The use of multiple antibiotics in combination therapy for bacterial infections has become routine in clinical practice, whereas the increasing demand for therapeutic drug monitoring (TDM) imposes stricter requirements on analytical methods. The combined administration of vancomycin (Van) and tobramycin (TOB) offers broader antimicrobial coverage across diverse pathogenic species. However, both antibiotics possess narrow therapeutic windows, making the parallel monitoring of their blood concentrations crucial for precise and safe dosing. In this study, an extended-gate field-effect transistor (EG-FET) sensor fabricated from gold-doped, paper-based laserinduced graphene (LIG) is presented. The sensor operates via an aptamer-based, label-free response mechanism, enabling the multiplexed and rapid therapeutic drug monitoring of Van and TOB. The incorporation of paper-based substrates not only simplifies device fabrication but also enhances the overall sensing sensitivity. The EG-FET sensor exhibits excellent linear responses toward Van and TOB over concentrations ranging from 0.1 nM to 100 mu M, with detection limits as low as 6.89 pM for Van and 52.9 pM for TOB. To enable point-of-care TDM applications, a portable and wireless sensing platform was assembled. Additionally, our EG-FET sensors can accurately detect Van and TOB in actual blood samples (including human blood and mice serum). This work represents the first demonstration of an EG-FET sensing platform enabling parallel and multiplexed detection of vancomycin and tobramycin, providing a promising strategy for multi-analyte therapeutic drug monitoring of antibiotics with narrow therapeutic windows.

Background/purpose:Oral manifestations are often the first signs of human immunodeficiency virus (HIV) infection. The purpose of this study was to analyze the scientometric characteristics and research trends of HIV/AIDS involving the oral cavity. Materials and methods:All the papers on oral involvement of HIV/AIDS were comprehensively retrieved from the Scopus database. The years of publication were divided into before 2006 and 2006-2024 in the analysis of research trends. Results:There were 1770 relevant papers on HIV/AIDS involving the oral cavity, with total citations of 26,307 and the h index of 63. The most common keyword of HIV-related oral diseases was thrush, followed by oral candidiasis, opportunistic infections, Kaposi sarcoma, hairy leukoplakia, periodontal disease, and dental caries. The trend of drug aspect, e.g., antifungal agent, nystatin, and azole drugs before 2006 has changed to reverse transcriptase inhibitors efavirenz and lamivudine. Importantly, the common keyword including public health, health survey, saliva, education, dental student, and knowledge, suggesting that HIV/AIDS remains a major challenge to public health. Herein, we highlight the awareness of early diagnosis, and screening and testing of HIV, e.g., using saliva seems well-suited in dental setting. Conclusion:This study is the first scientometric analysis of HIV-related oral diseases with an implication for public health, underpinning that dentists and stomatologists can play active roles in providing early recognition and timely diagnosis of HIV/AIDS when it involved the oral cavity.

Periodontitis, a chronic inflammatory disease driven by bacterial dysbiosis and oxidative stress, remains a major clinical challenge due to its complex pathogenesis and the lack of effective regenerative therapies. Here, we engineer an intelligent pH-responsive MXene-based nanosystem (MPDM) integrating polyethyleneimine (PEI) for pathogen-derived cfDNA capture, methyltransferase-like 3/14 (METTL3/14) for m6A-mediated osteogenic reprogramming, and 2,3-dimethylmaleic anhydride (DMMA) for dynamic charge-shielding to enhance targeting of inflammatory sites targeting. In vitro studies reveal that MPDM exhibits synergistic antibacterial activity, potent reactive oxygen species (ROS) scavenging capacity, and inflammation-triggered payload release. In a murine ligature-induced periodontitis model, micro-CT analysis revealed that MPDM reduced alveolar bone loss and increased the bone volume fraction by 32% (from 53% to 85%) compared to the diseased (Untreated) group. Transcriptomic analysis further reveals that MPDM downregulates toll-like receptor (TLR) and neutrophil extracellular trap (NET) formation signaling pathways, while suppressing osteoclast differentiation. By concurrently neutralizing pathogenic triggers and activating tissue repair, this work establishes a framework for next-generation nanotherapeutics in inflammatory bone disorders, with potential applicability to other multifactorial diseases.

