Background: Alzheimer's disease (AD) is a progressive neurodegenerative disease with no effective therapies. It is well known that chronic neuroinflammation plays a critical role in the onset and progression of AD. Well-balanced neuronal-microglial interactions are essential for brain functions. However, determining the role of microglia—the primary immune cells in the brain—in neuroinflammation in AD and the associated molecular basis has been challenging.

Methods: Inflammatory factors in the sera of AD patients were detected and their association with microglia activation was analyzed. The mechanism for microglial inflammation was investigated. IL6 and TNF-α were found to be significantly increased in the AD stage.

Results: Our analysis revealed that microglia were extensively activated in AD cerebra, releasing sufficient amounts of cytokines to impair the neural stem cells (NSCs) function. Moreover, the ApoD-induced NLRC4 inflammasome was activated in microglia, which gave rise to the proinflammatory phenotype. Targeting the microglial ApoD promoted NSC self-renewal and inhibited neuron apoptosis. These findings demonstrate the critical role of ApoD in microglial inflammasome activation, and for the first time reveal that microglia-induced inflammation suppresses neuronal proliferation.

Conclusion: Our studies establish the cellular basis for microglia activation in AD progression and shed light on cellular interactions important for AD treatment.

Background: Alzheimer's disease (AD) and lung cancer are leading causes of mortality among the older population. Epidemiological evidence suggests an antagonistic relationship between them, whereby patients with AD exhibit a reduced risk of developing cancer and vice versa. However, the precise mechanism by which AD antagonizes lung cancer progression warrants further elucidation.

Methods: To this end, we established a co-morbidity model using 5xFAD transgenic mice induced with the carcinogen urethane. We visualized and quantified surface lung tumor colonies, assessed pathological parameters associated with lung cancer and AD using histopathological analysis, and employed single-cell sequencing and molecular pathological analyses to explore the mechanisms by which AD confers resistance to lung cancer.

Results: Our findings revealed a significant reduction in lung tumor incidence in the AD group compared with that in the wild-type (WT) group. The results indicated a close association between AD-induced inhibition of lung tumor progression and iron homeostasis imbalance and increased oxidative stress. Moreover, greater CD8⁺ T cytotoxic lymphocyte and effector natural killer cell infiltration in the lung tumor tissues of AD mice and enhanced CD8⁺ T cytotoxic lymphocyte-mediated killing of target cells may be the primary factors contributing to the inhibition of lung tumor growth in the presence of AD.

Conclusion: This study identified essential mechanisms through which AD suppresses lung tumorigenesis, thereby providing targets for potential therapeutic interventions in these diseases.

Background: Neurodegenerative diseases (NDs), including Alzheimer‘s disease, Parkinson‘s disease, and Huntington‘s disease, are complex and challenging due to their intricate pathophysiology and limited treatment options.

Methods: This review systematically sourced articles related to neurodegenerative diseases, neurodegeneration, quercetin, and clinical studies from primary medical databases, including Scopus, PubMed, and Web of Science.

Results: Recent studies have included quercetin to impact the cellular and molecular pathways involved in neurodegeneration. Quercetin, a flavonoid abundant in vegetables and fruits, is gaining attention for its antioxidant, anti-inflammatory, and antiapoptotic properties. It regulates signaling pathways such as nuclear factor-κB (NF-κB), sirtuins, and phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt). These pathways are essential for cellular survival, inflammation regulation, and apoptosis. Preclinical and clinical studies have shown that quercetin improves symptoms and pathology in neurodegenerative models, indicating promising outcomes.

Conclusions: The study explores the potential of incorporating laboratory research into practical medical treatment, focusing on quercetin‘s neuroprotective effects on NDs and its optimal dosage.

