy-like behaviours of fear and pain, and to explore the role of the oxytocin-oxytocin receptor system in fear empathy. METHODS: We used C57BL mice to establish 2 models of fear empathy and pain empathy. We employed immunofluorescence histochemical techniques to observe the expression of c-Fos throughout the entire brain and subsequently quantified the number of c-Fos-positive cells in different brain regions. Furthermore, we employed chemogenetic technology to selectively manipulate these neurons in Oxt-Cre-/+ mice to identify the role of oxytocin in this process. RESULTS: The regions activated by fear empathy were the anterior cingulate cortex, basolateral amygdala, nucleus accumbens, paraventricular nucleus (PVN), lateral habenula, and ventral and dorsal hippocampus. The regions activated by pain empathy were the anterior cingulate cortex, basolateral amygdala, nucleus accumbens, and lateral habenula. We found that increasing the activity of oxytocin neurons in the PVN region enhanced the response to fear empathy. This enhancement may be mediated through oxytocin receptors. LIMITATIONS: This study included only male animals, which restricts the broader interpretation of the findings. Further investigations on circuit function need to be conducted. CONCLUSION: The brain regions implicated in the regulation of fear and pain empathy exhibit distinctions; the activity of PVN neurons was positively correlated with empathic behaviour in mice. These findings highlight the role of the PVN oxytocin pathway in regulating fear empathy and suggest the importance of oxytocin signalling in mediating empathetic responses.

Predictive value of a reduction in the level of high-density lipoprotein-cholesterol in patients with non-small-cell lung cancer undergoing radical resection and adjuvant chemotherapy: a retrospective observational study.

BACKGROUND: Cancer patients often exhibit chemotherapy-associated changes in serum lipid profiles, however, their prognostic value before and after adjuvant chemotherapy on survival among non-small-cell lung cancer (NSCLC) patients is unknown. METHODS: NSCLC patients undergoing radical resection and subsequent adjuvant chemotherapy from 2013 to 2017 at Sun Yat-sen University Cancer Center were retrospectively reviewed. Fasted serum lipid levels were measured before and after chemotherapy. The optimal lipid cut-off values at baseline and fluctuation were determined using X-tile™. The fluctuations in serum lipid levels and disease-free survival (DFS) were assessed. RESULTS: Serum cholesterol, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein-cholesterol (HDL-C), triglyceride, apolipoprotein (Apo) A-I, and ApoB all significantly increased after adjuvant chemotherapy. X-tile determined 1.52 mmol/L of HDL-C and 0.74 g/L of ApoB as the optimal cut-off values before chemotherapy. Patients with HDL-C ≥ 1.52 mmol/L (median DFS: not reached vs. 26.30 months, P = 0.0005) and a decreased HDL-C level after adjuvant chemotherapy (median DFS: 80.43 vs. 26.12 months, P = 0.0204) had a longer DFS. An HDL-C level that increased by ≥ 0.32 mmol/L after chemotherapy indicated a worse DFS. A high baseline ApoB level were associated with a superior DFS. In the univariate analysis and the multivariate Cox analyses, a high baseline HDL-C level and a HDL-C reduction after adjuvant chemotherapy were independent indicators for superior DFS. High baseline HDL-C was related to N0-1 stage (χ2 = 6.413, P = 0.011), and HDL-C fluctuation was significantly correlated with specific chemotherapy regimens (χ2 = 5.002, P = 0.025). CONCLUSIONS: Adjuvant chemotherapy increased various lipid levels in resected NSCLC patients. A higher HDL-C level before chemotherapy and a reduced HDL-C level after adjuvant chemotherapy were independent predictors of longer DFS in patients with curable NSCLC.

Phosphorus Co-Existing in Water: A New Mechanism to Boost Boron Removal by Calcined Oyster Shell Powder.

The removal of boron (B) from water by co-precipitation with hydroxyapatite (HAP) has been extensively studied due to its low cost, ease of use and high efficiency. However, there is no explicit mechanism to express how resolved B was trapped by HAP. Thus, in this work, the process of removing B from water was studied using a low-cost calcium (Ca) precipitation agent derived from used waste oyster shells. The results showed that the removal rate of B in the simulated wastewater by calcined oyster shell (COS) in the presence of phosphorus (P) is up to more than 90%, as opposed to virtually no removal without phosphate. For B removal, the treated water needs to be an alkaline solution with a high pH above 12, where B is removed as [CaB(OH)4]+ but is not molecular. Finally, the synergistic mechanism of co-precipitation between HAP and dissolved B, occlusion co-precipitation, was explained in detail. The proposed method discovered the relationship between Ca, P and B, and was aimed at removing B without secondary pollution through co-precipitation.

