GSDME-mediated pyroptosis promotes anti-tumor immunity of neoadjuvant chemotherapy in breast cancer.

Paclitaxel and anthracycline-based chemotherapy is one of the standard treatment options for breast cancer. However, only about 6-30% of breast cancer patients achieved a pathological complete response (pCR), and the mechanism responsible for the difference is still unclear. In this study, random forest algorithm was used to screen feature genes, and artificial neural network (ANN) algorithm was used to construct an ANN model for predicting the efficacy of neoadjuvant chemotherapy for breast cancer. Furthermore, digital pathology, cytology, and molecular biology experiments were used to verify the relationship between the efficacy of neoadjuvant chemotherapy and immune ecology. It was found that paclitaxel and doxorubicin, an anthracycline, could induce typical pyroptosis and bubbling in breast cancer cells, accompanied by gasdermin E (GSDME) cleavage. Paclitaxel with LDH release and Annexin V/PI doubule positive cell populations, and accompanied by the increased release of damage-associated molecular patterns, HMGB1 and ATP. Cell coculture experiments also demonstrated enhanced phagocytosis of macrophages and increased the levels of IFN-γ and IL-2 secretion after paclitaxel treatment. Mechanistically, GSDME may mediate paclitaxel and doxorubicin-induced pyroptosis in breast cancer cells through the caspase-9/caspase-3 pathway, activate anti-tumor immunity, and promote the efficacy of paclitaxel and anthracycline-based neoadjuvant chemotherapy. This study has practical guiding significance for the precision treatment of breast cancer, and can also provide ideas for understanding molecular mechanisms related to the chemotherapy sensitivity.

SSK1-Loaded Neurotransmitter-Derived Nanoparticles for Alzheimer's Disease Therapy via Clearance of Senescent Cells.

Age is a significant contributor to the onset of AD. Senolysis has been recently demonstrated to ameliorate aging-associated diseases that showing a great potential in AD therapy. However, due to the presence of BBB, the anti-AD activity of senolytics are significantly diminished. SSK1 is a prodrug that can be activated by ß-gal, a lysosomal enzyme commonly upregulated in senescent cells, and thus selectively eliminates senescent cells. Furthermore, the level of ß-gal is significantly correlated with conventional AD genes from clinical sequencing data. SSK1-loaded neurotransmitter -derived lipid nanoparticles are herein developed (SSK1-NPs) that revealing good BBB penetration and bioavailability of in the body. At the brain lesion, SSK1-NP treatment significantly reduces the expression of genes associated with senescence, induced senescent cells elimination, decreased amyloid-beta accumulation, and eventually improve cognitive function of aged AD mice. SSK1-NPs, a novel nanomedicine displaying potent anti-AD activity and excellent safety profile, provides a promising strategy for AD therapy.

The use of selenomethionine to reduce ammonia toxicity in porcine spleen by inhibiting endoplasmic reticulum stress and autophagy mediated by oxidative stress.

Ammonia (NH3) is a typical pollutant in the atmosphere and is well known for its harmful effects on plants, animals as well as human health. Previous studies have shown that NH3 exposure can cause damage to immune organs and impaired immune function in animals. Selenomethionine is a kind of organic selenium, which can not only promote the growth and development of the body, but also inhibit the generation of intracellular reactive oxygen species (ROS), and effectively improve the immune function of the body. Therefore, this study evaluated the toxic effect of NH3 exposure on spleen from a new perspective and investigated the protective effect of selenomethionine on ammonia-induced immunotoxicity. Twenty-four Large White*Duroc*Min pigs were randomly assigned to 4 groups: control group, NH3 group, selenium group, and NH3 + selenium group. Our results showed that NH3 inhalation caused autophagy in the pig spleen, a decrease in lymphocytes, and an increase in autophagic vesicles. Also, NH3 exposure led to a decrease in the activity of some antioxidant enzymes (decreased by about 50%) and a significant increase in the expression of genes related to oxidative stress and endoplasmic reticulum stress (ERS). Our results indicated that selenomethionine mitigated ammonia toxicity in pigs (alleviated about 20-55%). In summary, our findings should be of value in providing a theoretical basis for revealing the toxicity of the high-risk gas NH3, and providing a new perspective on the mechanism of Se against toxic substances.