Alzheimer's disease is the most prevalent chronic neurodegenerative disorder worldwide, with no sufficient cure. Ongoing research is focused on developing new therapies aimed at preventing or delaying the onset of symptoms, slowing disease progression, and improving cognitive and behavioral outcomes in individuals affected by Alzheimer's disease. Among the various pathological changes associated with this condition, blood–brain barrier (BBB) leakage plays a crucial role as it serves as a vital boundary for maintaining central nervous system (CNS) health. Preserving the integrity and functionality of the BBB is essential to protect the brain from amyloid-β accumulation, neuroinflammation, and neuronal degeneration. This review summarizes models of Alzheimer's disease characterized by BBB leakage over time. More importantly, we introduce Krüppel-like factor 4 (KLF4), a transcription factor involved in vascular systems, and discuss its relevance to Alzheimer's disease. By elucidating the functions of KLF4 within both vascular and CNSs, this review highlights its potential role in modulating BBB integrity in Alzheimer's pathology, which may contribute to therapeutic strategies for managing this debilitating condition.

The World Health Organization has declared that COVID-19 no longer constitutes a “public health emergency of international concern,” yet the long-term impact of SARS-CoV-2 infection on bone health continues to pose new challenges for global public health. In recent years, numerous animal model and clinical studies have revealed that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection can lead to secondary osteoporosis. The mechanisms involved are related to the virus's direct effects on bone tissue, dysregulation of the body's inflammatory response, hypoxia, noncoding RNA imbalance, and metabolic abnormalities. Although these studies have unveiled the connection between SARS-CoV-2 infection and osteoporosis, current research is not comprehensive and in depth. Future studies are needed to evaluate the long-term effects of SARS-CoV-2 on bone density and metabolism, elucidate the specific mechanisms of pathogenesis, and explore potential interventions. This review aims to collate existing research literature on SARS-CoV-2 infection-induced secondary osteoporosis, summarize the underlying mechanisms, and provide direction for future research.

Background: To investigate the toxicity of N-n-butyl haloperidol iodide (F2), a quaternary ammonium salt derivative of haloperidol, in mice for potential therapeutic purposes.

Methods: The acute median lethal dose (LD₅₀) of F2 was determined using the Bliss method following intravenous administration in mice. Routine surface electrocardiograms (ECGs) and arterial blood pressures (aBPs) were recorded under general anesthesia in untreated and pharmacologically vagotomized mice injected with F2. Sublethal doses of F2 were tested for their effects on aBP, heart rate, and biochemical parameters such as lactate dehydrogenase (LDH), blood urea nitrogen (BUN), and serum lactate levels. Histopathological changes in the heart, lungs, liver, and kidneys were evaluated after F2 administration.

Results: The acute LD₅₀ of F2 was determined to be 5.11 mg/kg. A 10 mg/kg dose of F2 caused severe hypotension, second-degree atrioventricular block, progressive prolongation of Pmurr intervals, and death due to cardiac asystole. Similar ECG and aBP changes were observed in atropine-pretreated mice, indicating that cholinergic effects do not play a major role in F2-induced toxicity. Sublethal doses of F2 (1.2 and 2.4 mg/kg) caused dose-dependent decreases in aBP and increases in heart rate. F2 induced significant, dose-dependent increases in LDH, BUN, and serum lactate levels. Histopathological analysis revealed acute lung lesions at 10 mg/kg, with no significant changes observed in the heart, liver, or kidneys.

Conclusion: Acute intravenous injection of F2 exhibits dose-dependent cardiopulmonary toxicity, characterized by severe hypotension, arrhythmias, and biochemical changes. These findings highlight the potential risks of F2 and the need for further evaluation of its safety profile for therapeutic use.

Background: Reliable animal models are crucial to drug development for focal segmental glomerulosclerosis (FSGS), a rare kidney disease. Variability in success rates in literature and significant ethical concerns with animal welfare necessitate further optimization of adriamycin (ADR)–induced FSGS model developed on BALB/c mice.