[Regulation of extracellular ATP onchlorophyll content and fluorescence characteristics of Angelica sinensis seedlings under drought and low temperature stress].

As an important signal molecule, extracellular ATP(eATP) can regulate many physiological and biochemical responses to plant stress. In this study, the regulation of extracellular ATP(eATP) on chlorophyll content and chlorophyll fluorescence parameters of Angelica sinensis seedlings were studied under drought and low temperature stress. The results showed that all the chlorophyll content, the actual photochemical efficiency [Y(Ⅱ)], the electron transfer rate(ETR), the photochemical quenching coefficient(qP and qL) of A. sinensis leaves were significantly decreased under drought and low temperature stress, respectively. At the same time, non-photochemical quenching(NPQ and qN) were also all significantly increased, respectively. The application of eATP alleviated the decrease of chlorophyll content, Y(Ⅱ), ETR, qP and qL of A. sinensis leaves under drought and low temperature stress, and eliminated the increase of qN and NPQ. The results indicated that eATP could effectively increase the open ratio of PSⅡ reaction centers, and improve the electron transfer rate and light energy conversion efficiency of PSⅡ of A. sinensis leaves under drought and low temperature stress. It is beneficial to enhance the chlorophyll synthesis and the adaptability of PSⅡ about A. sinensis seedlings to drought and low temperature stress.

High salt diet exacerbates cognitive deficits and neurovascular abnormalities in APP/PS1 mice and induces AD-like changes in wild-type mice.

High salt diet (HSD) is a risk factor of hypertension and cardiovascular disease. Although clinical data do not clearly indicate the relationship between HSD and the prevalence of Alzheimer's disease (AD), animal experiments have shown that HSD can cause hyperphosphorylation of tau protein and cognition impairment. However, whether HSD can accelerate the progression of AD by damaging the function of neurovascular unit (NVU) in the brain is unclear. Here, we fed APP/PS1 mice (an AD model) or wild-type mice with HSD and found that the chronic HSD feeding increased the activity of enzymes related to tau phosphorylation, which led to tau hyperphosphorylation in the brain. HSD also aggravated the deposition of Aß42 in hippocampus and cortex in the APP/PS1 mice but not in the wild-type mice. Simultaneously, HSD caused the microglia proliferation, low expression of Aqp-4, and high expression of CD31 in the wild-type mice, which were accompanied with the loss of pericytes (PCs) and increase in blood brain barrier (BBB) permeability. As a result, wild-type mice fed with HSD performed poorly in Morris Water Maze and object recognition test. In the APP/PS1 mice, HSD feeding for 8 months worsen the cognition and accompanied the loss of PCs, the activation of glia, the increase in BBB permeability, and the acceleration of calcification in the brain. Our data suggested that HSD feeding induced the AD-like pathology in wild-type mice and aggravated the development of AD-like pathology in APP/PS1 mice, which implicated the tau hyperphosphorylation and NVU dysfunction.

A series of fluorescent dyes based on 4-phenylacetylene-1,8-naphthalimide: Synthesis, theoretical calculations, photophysical properties and application in two-color imaging and dynamic behavior monitoring of lipid droplets and lysosomes.

A series of fluorescent dyes (NapPAs) based on 4-phenylacetylene-1,8-naphthalimide were synthesized and characterized, whose conjugated structures were extended by the introduction of phenylethynyl. Furthermore, changes in the photophysical properties of the dyes when substituents with varying electron richness were introduced at the p-position of phenylacetylene were studied. The theoretical calculation of the dye molecules was carried out by B3LYP functional and 6-31G(d,p) basis set, and the effects of different substituents at the p-position of phenylacetylene on the electronic structure and photophysical properties of the dyes were studied by theoretical calculation results. Theoretical calculations provided a reliable means of predicting the properties of dyes, which could help in the design of more efficient and novel dyes. To verify the practicability of the dyes, two dyes with excellent photophysical properties (large Stokes shift, high polarity-viscosity sensitivity, good biocompatibility) were selected as fluorescent probes for visualization of LDs and two-color imaging of LDs and lysosomes. Cell imaging showed that NapPA-LDs and NapPA-LDs-Lyso serve as excellent imaging tools to monitor the dynamic changes, movements, and behaviors of LDs and lysosomes in real time. Notably, NapPA-LDs-Lyso held promise as a potential tool to study the interaction between LDs and lysosomes.