Cadmium induces testosterone synthesis disorder by testicular cell damage via TLR4/MAPK/NF-κB signaling pathway leading to reduced sexual behavior in piglets.

Cadmium (Cd) is a highly toxic metal pollutant that can endanger the life and health of animals. Toll-like receptor 4 (TLR4) can result in testicular cell damage by positively regulating mitogen-activated protein kinase (MAPK)/nuclear factor-kappaB (NF-κB) signaling pathway. Meanwhile, Testosterone (T) synthesis disorder can affect sexual behavior. However, the harmful influence of Cd on animal sexual behavior during its growth and development and the role of TLR4/MAPK/NF-κB signaling pathway in testicular cell damage and testosterone production remained poorly understood. Forty-two-day-old male piglets were fed with diets that contained CdCl2 (20 mg Cd/kg) for 40 days to explore the toxic effects of Cd on sexual behavior. The results showed that Cd activated TLR4, promoted MAPK (p-ERK, p-JNK, and p-p38)/NF-κB expression, induced apoptosis (Caspase-3, Cleaved Caspase3, Bax, Cyt-c, and Caspase-9 expression increased, but Bcl-2 expression decreased) and necroptosis (MLKL, RIPK1, and RIPK3 expression increased) in piglet testis. In addition, Cd exposure decreased mRNA expression of STAR, CYP11A1, 3ß-HSD, CYP17A1, and 17ß-HSD of testis and the concentrations of T and thyroid-stimulating hormone (TSH). Both the mRNA and protein expression levels of the major genes in TLR4/MAPK/NF-κB signaling pathway, apoptosis signaling pathway, and necroptosis signaling pathway increased significantly and the expression levels of testosterone decreased gradually in pig Leydig cells cultured in vitro after being treated with different concentrations of Cd. Moreover, Cd reduced sexual behavior (the parameters of sniffing, chin resting, and mounting decreased) in piglets. In conclusion, Cd induced testicular cell damage via TLR4/MAPK/NF-κB signaling pathway leading to testosterone synthesis disorder and sexual behavior reduction in piglets.

Immunosuppression, oxidative stress, and apoptosis in pig kidney caused by ammonia: Application of transcriptome analysis in risk assessment of ammonia exposure.

Ammonia (NH3) is a recognized environmental contaminant around the world and has adverse effects on animal and human health. However, the mechanism of the renal toxicity of NH3 is not well understood. Pigs are considered an ideal model for biomedical and toxicological research because of the similarity to humans in physiological and biochemical basis. Therefore, in this study, twelve pigs were selected as research objects and randomly divided into two groups, namely the control group and the NH3 group. The formal experiment lasted 30 days. The effects of excessive NH3 inhalation on the kidney of fattening pig were evaluated by chemical analysis, ELISA, transcriptome analysis and real-time quantitative PCR (qRT-PCR) from the renal antioxidant level, renal function, blood ammonia content and gene level. Our results showed that excessive NH3 exposure could cause an increase in blood NH3 content, a reduction in renal GSH-Px, SOD and GSH, as well as an increase in MDA levels and an increase in serum creatinine, urea and uric acid levels. In addition, transcriptome analysis showed that NH3 exposure caused changes in 335 differentially expressed genes (DEGs) (including 126 up-regulated DEGs and 109 down-regulated DEGs). Some highly expressed DEGs were enriched into GO terms associated with immune function, oxidative stress, and apoptosis and were verified by qRT-PCR. The qRT-PCR results were comsistent with the transcriptome results. Our results indicated that NH3 exposure could cause changes in renal transcriptional profiles and kidney function, and induce kidney damage in the fattening pigs through oxidative stress, immune dysfunction and apoptosis. Our present study provides novel insights into the immunotoxicity mechanism of NH3 on kidney.

Exposure to the environmental pollutant ammonia causes changes in gut microbiota and inflammatory markers in fattening pigs.