Methods: High-performance liquid chromatography (HPLC) was used to assess ADR stability in water and upon light exposure. To identify the optimal ADR level, single intravenous ADR injections with dosing levels from 10 to 17 mg/kg body weight were administered to BALB/c mice to induce FSGS-like pathology. Body weight and proteinuria of FSGS mice were monitored and analyzed for FSGS model–associated morbidity. Animals were euthanized for hematological and kidney histological assessments 8 weeks post induction. To identify the suitable experiment time frame of the ADR-induced FSGS mouse model, a longitudinal study was performed, with an 11-week continuous monitoring of the symptoms.

Results: ADR was found to be unstable in aqueous media and light sensitive. A dosing level of 10.5 mg/kg of ADR was optimal for consistent FSGS mouse model induction on BALB/c strain, characterized by minimal mortality and sustained FSGS-like symptoms. Findings from the longitudinal study suggest that 6 weeks post ADR induction may represent the peak of FSGS pathology severity in this mouse model. This time frame may be used for FSGS drug development projects.

Conclusion: Based on the outcome from this study, we identified the optimal ADR dosing level and model testing duration. A standard operating procedure (SOP) for the ADR-induced FSGS mouse model was established to facilitate FSGS basic research and drug development.

Background: Pregnancy affects learning and memory in women. Thus, to investigate the effects of pregnancy, the authors examined the brain electrophysiology of pregnant mice.

Methods: Using the whole-cell patch-clamp technique on isolated brain slices, we detected and compared the electrophysiological changes in the hippocampal CA1 (HIP CA1) region, medial prefrontal cortex (mPFC), and basolateral amygdala (BLA) among 15 pregnant and 15 nonpregnant mice.

Results: In pregnant mice, there was a trend toward an increase in the frequency of miniature excitatory postsynaptic currents (mEPSCs) (p = 0.092) and a trend toward a decrease in the amplitude of miniature inhibitory postsynaptic currents (mIPSC) (p = 0.071) in the HIP CA1. In the BLA, both the amplitudes of mEPSCs and mIPSCs were significantly reduced (p = 0.004 and 0.042, respectively). In the mPFC, the amplitudes of mEPSCs and hyperpolarization-activated currents (Ih), as well as the frequencies of mIPSCs, were higher compared to nonpregnant mice (p = 0.035, 0.009, and 0.038, respectively).

Conclusions: In pregnant mice, the electrophysiological change in neurons in the mPFC and BLA might contribute to the cognitive and emotional changes during pregnancy. A trend toward electrophysiological change in the HIP CA1 revealed that the mechanism of cognitive change during pregnancy might differ from that of other conditions.

Background: In a previous study, we found that Atractylodes macrocephala and Paeoniae radix (AM-PR) was useful for the alleviation of functional constipation (FC). However, the precise mechanism underlying the compatibility between AM and PR in the treatment of FC remains uncertain. This study aims to analyze the pharmacokinetic differences in the active ingredients in the blood of rat models with FC when applied individually and in combination with AM-PR. It also seeks to compare the changes in the content of the active ingredient when applied individually and in combination with in vitro AM-PR, further in-depth investigation into its material foundation in terms of pharmacokinetics, as well as the composition of the substance.

Methods: Blood microdialysis samples were collected using microdialysis technology. These samples from rats with FC were compared after administration of AM, PR, and AM-PR. The concentration of the main active ingredients was determined using the Ultra Performance Liquid Chromatography-Tunable Ultraviolet (UPLC-TUV) method. The concentration of the main active ingredients of the decoction compatibility before and after combining AM-PR was also determined using the UPLC-TUV method.