BackgroundIn the past few decades, selective serotonin reuptake inhibitors (SSRIs) became widely used antidepressants worldwide. Therefore, the adverse reactions of patients after SSRI administration became a public and clinical concern. In this study, we conducted a pharmacovigilance study using the Adverse Event Reporting System (FAERS) database of the US Food and Drug Administration. Our main goal was to evaluate adverse events related to SSRIs, with a particular focus on abnormal weight gain and glucose/lipid metabolism disorders.MethodThe adverse event data for representative SSRIs (citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline) was extracted from the FAERS database from 2004Q1 to 2023Q4. The reporting odds ratio and proportional reporting ratio were employed to explore relevant adverse event reports (ADEs) signals. Univariate logistic regression analysis was utilized to explore factors associated with glucose/lipid metabolism abnormality following SSRIs treatment.ResultsWe identified 143,744 ADE reports associated with SSRIs and revealed significant abnormal signals related to weight gain and glucose/lipid metabolism in depressed patients. Variations were observed among different SSRIs medications. Specifically, citalopram was associated with abnormal weight gain (ROR: 4, 95% CI: 3.1-5.2) and hepatic steatosis (ROR: 2.8, 95% CI: 2.1-3.6); escitalopram was correlated with gestational diabetes (ROR: 9.1, 95% CI: 6.6-12.4) and cholestasis (ROR: 2.4, 95% CI: 1.75-3.38); fluoxetine was associated with obesity (ROR: 2.8, 95% CI: 2.08-3.78); fluvoxamine was linked to arteriospasm coronary (ROR: 13.87, 95% CI: 4.47-43.1); and sertraline was implicated in neonatal jaundice (ROR: 16.1, 95% CI: 12.6-20.6). Females and younger age are important risk factors for the development of associated adverse effects.ConclusionOur study screened for adverse effects associated with abnormal glucose/lipid metabolism, such as abnormal body weight and fatty liver, in depressed patients taking selective serotonin reuptake inhibitors by utilizing FAERS database. This provides valuable insights for healthcare professionals in accepting and managing patients treated with SSRIs.

Vancomycin (Van), a widely utilized glycopeptide antibiotic in clinical settings, necessitates precise bloodstream concentration monitoring due to its narrow therapeutic window, ensuring drug efficacy while preventing adverse effects. In this work, we have engineered an extended-gate field-effect transistor (EG-FET) sensor tailored for vancomycin detection. This novel sensor configuration comprises a detachable multi-doped graphene EG electrode sensing element paired with a commercial field-effect transistor (FET). The EG electrode design integrates a sophisticated multistage doping process, incorporating MnO2 and Au nanoparticles into laser-induced graphene (LIG), thereby augmenting both functional and electrical characteristics of LIG. To achieve specific recognition, a vancomycin aptamer is immobilized onto the electrode surface, enabling selective binding with vancomycin and translating this interaction into a measurable electrical signal. This collaborative mechanism empowers the EG-FET sensor to exhibit exceptional sensitivity and selectivity towards vancomycin. Notably, the sensor demonstrates a wide linear response ranging from 1 nM to 100 μM, spanning the entire therapeutic window of vancomycin (6-35 μM), boasting an impressive detection limit of 0.187 nM. We have innovated a portable wireless sensing system, coupled with a Janus membrane for expedited plasma separation, consolidating a portable platform dedicated to vancomycin sensing. Furthermore, we have realized the detection of vancomycin concentration in patient's blood using this sensor, and the results are reliable. This comprehensive study underscores the immense potential of multi-doped graphene EG-FET sensors in the realm of antibiotic detection, thereby contributing a pivotal tool towards the realization of precision medicine strategies.