Ammonia (NH3) is a major pollutant in livestock houses and atmospheric environment. It has been demonstrated that NH3 can cause a series of damage to animals and human. However, toxicity evaluation of NH3 on farm animals was rarely reported, especially in the intestinal microflora. Therefore, in this study, twenty-four 125-day-old fattening pigs were randomly divided into 4 groups: control group, NH3 group (88.2 mg m-3 < NH3 concentration < 90.4 mg m-3), Se group (Se content: 0.5 mg kg-1), and NH3 + Se group (88.2 mg m-3 < NH3 concentration < 90.4 mg m-3, Se content: 0.5 mg kg-1), and the effects of NH3 and L-Selenomethionine on the microbiota composition in the jejunum and the levels of inflammatory markers in feces of fattening pigs were examined by 16S rDNA and ELISA, respectively. Our results showed that the content of Matrix metalloproteinase-9 (MMP-9), Myeloperoxidase (MPO), Lactoferrin (LTF) and Calprotectin in the ammonia group (A group) were significantly elevated compared to the control group, and the content of MMP-9, MPO, LTF and Calprotectin in the A + Se group were significantly reduced. A significant difference in microbiota composition in the phylum, class, family and genus levels was found in the A group and the NH3 + Se group. There was a negative correlation between Streptococcus and Calprotectin. Our results indicated that excessive NH3 inhalation could cause changes in inflammatory markers and beta diversity of intestinal microflora in fattening pigs. We found there was a positive correlation between MPO and Pseudomonas. In addition, we first proposed that L-Selenomethionine could improve the imbalance of microbial flora and the inflammatory injury caused by NH3. Changes in intestinal microflora and inflammatory markers can be used as important indicators to evaluate NH3 toxicity, and studying changes in intestinal microflora is also an important mechanism to reveal NH3 toxicity.

Wearable Sweat Band for Noninvasive Levodopa Monitoring.

Levodopa is the standard medication clinically prescribed to patients afflicted with Parkinson's disease. In particular, the monitoring and optimization of levodopa dosage are critical to mitigate the onset of undesired fluctuations in the patients' physical and emotional conditions such as speech function, motor behavior, and mood stability. The traditional approach to optimize levodopa dosage involves evaluating the subjects' motor function, which has many shortcomings due to its subjective and limited quantifiable nature. Here, we present a wearable sweat band on a nanodendritic platform that quantitatively monitors levodopa dynamics in the body. Both stationary iontophoretic induction and physical exercise are utilized as our methods of sweat extraction. The sweat band measures real-time pharmacokinetic profiles of levodopa to track the dynamic response of the drug metabolism. We demonstrated the sweat band's functionalities on multiple subjects with implications toward the systematic administering of levodopa and routine management of Parkinson's disease.

From predator to protector: Myxococcus fulvus WCH05 emerges as a potent biocontrol agent for fire blight.

Fire blight, caused by the Gram-negative bacterium Erwinia amylovora, poses a substantial threat to pome fruit production worldwide. Despite existing control strategies, a pressing need remains for sustainable and environmentally friendly fire blight management. Myxobacteria, renowned for their predatory behavior and potent enzymes, emerge as a groundbreaking biocontrol approach with significant potential. Here, we report the biocontrol potential of a novel Myxococcus fulvus WCH05, against E. amylovora. Using various in vitro and planta assays, we demonstrated the multifaceted biocontrol abilities of strain WCH05. In plate predation assays, strain WCH05 exhibited not only strong predation against E. amylovora but also broad-spectrum activities against other plant pathogenic bacteria. Pre-treatment with strain WCH05 significantly decreased pear blossom blight incidence in detached inflorescence assays, achieving a controlled efficacy of 76.02% that rivaled the antibiotic streptomycin (79.79%). In greenhouse trials, strain WCH05 effectively reduced the wilting rate and disease index in young pear seedlings, exhibiting both protective (73.68%) and curative (68.66%) control. Further investigation revealed that the biocontrol activity of strain WCH05 relies on both direct contact and extracellular enzyme secretion. While cell extracts lacked inhibitory activity, ammonium sulfate-precipitated secreted proteins displayed potent lytic activity against E. amylovora. Substrate spectrum analysis identified peptidases, lipases, and glycosidases among the secreted enzymes, suggesting their potential roles in pathogen degradation and biocontrol efficacy. This study presents the first evidence of Myxococcus fulvus WCH05 as a biocontrol agent against fire blight. Its potent predatory abilities and enzymatic arsenal highlight its potential for sustainable disease management in pome fruit production. Future research will focus on identifying and characterizing specific lytic enzymes and optimizing strain WCH05 application strategies for field efficacy.