Results: Our findings reveal that upon combination, the time to maximum concentration (T_max) of isochlorogenic acid A (ICA-A) and ataridolide II (ATR-II) T_max was prolonged, terminal elimination half-life (T_1/2) was reduced, and maximum plasma concentrations (C_max) increased. The T_max of ataridolide III (ATR-III) remained consistent, whereas its T_1/2 and C_max were significantly reduced. Conversely, for peoniflorin (PAE), T_max occurred sooner, T_1/2 was shortened, and C_max increased. The T_max for albiflorin (ALB) remained consistent, whereas T_1/2 and C_max witnessed significant increases. The area under the moment curve (AUMC) (0–t) and AUMC (0–∞) of PAE, ALB, ICA-A, ATR-II experienced an increase after AM-PR administration in rats, attributable to the heightened C_max. In comparison to individual herb administration, the T_max of ALB was advanced in combination, the T_max of PAE remained unchanged, and the T_max of ICA-A and ART-II was delayed, with an increased area under the concentration–time curve (AUC) (0–t), indicating enhanced C_max and bioavailability. Furthermore, the dissolution rates of PAE, ICA-A, and ATR-II significantly improved after compatibility.

Conclusions: This study partially clarifies the rationale and compatibility of AM-PR in treating FC and offers a new perspective on the pharmacokinetic interactions of AM-PR in FC treatment.

Background: Refined models of kidney disease are critical to better understand disease processes and study novel treatments while minimizing discomfort in research animals. The objective of this study was to report a technique for minimally invasive partial kidney embolism in cats and describe outcomes following transcatheter administration of embolic microspheres with subsequent contralateral nephrectomy.

Methods: Eleven, apparently healthy, male, purpose-bred cats underwent unilateral kidney embolism with 0.25 or 0.5 mL of embolic microparticle (40–120 μm) suspension (0.2 mL microspheres/mL) delivered into the right renal artery under fluoroscopic guidance, followed 5 months later by contralateral nephrectomy. One month after nephrectomy, blood and urinary markers of kidney function were evaluated, and embolized kidneys were harvested for histopathology evaluation.

Results: Renal artery embolization was possible in all cats. Two cats did not complete the study, one after experiencing congestive heart failure (n = 1) and the other following evidence of complete kidney embolism precluding nephrectomy (n = 1) post-embolization. At study end, compared to baseline, cats had significant increases in median (range) serum creatinine (159.1 μmol/L [141.4–530.4] versus 128.2 μmol/L [92.8–150.3]; p = 0.0004), urea nitrogen (15.71 mmol/L [9.29–47.85] versus 7.50 mmol/L [6.07–8.57]; p < 0.0001), and symmetric dimethylarginine (0.74 μmol/L [0.59–3.12] versus 0.67 μmol/L [0.54–0.72]; p = 0.0288) concentrations. No differences in markers of kidney function were documented between dose groups.

Conclusions: Minimally invasive kidney embolism is a promising technique for modeling kidney disease in cats. Understanding optimal dose, timing of nephrectomy, and longer-term consequences requires additional work.

Background: Quantifying the rich home-cage activities of tree shrews provides a reliable basis for understanding their daily routines and building disease models. However, due to the lack of effective behavioral methods, most efforts on tree shrew behavior are limited to simple measures, resulting in the loss of much behavioral information.

Methods: To address this issue, we present a deep learning (DL) approach to achieve markerless pose estimation and recognize multiple spontaneous behaviors of tree shrews, including drinking, eating, resting, and staying in the dark house, etc.

Results: This high-throughput approach can monitor the home-cage activities of 16 tree shrews simultaneously over an extended period. Additionally, we demonstrated an innovative system with reliable apparatus, paradigms, and analysis methods for investigating food grasping behavior. The median duration for each bout of grasping was 0.20 s.

Conclusion: This study provides an efficient tool for quantifying and understand tree shrews' natural behaviors

Background: China is a high-burden country for multidrug-resistant tuberculosis/rifampin-resistant tuberculosis (MDR/RR-TB). Fluoroquinolones (FQs) are key drugs for the treatment of patients with MDR/RR-TB. However, research on the resistance of FQs in Beijing is limited.

Methods: We collected clinical isolates from all patients with pulmonary TB in Beijing from January 2016 to December 2021, conducted drug-sensitivity tests and sequencing for levofloxacin (LFX) and moxifloxacin (MFX), and collected the treatment plans and outcomes of the patients.