BACKGROUND:The emergence of cyclin-dependent kinases 4/6 inhibitors (CDK4/6i) represented a major breakthrough in the treatment of breast cancer over the past decade. In both clinical trials and real-world settings, it was observed that patients using CDK4/6i might experience psychiatric adverse events (PAEs). Herein, we conducted a pharmacovigilance study to comprehensively assess the correlation between CDK4/6i and PAEs. METHOD:We obtained individual case safety reports submitted to the FDA Adverse Events Reporting System (FAERS) during the period from January 2015 to December 2023. In disproportionality analysis, the reporting odds ratio (ROR) and information component (IC) values were calculated for each adverse event-drug combination. Univariate logistic regression analysis was utilized to explore factors associated with PAEs following CDK4/6i treatment. RESULTS:A total of 95,591 reports related to CDK4/6i were identified, with 6.72% reporting PAEs, and this proportion exhibited an annual upward trend. Based on the ROR and IC values, 17 categories of PAEs were defined as CDK4/6i-related PAEs. Among these PAEs, insomnia, stress, eating disorder, depressed mood, and sleep disorder were very common, each accounting for over 10% of CDK4/6i reports. Ribociclib showed the highest risk signal of CDK4/6i-related PAEs (ROR = 1.89[1.75-2.04], IC025 = 0.79), followed by palbociclib (ROR = 1.47[1.41-1.53], IC025 = 0.49), while abemaciclib did not exhibit a significant signal (ROR = 0.52[0.44-0.62], IC025 = -1.13). Female sex, younger age and weight exceeding 80 kg were significant risk factors for the incidence of CDK4/6i-related PAEs. CONCLUSIONS:Using data from a real-world, large-scale spontaneous reporting system for adverse drug reactions, our study delineated the spectrum of PAEs to CDK4/6i. This potentially offered valuable insights for healthcare professionals to manage the risk of PAEs in patients receiving CDK4/6i treatment, particularly those with psychiatric disorders.

The growing burden of psychological stress among diabetes patients has contributed to a rising incidence of depression within this population. It is of significant importance to conduct research on the impact of stress on diabetes patients and to explore potential pharmacological interventions to counteract the stress-induced exacerbation of their condition. Gastrodin is a low molecular weight bioactive compound extracted from the rhizome of Gastrodiae elata Blume, and it may be a preventive strategy for diabetes and a novel treatment for depression symptoms. However, its relevant pharmacological mechanisms for protecting against the impacts of psychological stress in diabetic patients are unclear. In this study, we performed 5 weeks CUMS intervention and simultaneously administered gastrodin (140 mg/kg, once daily) on T2DM mice, to investigate the potential protective effects of gastrodin. The protective effect of gastrodin was evaluated by behavioral tests, biochemical analysis, histopathological examination, RT-qPCR and gut microbiota analysis. We found that the depressive-like behavior and glucolipid metabolism could be deteriorated by chronic stress in type 2 diabetic mice, while gastrodin showed a protective effect against these exacerbations by regulating HPA hormones, activating FXR and Cyp7a1, reducing inflammatory and oxidative stress responses, and regulating ileal gut microbiota abundance. Gastrodin might be a potential therapeutic agent for mitigating the deterioration of diabetes conditions due to chronic stress.

Objective: Whether peripheral blood 5-hydroxytrptamine (5-HT) levels serve as biomarker for depression diagnosis/response evaluation has not been well determined. This work was explored to address this inconclusive issue. Methods: Animals were randomized into normal control group (NC, n = 10) and chronic unpredictable mild stress model group (CUMS-model, n = 20), respectively. Animals in CUMS-model group were subjected to chronic stress, then they were randomly subdivided into CUMS subgroup and CUMS + fluoxetine subgroup (CUMS + FLX). After FLX treatment, blood and tissues were collected. 5-HT and relevant protein expression were measured. Results: In mice model, there was a significant increase in serum and a significant reduction in plasma 5-HT levels in CUMS-model group versus NC group, while platelet 5-HT levels change little. After FLX treatment, serum and platelet 5-HT levels were significantly decreased in CUMS + FLX subgroup, while plasma 5-HT levels had not much change versus CUMS subgroup. Chronic stress enhanced colon and platelet serotonin transporter (SERT) expression and FLX treatment mitigated SERT expression. In rats' model, there was a significant increase in serum 5-HT levels while plasma and platelet 5-HT levels showed little change in CUMS group versus NC group. After FLX treatment, serum, plasma and platelet 5-HT levels were significantly decreased in CUMS + FLX subgroup versus CUMS subgroup. The profile of relevant proteins expression changed by FLX were like those in mice. Conclusion: Serum 5-HT levels might serve as a potential biomarker for depression diagnosis, meanwhile serum and platelet 5-HT levels might respond to antidepressant treatment.