Systemic Administration of Neurotransmitter-Derived Lipidoids-PROTACs-DNA Nanocomplex Promotes Tau Clearance and Cognitive Recovery for Alzheimer's Disease Therapy.

Alzheimer's disease (AD) poses a significant burden on the economy and healthcare systems worldwide. Although the pathophysiology of AD remains debatable, its progression is strongly correlated with the accumulation of tau aggregates. Therefore, tau clearance from brain lesions can be a promising strategy for AD therapy. To achieve this, the present study combined proteolysis-targeting chimera (PROTAC), a novel protein-degradation technique that mediates degradation of target proteins via the ubiquitin-proteasome system, and a neurotransmitter-derived lipidoid (NT-lipidoid) nanoparticle delivery system with high blood-brain barrier-penetration activity, to generate a novel nanomedicine named NPD. Peptide 1, a cationic tau-targeting PROTAC is loaded onto the positively charged nanoparticles using DNA-intercalation technology. The resulting nanomedicine displayed good encapsulation efficiency, serum stability, drug release profile, and blood-brain barrier-penetration capability. Furthermore, NPD potently induced tau clearance in both cultured neuronal cells and the brains of AD mice. Moreover, intravenous injection of NPD led to a significant improvement in the cognitive function of the AD mice, without any remarkable abnormalities, thereby supporting its clinical development. Collectively, the novel nanomedicine developed in this study may serve as an innovative strategy for AD therapy, since it effectively and specifically induces tau protein clearance in brain lesions, which in turn enhances cognition.

AMPK inhibition sensitizes acute leukemia cells to BH3 mimetic-induced cell death.

BH3 mimetics, including the BCL2/BCLXL/BCLw inhibitor navitoclax and MCL1 inhibitors S64315 and tapotoclax, have undergone clinical testing for a variety of neoplasms. Because of toxicities, including thrombocytopenia after BCLXL inhibition as well as hematopoietic, hepatic and possible cardiac toxicities after MCL1 inhibition, there is substantial interest in finding agents that can safely sensitize neoplastic cells to these BH3 mimetics. Building on the observation that BH3 mimetic monotherapy induces AMP kinase (AMPK) activation in multiple acute leukemia cell lines, we report that the AMPK inhibitors (AMPKis) dorsomorphin and BAY-3827 sensitize these cells to navitoclax or MCL1 inhibitors. Cell fractionation and phosphoproteomic analyses suggest that sensitization by dorsomorphin involves dephosphorylation of the proapoptotic BCL2 family member BAD at Ser75 and Ser99, leading BAD to translocate to mitochondria and inhibit BCLXL. Consistent with these results, BAD knockout or mutation to BAD S75E/S99E abolishes the sensitizing effects of dorsomorphin. Conversely, dorsomorphin synergizes with navitoclax or the MCL1 inhibitor S63845 to induce cell death in primary acute leukemia samples ex vivo and increases the antitumor effects of navitoclax or S63845 in several xenograft models in vivo with little or no increase in toxicity in normal tissues. These results suggest that AMPK inhibition can sensitize acute leukemia to multiple BH3 mimetics, potentially allowing administration of lower doses while inducing similar antineoplastic effects.

[Effect of shuganjianpifang on the expression of BCL-2 and BAX in rats livers with hepatic fibrosis].