Results: A total of 8512 clinical isolates were collected from patients with pulmonary TB, and 261 RR-TB strains were screened. The proportions of drug-sensitive and drug-resistant strains significantly differed by age group and treatment history. The rates of LFX and MFX resistance were 27.6% (72/261) and 36.4% (95/261), respectively. The detection rates of MDR-TB and pre-extensively drug-resistant TB (pre-XDR-TB) were 73.2% (191/261) and 36.4% (95/261), respectively, and the trends were significant (χ² trend = 9.995, p = 0.002; χ² trend = 12.744, p = 0.026). Among the 261 RR-TB strains, 14.9% (24/261) were sensitive to LFX but resistant to MFX. Among the four patients with LFX-resistant TB who received LFX treatment failed in three patients (Fisher's exact test, p = 0.009). The common mutation sites were 94 and 90 in gyrA. A novel mutation Ala90Ser was discovered.

Conclusions: FQs resistance trends in RR-TB patients in Beijing are striking. Strains showed incomplete cross-resistance to LFX and MFX. Testing for FQs resistance and developing a reasonable treatment plan are recommended. Attention should be given to the changing trends in MDR-TB and pre-XDR-TB.

Chinese hamster with Chinese characteristics is used in experiments, and it is of great value in the field of medical biology research. However, at present, there is no high-efficiency method for evaluating the genetic quality of Chinese hamsters. Here, we developed a novel Chinese hamster genetic quality detection system using single-nucleotide polymorphism (SNP) markers. To find SNP loci, we conducted whole genome sequencing on 24 Chinese hamsters. Then, we employed an SNP locus screening criterion that we set up previously and initially screened 214 SNP loci with wide genome distribution and high polymorphism level. Subsequently, we developed the SNP detection system using a multitarget region capture technique based on second-generation sequencing, and a 55 SNP panel for genetic evaluation of Chinese hamster populations was developed. PopGen.32. analysis results showed that the average effective allele number, Shannon index, observed heterozygosity, expected heterozygosity, average heterozygosity, polymorphism information, and other genetic parameters of Chinese hamster population A were higher than those in population B. Using scientific screening and optimization, we successfully developed a novel Chinese hamster SNP genetic detection system that can efficiently and accurately analyze the genetic quality of the Chinese hamster population.

Adenomatous polyposis coli (APC) mutations are the most frequently identified genetic alteration in sporadic colorectal cancer (CRC) cases, and a myriad of genetically engineered Apc-mutant CRC mouse models have been developed using various genetic manipulation techniques. The advent of the CRISPR/Cas9 system has revolutionized the field of genetic engineering and facilitated the development of new genetically engineered mouse models. In this study, we aimed to develop a novel Apc knockout allele using the CRISPR/Cas9 system and evaluate the phenotypic effects of this new allele in two different mouse strains. For this purpose, exon 16 of mouse Apc gene was targeted with a single-guide RNA, and the mouse carrying an Apc frameshift mutation at codon 750 (Δ750) was chosen as the founder. The mutant FVB-Apc^Δ750 mice were backcrossed with wild-type C57BL/6 mice, and the phenotypic effects of the knockout allele were evaluated in F8-FVB-Apc^Δ750, F4-B6;FVB-Apc^Δ750, and F1-B6;FVB-Apc^Δ750 by a macroscopic and microscopic examination of the gastrointestinal system. The result showed that the mean polyp number was significantly higher in F4-BL6;FVB-Apc^Δ750 than in F8-FVB-Apc^Δ750. Intestinal polyposis was more prominent in F4-BL6;FVB-Apc^Δ750, whereas a higher number of colon polyps than intestinal polyps were observed in F8-FVB-Apc^Δ750. Additionally, F1-BL6;FVB-Apc^Δ750 mixed background mice developed gastric polyps that morphologically resembled the pyloric gland adenoma of humans. In conclusion, we developed a novel CRISPR-mediated Apc knockout allele using two mouse strains. We showed that this allele can exert a strain-specific effect on the phenotype of mice and can cause gastric polyp formation.