Synergistic effects of hIAPP and Aß1-42 impaired the olfactory function associated with the decline of adult neurogenesis in SVZ.

According to many in the field，the prevalence of Alzheimer's disease (AD) in type II diabetes (T2DM) populations is considerably higher than that in the normal population. Human islet amyloid polypeptide (hIAPP) is considered to be a common risk factor for T2DM and AD. Preliminary observations around T2DM animal model show that the decrease of adult neural stem cells (NSCs) in the subventricular zone (SVZ) is accompanied by olfactory dysfunction. Furthermore, impaired olfactory function could serve as to an early predictor of neurodegeneration，which is associated with cognitive impairment. However, the synergistic effects between hIAPP and amyloid-beta (Aß) 1-42 in the brain and the neurodegeneration remains to be further clarified. In this study, olfactory capacity, synaptic density, status of NSC in SVZ, and status of newborn neurons in olfactory bulb (OB) were assessed 6 months after stereotactic injection of oligomer Aß1-42 into the dens gyrus (DG) of hIAPP-/+ mice or wild-type homogenous mice. Our results set out that Aß42 and amylin co-localized into OB and raised Aß42 deposition in hIAPP-/+ mice compared with wild-type brood mice. In addition, 6 months after injection of Aß1-42 in hIAPP-/+ mice, these mice showed increased olfactory dysfunction, significant loss of synapses, depletion of NSC in SVZ, and impaired cell renewal in OB. Our present study suggested that the synergistic effects between hIAPP and Aß1-42 impairs olfactory function and was associated with decreased neurogenesis in adults with SVZ.

HIF-1α inhibition promotes the efficacy of immune checkpoint blockade in the treatment of non-small cell lung cancer.

The response to immune checkpoint inhibitors (ICIs) monotherapy remains unsatisfactory in patients with NSCLC. Thus, combining ICIs with other potential modalities is of great significance to enhance the response of single drug alone. Here, we identified that HIF-1α inhibition was capable of promoting anti-tumor immunity in NSCLC. We applied NSCLC cell lines and mouse models to evaluate the synergy of combined HIF-1α inhibition and PD-1 blockade on tumor growth and the function of tumor infiltrating lymphocytes (TILs). Public datasets were utilized to investigate patients' prognosis based on expressions of HIF-1α and LOXL2 as well as EMT-associated markers and CD8+ TILs. Moreover, we explored the correlation between HIF-1α and LOXL2 levels and CD8+ TILs in tumor samples from patients with NSCLC by immunohistochemistry, as well as their association to patients' survival. In vitro, PX-478, an HIF-1α inhibitor, promoted tumor cell apoptosis induced by T cells when combined with ICIs. Furthermore, mice treated with PX-478 and anti-PD-1 antibodies exhibited a marked delay in tumor growth and prolonged survival, which correlated with increased TILs and granzyme B secretion. Besides, patients with high HIF-1α expression exhibited high levels of EMT-related markers and low TILs, indicating an immunosuppressive phenotype. Mechanistically, we observed that HIF-1α inhibition suppressed the EMT phenotypes induced by hypoxia and further alleviated tumor immunosuppression, which was related to blockage of HIF-1α/LOXL2 signaling pathway. In summary, we identified that HIF-1α inhibition could synergize with anti-PD-1 to impair tumor growth in vitro and in vivo. Our data suggest that HIF-1α inhibitors represent a promising treatment to enhance anti-tumor immunity and provide preclinical rationale to evaluate the combination of ICIs with HIF-1α inhibition clinically in NSCLC.

Rotenone aggravates PD-like pathology in A53T mutant human α-synuclein transgenic mice in an age-dependent manner.