OBJECTIVE: To observe the effect of shuganjianpifang on BCL-2, BAX expressions in livers of hepatic fibrosis rats and its mechanism. METHODS: Sixty SD rats were randomly divided into six groups. Rat liver fibrosis was induced by CCl4 twice a week for 12 weeks. Shuganjianpifang was used daily via lavage at 7th week for 6 weeks. The contents of ALT, AST, T-BiL and Alb in serum were measured. Liver samples were taken to examine the degree of liver fibrosis by HE staining. The experessions of BCL-2 and BAX were detected by immunohisto chemistry. The expression of BCL-2, BAX mRNA was detected by RT-PCR technology. RESULTS: As compared with the fibrotic model group, shuganjianpifang significantly reduced histopathological change, such as steatosis, deposition, decreased the contents of ALT, AST and T-BiL, up-regulated the expression of Alb. Meanwhile shuganjianpifang could effectively inhibit the expression of BAX, significantly enhanced the expression BCL-2 in liver fibrosis rats. CONCLUSION: Shuganjianpifang can resist hepatic fibrosis possibly by up-regulating BCL-2 expression and down-regulating BAX expression.

[Effects of extracts from ziziphi spinosae semen and schisandrae chinensis fructus on amino acid neurotransmitter in rats with insomnia induced by PCPA].

OBJECTIVE: To observe the effects of extract from Ziziphus Spinosa Semen and Schisandrae Chinensis Fructus on the content of amino acid neurotransmitter in the hypothalamus of insomnia rats induced by P-Chlorophenylalanine (PCPA) and its mechanism. METHODS: The model of insomnia rats were established by PCPA intraperitoneal injection, after the modeling, all the therapeutic group were treated with corresponding drug for one week. The hypothalamus pathological changes of the rats were observed. The contents of GABA, Glu in the hypothalamus were detected by Elisa. The GABA, Glu protein expression were detected by immunohistochemical. GABA(A), R(alpha1) and GABA(A)R(gamma2) mRNA expressions were detected by RT-PCR. RESULTS: Compared with model group, the content of GABA in the hypothalamus of rats increased obviously in the alcohol-water group (P < 0.05 or P < 0.01), while the content of Glu decreased obviously (P < 0.05 or P < 0.01). CONCLUSION: The extract from Ziziphus Spinosae Semen and Schisandrae Chinensis Fructus has obviously Sedative-hypnotic effect. Its mechanism may be related to regulating the content of amino acid neurotransmitter in the hypothalamus of rats.

A comparison of the efficacy of tocilizumab versus azathioprine for neuromyelitis optica spectrum disorder: A study protocol for systematic review and meta-analysis.

BACKGROUND: Neuromyelitis optica spectrum disorder (NMOSD) is a chronic inflammatory disease of the nervous system, which is frequently accompanied by a pathological humoral immune response against aquaporin-4 water channel. The most common feature of the disorder is recurrent episodes of longitudinally extensive transverse myelitis and optic neuritis. Frequent relapse leads to the gradual accumulation of neurological dysfunction. Azathioprine (AZA) is an empirical attack -preventive immunotherapies drug to prevent the relapse of NMOSD, and tocilizumab (TCZ) has been also reported reduce the activity of NMOSD. Therefore, we designed this systematic review and meta-analysis to evaluate the efficacy between TCZ and AZA in the treatment of NMOSD patients. METHODS: This study followed the PRISMA guidelines. We searched the English literature between 2000 and 2022 by using relevant medical subject heading and entry terms in PubMed, MEDLINE, Embase and CENTRAL databases. A meta-analysis of drug efficacy was performed using expanded disability status scale score and annualized relapse rate (ARR) as the primary outcome indicators. RESULTS: The literature search found a total of 1546 articles about TCZ and AZA in the treatment of NMOSD, 27 of which were included in this study after a series of screening. 930 and 148 patients with NMOSD were enrolled, who had been treated with AZA and TCZ, respectively. The pooled standardized mean difference (SMD) of expanded disability status scale score before and after AZA treated was -0.40 (95%CI: -0.50, -0.30) (I2 = 65.4%, P < .001), before and after TCZ treated was -0.84 (95%CI: -1.08, -0.60) (I2 = 45.6%, P = .076). The SMD of ARR before and after AZA treated was -1.01 (95%CI: -1.12, -0.90) (I2 = 83.4%, P < .001), before and after TCZ treated was -1.27 (95%CI: -1.52, -1.03) (I2 = 52.7%, P = .039). In addition, TCZ reduce ARR more significantly compared with AZA (P = .031). CONCLUSION: The results of this study showed that the treatment of NMOSD patients with AZA and TCZ are associated with decreased number of relapses and disability improvement as well. In addition, compared with AZA, TCZ more significantly reduce ARR.