Early chronic kidney disease (CKD) has strong concealment and lacks an efficient, non-invasive, and lable-free detection platform. Cystatin C (Cys C) in urine is closely related to the progress of CKD (especially at the early stage), which is an ideal endogenous marker to evaluate the impairment of renal function. Thus, the accurate detection of urinary Cys C (u-Cys C) is great significant for early prevention and treatment and delaying the course of the disease of CKD patients. Herein, we developed an extended-gate field-effect transistor (EG-FET) sensor for ultrasensitive detection of u-Cys C, which consists of a monolithic interface-engineered graphene EG electrode array and a commercially available MOSFET. Laser-induced graphene (LIG) loaded with sputtered Au NPs in the presence of adhesive Cr (Au NPs/Cr/LIG) boosts the electrical performance of the EG electrode. Meanwhile, Au NPs also serve as linkers to immobilize papain that can selectively form protein complexes with Cys C. Supported by the synergistic effect of multilevel interface-engineered graphene, our sensor exhibits a good linear correlation within the u-Cys C concentration range of 5 ag/μL to 50 ng/μL with low detection limit of 0.05 ag/μL. Our work makes accurate, specific and rapid detection of u-Cys C feasible and promising for early screening for CKD.

Circular RNA (circRNA) has been demonstrated to play a pivotal role in tumor development. This study aimed to investigate the regulatory mechanism of circMBOAT2 in non-small cell lung cancer (NSCLC) and its association with tumor growth induced by chronic stress. We constructed stably transfected A549 and H1299 cell lines with circMBOAT2 overexpression and knockdown. Colony formation, scratch healing, Transwell and CCK-8 assays were conducted to evaluate the effects of circMBOAT2 in the presence or absence of norepinephrine (NE) treatment on the proliferation, migration, and invasion of NSCLC cells, respectively. Additionally, A chronic unpredictable mild stress (CUMS)-induced depression with heterotopic transplantation LLC and injection of antisense oligonucleotides (ASOs) targeting circMBOAT2 mouse model was established to evaluate the effect of chronic stress on tumorigenesis via circMBOAT2. Moreover, we investigated the regulatory effect of CCCTC binding factor (CTCF) on circMBOAT2 expression through in vivo and in vitro silencing of CTCF. Our results revealed a significant upregulation of circMBOAT2 in NSCLC cell lines and tumor tissues. circMBOAT2 knockdown inhibited the proliferation, migration, and invasion of NSCLC cells, while NE treatment reversed the cell suppression effect caused by circMBOAT2 knockdown. Notably, CUMS promoted tumor growth, while silencing circMBOAT2 inhibited tumor growth in vivo. Furthermore, we identified CTCF as the upstream regulator of circMBOAT2, which exhibited upregulation in NSCLC cells and tissues. Knockdown of CTCF reversed the promotional effect of CUMS on circMBOAT2 expression and tumor growth. Our findings provide evidence that CTCF mediates chronic stress in promoting of NSCLC progression through circMBOAT2. circMBOAT2 may serve as a potential biomarker and therapeutic target for NSCLC as well as the treatment of comorbid depression in NSCLC patients.

The serotonin hypothesis of depression is still influential, but the relationship between peripheral 5-HT levels and depression is still unknown. This review aimed to verify whether peripheral 5-HT levels could be used as a biomarker for depression diagnosis and treatment. PubMed and EMBASE were searched using terms appropriate to the area of research. Articles from 1957 to 2022 in the following terms were identified: depression, 5-HT, serotonin and peripheral (serum, plasma, blood platelets). 33 studies were included: seven clinical trials about periphery 5-HT levels in depressive patients compared to normal subjects, 15 clinical trials about changes of peripheral 5-HT levels in patients with depression after drug treatment and 11 animal experiments about peripheral 5-HT levels in animal models of depression. Peripheral 5-HT levels presented three different outcomes before and after antidepressant treatments: increased, decreased and no significant change. In conclusion, changes in peripheral 5-HT levels did not show consistent results among these studies. Peripheral 5-HT level could not be used as a biomarker both for depression diagnosis and for antidepressant efficacy evaluation.

Background Imbalances in bile acid (BA) synthesis and metabolism are involved in the onset of diabetes and depression in humans and rodents. However, the role of BAs and the farnesoid X receptor (FXR)/fibroblast growth factor (FGF) 15 signaling pathway in the development of diabetes and depression is still largely unknown. Therefore, we investigated the potential molecular mechanisms of BAs that may be associated with glucolipid metabolism disorders in diabetic mice subjected to chronic stress. Methods The type 2 diabetes mellitus (T2DM) mouse model was induced by feeding mice a high-fat diet and administering an intraperitoneal injection of streptozotocin (STZ). The chronic unpredictable mild stress (CUMS) procedure was performed by introducing a series of mild stressors. Forty mice were randomly divided into the regular chow feeding group and the high-fat diet feeding group. After two weeks of feeding, the mice were randomly divided into four groups: the Control group, CUMS group, T2DM group, and T2DM+CUMS group. The T2DM group and T2DM+CUMS group received an intraperitoneal injection of STZ to induce the T2DM model. The CUMS and T2DM+CUMS groups were exposed to CUMS to induce depressive-like phenotypes. Blood and tissue samples were obtained for pertinent analysis and detection. Results Compared with the T2DM mice, T2DM+CUMS mice had higher blood glucose and lipid levels, insulin resistance, inflammation of the liver and pancreas, impaired liver function, and increased total bile acids. These changes were accompanied by attenuated FXR signaling. Chronic stress was found to attenuate FXR expression and its downstream target, FGF15, in the ileum when compared with the T2DM group. Conclusion FXR may play a role in the diabetic disorder of glucolipid metabolism when aggravated by chronic stress. FXR and its downstream target, FGF15, may be therapeutic targets for treating comorbid T2DM and depression.