Multiple factors such as genes, environment, and age are involved in developing Parkinson's disease (PD) pathology. However, how various factors interact to cause PD remains unclear. Here, 3-month and 9-month-old hα-syn+⁣/- mice were treated with low-dose rotenone for 2 months to explore the mechanisms that underline the environment-gene-age interaction in the occurrence of PD. We have examined the behavior of mice and the PD-like pathologies of the brain and gut. The present results showed that impairments of the motor function and olfactory function were more serious in old hα-syn+/- mice with rotenone than that in young mice. The dopaminergic neuron loss in the SNc is more in old hα-syn+/- mice with rotenone than in young mice. Expression of hα-syn+/- is increased in the SNc of hα-syn+/- mice following rotenone treatment for 2 months. Furthermore, the number of activated microglia cells increased in SNc and accompanied the high expression of inflammatory cytokines, namely, TNF-α and IL-18 in the midbrain of old hα-syn+/- mice treated with rotenone. Meanwhile, we found that after treatment with rotenone, hα-syn positive particles deposited in the intestinal wall, intestinal microflora, and T lymphocyte subtypes of Peyer's patches changed, and intestinal mucosal permeability increased. Moreover, these phenomena were age-dependent. These findings suggested that rotenone aggravated the PD-like pathologies and affected the brain and gut of human α-syn+/- transgenic mice in an age-dependent manner.

Gemcitabine and APG-1252, a novel small molecule inhibitor of BCL-2/BCL-XL, display a synergistic antitumor effect in nasopharyngeal carcinoma through the JAK-2/STAT3/MCL-1 signaling pathway.

Advanced nasopharyngeal carcinoma (NPC) has a poor prognosis, with an unfavorable response to palliative chemotherapy. Unfortunately, there are few effective therapeutic regimens. Therefore, we require novel treatment strategies with enhanced efficacy. The present study aimed to investigate the antitumor efficacy of APG-1252-M1, a dual inhibitor of BCL-2/BCL-XL, as a single agent and combined with gemcitabine. We applied various apoptotic assays and used subcutaneous transplanted NPC model to assess the in vitro and in vivo antitumor activity. Moreover, phospho-tyrosine kinase array was used to investigate the combined therapy's potential synergistic mechanism. In addition, further validation was performed using immunohistochemistry and western blotting. In vitro, we observed that APG-1252-M1 had moderate antitumor activity toward NPC cells; however, it markedly improved gemcitabine's ability to promote NPC cell apoptosis and suppress invasion, migration, and proliferation. Specifically, APG-1252 plus gemcitabine exhibited even remarkable antitumor activity in vivo. Mechanistically, the drug combination synergistically suppressed NPC by activating caspase-dependent pathways, blocking the phospho (p)-JAK-2/STAT3/MCL-1 signaling pathway, and inhibiting epithelial-mesenchymal transition. In conclusion, the results indicated that the combination of APG-1252 and gemcitabine has synergistic anticancer activities against NPC, providing a promising treatment modality for patients with NPC.

Interaction of human IAPP and Aß1-42 aggravated the AD-related pathology and impaired the cognition in mice.

Alzheimer's disease (AD) and type 2 diabetes mellitus (T2DM) have a common pathology. Both diseases are characterized by local deposition of amyloid proteins in the brain or islet organ, but their phenotypes and clinical manifestation vary widely. Although the sources of islet amyloid polypeptide (IAPP) and amyloid beta (Aß) are independent, their fibrillar sequences are highly homologous. The prevalence of AD in T2DM populations is considerably higher than that in the normal population, but a mechanistic linkage remains elusive. Therefore, the present study aimed to explore the effects of Aß42 deposition in the brain on the persistently expression of human IAPP (hIAPP). Additionally, cognitive ability, synaptic plasticity, the state of neural stem cells and mitochondrial function were evaluated at 2 or 6 months after stereotaxically injected the oligomer Aß1-42 into the dentate gyrus of hIAPP (-/+) mice or the wild-type littermates. We found that Aß42 and amylin were co-located in hippocampus and Aß42 levels increased when Aß1-42 was injected in hIAPP transgenic mice compared with that of the wild-type littermates. Furthermore, at 6 months after Aß1-42 injection in hIAPP (-/+) mice, it exhibits exacerbated AD-related pathologies including Aß42 deposition, cognitive impairment, synapse reduction, neural stem cells exhaustion and mitochondrial dysfunction. Our present study suggested that hIAPP directly implicated the Aß42 production and deposition as an important linkage between T2DM and AD.