Effects of short-distance transportation on physiological indexes, intestinal morphology, microbial community, and the transcriptome of the jejunum in weaned piglets.

Transportation of livestock is unavoidable in animal production. A total of 72 piglets were randomly divided into the CON group and the TSG group, and the piglets in CON group were transported for two hours. The purpose of this study was to determine the effects of short-distance road transportation lasting 2 h on the jejunum of weaned piglets. Our results showed that compared with the control group, there was no impact on the growth performance of piglets in the transport group (P > 0.05). The concentrations of cortisol, heat shock protein (HSP)70, HSP90, C-reactive protein, interleukin (IL)-6, IL-8, IL-12, and interferon-γ and the activity of reactive oxygen species were increased in the jejunum of piglets in the transport group (P < 0.05 compared with the control group). The concentrations of glutathione peroxidase, claudin-1, occludin, and zonula occludens-1 showed no between-group differences (P > 0.05). Regarding intestinal morphology, the transport group showed infiltration of a small amount of lymphocytes into the jejunum mucosa epithelium that was accompanied by edema of the lamina propria, whereas the control group showed no obvious abnormalities. At the genus level, in the transport group, the 16S rRNA sequencing revealed a downward trend in the relative abundance of Lactobacillus and an upward trend in the relative abundance of Muribaculaceae_unclassified. There was also increased mRNA expression of genes associated with inflammation in the transport group, but the genes and pathways related to apoptosis were not activated. In summary, weaned piglets undergoing 2 h of short-distance road transportation showed stress and inflammatory reactions of the jejunum but did not exhibit oxidative damage or activation of the apoptosis pathway of the jejunum. Furthermore, the growth performance of the piglets was not affected by the trip.

Engineered mesenchymal stem cell-derived extracellular vesicles: A state-of-the-art multifunctional weapon against Alzheimer's disease.

With the increase of population aging, the number of Alzheimer's disease (AD) patients is also increasing. According to current estimates, approximately 11% of people over 65 suffer from AD, and that percentage rises to 42% among people over 85. However, no effective treatment capable of decelerating or stopping AD progression is available. Furthermore, AD-targeted drugs composed of synthetic molecules pose concerns regarding biodegradation, clearance, immune response, and neurotoxicity. Mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) are essential intercellular communication mediators holding great promise as AD therapeutics owing to their biocompatibility, versatility, effortless storage, superior safety, and the ability to transport messenger and noncoding RNAs, proteins, lipids, DNAs, and other bioactive compounds derived from cells. The functionalisation and engineering strategies of MSC-EVs are highlighted (e.g. preconditioning, drug loading, surface modification, and artificial EV fabrication), which could improve AD treatment by multiple therapeutic effects, including clearing abnormal protein accumulation and achieving neuroprotection and immunomodulatory effects. Herein, this review summarises state-of-the-art strategies to engineer MSC-EVs, discusses progress in their use as AD therapeutics, presents the perspectives and challenges associated with the related clinical applications, and concludes that engineered MSC-EVs show immense potential in AD therapy.

Effects of early intermittent maternal separation on behavior, physiological, and growth performance in piglets.