Background: Developing a granulomatous liver injury preclinical model may pave the way to understanding hepatic-TB (tuberculosis) and autoimmune granulomatous liver diseases. Antitubercular (ATT) and other drugs' metabolism in the presence of a specific type of liver injury is not well understood. The present study aimed to establish a preclinical model of granulomatous hepatitis by using the BCG (Bacillus Calmette-Guérin) vaccine, further studying it in the presence of ATT dosing, and analyze the pharmacokinetics of isoniazid, rifampicin, and their respective primary metabolites.

Methods: We used 56 rats in seven equal groups. Group I functioned as a normal control (NC) receiving normal saline only. Groups II–IV received intravenous injections of low-, medium-, and high-dose BCG vaccine daily for 21 days. Groups V, VI, and VII received isoniazid (H) alone, rifampicin (R) alone, and isoniazid + rifampicin (HR) for a subsequent 15 days in addition to high dose BCG for the first 21 days, respectively. Liver function tests (LFT) were monitored on days 0, 21, 28, and 36. Rats were sacrificed later for oxidative stress and histopathological examination.

Results: The study observed BCG dose-specific LFT derangements in groups II–IV compared to group I on day 21 (p < 0.05). Isoniazid, rifampicin, and combination intervention groups demonstrated normalization of the BCG-led LFT changes. Histology and oxidative stress parameters confirmed model development and biochemical changes. Isoniazid area under the curve (AUC) showed a reduction of 16.9% in BCG + HR group in comparison to the BCG + H group (p = 0.01). Des-acetyl-rifampicin AUC and maximum-concentration value demonstrated a significant rise in BCG + HR group in comparison to the BCG + R group (p = 0.001).

Conclusion: A novel preclinical model of granulomatous liver injury was developed using the BCG vaccine strain and validated with ATT response.

This study evaluated the antibacterial effects of 2% lidocaine and its combination with 0.9% saline solution on Escherichia coli infection in superficial surgical wounds in Wistar rats. The goal was to determine if these treatments could effectively reduce E. coli Colony Forming Units (CFUs) below the critical threshold of 1 × 10⁵. Seventy male Wistar rats were divided into seven groups, each undergoing different interventions to assess the antibacterial efficacy of lidocaine, with outcomes measured through bacterial cultures and CFU quantification. Results demonstrated a Log₁₀ reduction of approximately 0.44 in E. coli CFUs following infiltration with 2% lidocaine. The combined use of 2% lidocaine infiltration and 0.9% saline irrigation resulted in nearly complete suppression of bacterial growth. These findings suggest that these simple interventions could be valuable in emergency surgical settings to mitigate the risk of surgical site infections and serve as effective prophylactic measures.

Sugars are one of the major metabolites and are essential for nucleic acid synthesis and energy production. In addition, sugars can act as signaling molecules. To study sugar signaling at the systemic level, there is an urgent need to systematically identify sugar-sensing proteins and nucleic acids. I propose the terms “swodkoreceptor” and “swodkocrine signaling,” derived from the Polish word “słodki” meaning “sweet,” to comprise all sugar-sensing proteins and signaling events, respectively, regardless of their cellular location and signaling domains. This proposal is intended to facilitate the inclusion of proteins such as the Escherichia coli LacI repressor as an allolactose receptor, human glucokinase regulatory protein (GCKR) as a fructose receptor, and other sugar-binding based allosterically regulated enzymes and transcription factors as sugar-sensing receptors. In addition, enzyme-interacting proteins whose interaction state is regulated by sugar binding have also been proposed as sugar receptors. The systemic study of protein- and nucleic-acid-based swodkoreceptors may help to identify organelle-specific swodkoreceptors and to also address receptor duality. The study of intra- and inter-organism swodkocrine signaling and its crosstalk with gasocrine signaling may help to understand the etiology of diseases due to dysregulation in sugar homeostasis and signaling.