Background and Objective: Chronic stress promotes tumor progression but the specific mechanism in the sympathetic nervous system is unclear. To explore the mechanism of whether chronic stress affects hormone levels and thus tumor progression, this study was conducted. Materials and Methods: A tumor-bearing mouse model was constructed by inoculating tumor cells and depression-like phenotype by chronic unpredictable mild stress, CUMS. The A549 cells were exposed to stress hormones. Mice were divided into 4 groups (n = 8): Control group, Tumor group, CUMS group and Tumor+CUMS group. Detecting the changes of mice models of tumor, CUMS and Tumor+CUMS in serum hormone and molecules of epithelial-mesenchymal transformation (EMT) in tumor tissues. The change of molecules of EMT when exposing A549 cells to cortisol and norepinephrine. Results: Chronic stress led to the increase of serum corticosterone and noradrenaline and enhanced the metastasis and invasion of cancer cells. In vivo chronic stress resulted in increased expression of tumor TGF-beta 1 and the changes of EMT-related molecules were also consistent with its course. In vitro, A549 cells showed morphological changes under CORT and NE, enhanced cloning, migration and invasion ability, up-regulated the expressions of TGF-beta 1, N-cadherin and Vimentin, down-regulated E-cadherin and ZO-1. The opposite phenomenon occurred after knocking down TGF-beta 1. However, CORT and NE reversed these changes. Conclusion: The high stress hormone levels caused by chronic stress affected the expression of TGF-beta 1 and thus promoted the tumor EMT.

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Objective: Gut microbiota play a key role in the pathogenesis of obesity and depression. Probiotics are a preventive strategy for obesity and a novel treatment for depression symptoms. However, the ameliorative or therapeutic effect of potential probiotic candidate Lactobacillus reuteri (L. reuteri) on obesity and depression comorbidity still remains unclear. We investigated the effects of chronic unpredictable mild stress (CUMS) in high-fat diet-fed mice and the effects of Lactobacillus reuteri strain 8008 on various disease indicators of obesity and depression comorbidity disease.Methods: Forty male C57BL/6 mice were randomized into 2 groups: the normal control (NC) group (n = 10) and the high-fat diet (HFD) group (n = 30), being fed with normal diet (ND) or high-fat diet (HFD) for 8 weeks, respectively. Then the obese mice fed with HFD were randomly allocated into 3 sub-groups: the HFD group (n = 10); the HFD + CUMS group (n = 10); the HFD + CUMS + L.r group (n = 10). The latter 2 subgroups underwent CUMS for 4 weeks to build the obesity and depression comorbidity mice model. During the duration of treatment, mice were gavaged with 0.5 mL PBS solution or L. reuteri (2 × 109 CFU/mL) once a day, respectively. The body weight, food intake, organ weight, behavioral indicators, histology, blood lipids, levels of inflammatory cytokines and tight junction proteins and abundance of colonic contents bacteria were measured.Results: The obesity and depression comorbidity mice model was successfully established after HFD feeding and chronic stress. The comorbid mice demonstrated inflammatory responses increase in liver and adipose tissues, worsened damage to the intestinal barrier as well as gut microbiota disorder. Gavaged with L. reuteri attenuated depressive-like behavior, improved blood lipids and insulin resistance, reduced inflammation in liver and adipose tissues, improved intestinal tight junctions as well as the microbiome dysbiosis in obesity and depression comorbidity mice.Conclusion:Lactobacillus reuteri strain 8008 could alleviate depressive-like behaviors and related indicators of obesity disorders by regulating the gut microbiota in obesity and depression comorbid mice.