In pig production, the management of piglets by batch lactation due to the increase in litter sizes of sows may result in intermittent early neonatal maternal separation (NMS). We speculated that NMS may affect the piglets cognitive growth performance and health. To determine the extent of the effect, 12 litters of crossbred piglets (Large White × Duroc × Min-pig) were used in this trial. Piglets in the control (Con) group (n = 6) were given a standard feeding method during lactation. Piglets in the experimental group (n = 6) were subjected to the NMS model, in which sows were led out of the enclosure with food every day (8:00-11:00 and 13:00-16:00) starting from postnatal day (PND) 7. During the separation, the piglets were supplemented with milk. All experimental piglets were weaned on PND 35. The piglets were observed for aggression, play, mutual sniffing, and exploratory behavior on PNDs 7, 8, 21, 22, 34, 35, 38, 39, 51, 52, 64, and 65. Physiological indicators, namely serum adrenaline, cortisol, interleukin (IL)-1ß, IL-4, IL-6, and tumor necrosis factor (TNF)-α were measured on PNDs 35, 38, and 65, while piglet growth performance was evaluated during suckling and 1 month after weaning. The results showed that aggressive behavior in the MS group was significantly higher than that in the Con group (P < 0.05). Playful and mutual sniffing behaviors in the MS group were significantly lower than those in the Con group except for PNDs 38 and 39 (P < 0.05). Active exploratory behavior in the MS group was significantly higher than that in the Con group on PNDs 7 and 8, and PNDs 21 and 22 (P < 0.05). The frequency of belly-nosing behavior was significantly higher in the MS group than that in the Con group except for PNDs 64 and 65 (P < 0.05). Compared with the Con group, epinephrine, IL-1ß, IL-6, and TNF-α concentrations on PNDs 35, 38, and 65 were significantly increased in the MS group (P < 0.01), while IL-4 concentration was significantly decreased (PND 35: P < 0.05; PNDs 38 and 65: P < 0.01). Compared with the Con group, the piglet diarrhea rate in the MS group during suckling was significantly increased (P < 0.01), the weaning weight was significantly decreased (P < 0.05), and it had no significant effect on the body weight at the end of the trial (P > 0.05). In conclusion, the early intermittent NMS created stress and affected the growth performance of piglets during suckling. However, the growth rate was improved by compensatory measures during late weaning.

Although management methods, such as split-suckling and foster care, in pig production can improve piglet survival rates, these methods inevitably lead to neonatal maternal separation which is an early stress on the body, and can have serious negative effects on the body. In this experiment, we investigated the effect level of neonatal maternal separation on behavior, physiology, and growth performance of piglets. The study found that early intermittent maternal separation leads to anxiety and behavioral changes in piglets, negatively affecting diarrhea rates and weaning weights in suckling piglets, but the effects on growth performance in lactating piglets can be ameliorated during the nursing period.

Socializing Models During Lactation Alter Colonic Mucosal Gene Expression and Fecal Microbiota of Growing Piglets.

The enrichment of the social environment during lactation alleviates the stress of weaned piglets. It is significant to understand how the enriched social environment improves the weaning stress of piglets. RNA sequencing (RNA-seq) of colonic mucosa, 16S rRNA sequencing of feces, and short-chain fatty acids (SCFAs) of colonic content were used to determine the effects of social contact during lactation. In this study, thirty litter lactating piglets were divided into intermittent social contact (ISC) group that contacted with neighbors intermittently, continuous social contact (CSC) group that contacted with neighbors starting at day (D) 14 after birth, and control (CON) group in which piglets were kept in their original litter. The piglets were weaned at D35 and regrouped at D36. The colonic mucosal RNA-seq, fecal microbes, and SCFAs of colonic contents of 63-day-old piglets were analyzed. The results of RNA-seq showed that compared with the CON group, the pathways of digestion and absorption of minerals, protein, and vitamins of piglets were changed in the ISC group, whereas the pathways of retinol metabolism and nitrogen metabolism in the colonic mucosal were affected and stimulated the immune response in the CSC group. Compared with the CON group, the abundances of pernicious microorganisms (Desulfovibrio, Pseudomonas, Brevundimonas, etc.) in the CSC group and pernicious microorganisms (Desulfovibrio, Neisseria, Sutterella, etc.) and beneficial bacteria (Bifidobacterium, Megamonas, and Prevotella_9) in the ISC group were significantly higher (p < 0.05). The abundances of proinflammatory bacteria (Coriobacteriaceae_unclassified, Coprococcus_3, and Ruminococcus_2) in the CSC group were significantly increased (p < 0.05), but the abundances of SCFAs producing bacteria (Lachnospiraceae_UCG-010, Parabacteroides, Anaerotruncus, etc.) and those of anti-inflammatory bacteria (Eubacterium, Parabacteroides, Ruminiclostridium_9, and Alloprevotella) were significantly reduced (p < 0.05) in the CSC group. Compared with the CON group, the concentrations of microbial metabolites, acetate, and propionate in the colonic contents were reduced (p < 0.05) in the ISC group, whereas the concentration of acetate was reduced (p < 0.05) in the CSC group. Therefore, both ISC and CSC during lactation affected the composition of fecal microbes and changed the expression of intestinal mucosal genes related to nutrient metabolism and absorption of piglets.

Recent Advancements in Strategies for Abnormal Protein Clearance in Alzheimer's Disease.

Alzheimer's disease (AD) is an intricate neurodegenerative disease with chronic and progressive development whose typical neuropathological features encompass senile plaques and neurofibrillary tangles, respectively formed by the extracellular deposition of amyloid-beta (Aß) and the intracellular accumulation of hyperphosphorylated tau protein in the brain, particularly in limbic and cortical regions. The pathological changes are considered to be caused by the loss of Aß and tau protein clearance mechanisms under pathological conditions, which leads to an imbalance between the rates of clearance and production. Consequently, the main strategies for treating AD aim to reduce the production of Aß and hyperphosphorylated tau protein in the brain, inhibit their accumulation, or accelerate their clearance. Although drugs utilizing these therapeutic strategies have been studied successively, their therapeutic effects have generally been less than ideal. Fortunately, recent advances have been made in clearance strategies for these abnormally expressed proteins, including immunotherapies and nanomedicines targeting Aß or tau, which could represent an important breakthrough for treating AD. Here, we review recent development of the strategies for the removal of abnormal proteins and provide new ideas and methods for treating AD.

Nanoparticles-based anti-aging treatment of Alzheimer's disease.

Age is the strongest risk factor for Alzheimer's disease (AD). In recent years, the relationship between aging and AD has been widely studied, with anti-aging therapeutics as the treatment for AD being one of the mainstream research directions. Therapeutics targeting senescent cells have shown improvement in AD symptoms and cerebral pathological changes, suggesting that anti-aging strategies may be a promising alternative for AD treatment. Nanoparticles represent an excellent approach for efficiently crossing the blood-brain barrier (BBB) to achieve better curative function and fewer side effects. Thereby, nanoparticles-based anti-aging treatment may exert potent anti-AD therapeutic efficacy. This review discusses the relationship between aging and AD and the application and prospect of anti-aging strategies and nanoparticle-based therapeutics in treating AD.

Effects of music stimulus on behavior response, cortisol level, and horizontal immunity of growing pigs.

An enriched environment is widely used to improve domestic animals' welfare and promote their natural behaviors. Music can reduce abnormal behavior in humans, nonhuman primates, and rodents. However, little is known about the effects of music on pigs. This study aims to explore the effects of repeated music stimulation on the behavior, physiology, and immunity of growing pigs. A total of 72 hybrid piglets (Large White × Duroc × Minpig) were randomly divided into three groups, including music (Mozart K.448, 60 to 70 dB), noise (recorded mechanical noise, 80 to 85 dB), and control (natural background sound, <40 dB), and 6 h sound stimulation was given per day (1000 to 1600 hours) from 40 to 100 d of age. The behavioral activities of the pigs were observed during the music stimulation, and their serum cortisol, salivary cortisol, and serum immune indices were also measured. Compared with the control group, the music group and noise group increased activity but decreased lying of pigs (P < 0.05). A significant increase in tail-wagging, playing, and exploring behaviors of pigs was found in the music group (P < 0.05), and the noise significantly increased the aggressive behavior of the pigs (P < 0.05). Tail-wagging, playing, exploring, manipulating, and aggressive behaviors decreased over time. Short-term (8 d) music stimulus had a lower cortisol level than that of the noise and control groups (P < 0.05), whereas long-term (60 d) music stimulus increased immunoglobulin G (IgG), interleukin-2 (IL-2), and interferon-gamma (IFN-γ) levels (P < 0.05) and decreased interleukin-4 (IL-4) level (P < 0.05). Long-term noise stimulus significantly reduced the level of IgG (P < 0.05) but did not affect the level of IL-2, IL-4, and IFN-γ levels (P > 0.05). In conclusion, short-term music stimulus (8 d) reduced the stress response, whereas long-term music stimulus (60 d) enhanced the immune responses. In addition, the noise increased the aggressive behavior, and long-term noise reduced the immunity of the growing pigs.