A cingulate-hippocampal circuit mediates early depressive-like behavior in the mouse model of Alzheimer disease.

Depressive symptoms usually precede the cognitive decline in Alzheimer disease (AD) and worsen the clinical outcome. However, the neural circuitry mediating early emotional dysfunction, especially depressive symptoms in AD, remains elusive. Anterior cingulate cortex (ACC) is closely related to depression and vulnerable in AD. By quantitative whole-brain mapping and electrophysiological recording, we found that the decreased axonal calcium activity in neurons of ACC and the glutamatergic projection from ACC to the ventral hippocampal CA1 (vCA1) is significantly impaired in 3-month-old 5×FAD mice, which exhibit depressive-like phenotype before cognition defects in early stage. The activation of ACC-vCA1 circuit by chemogenetic manipulation efficiently ameliorated the early depressive-like behaviors in 5×FAD mice. We further identified the upregulated neuregulin-1 (Nrg1) in ACC impaired the excitatory synaptic transmission from the ACC to vCA1 in AD. Our work reveals the role of ACC-vCA1 circuit in regulating AD associated depression symptom in a mouse model of AD.

Menin Deficiency Induces Autism-Like Behaviors by Regulating Foxg1 Transcription and Participates in Foxg1-Related Encephalopathy.

FOXG1 syndrome is a developmental encephalopathy caused by FOXG1 (Forkhead box G1) mutations, resulting in high phenotypic variability. However, the upstream transcriptional regulation of Foxg1 expression remains unclear. This report demonstrates that both deficiency and overexpression of Men1 (protein: menin, a pathogenic gene of MEN1 syndrome known as multiple endocrine neoplasia type 1) lead to autism-like behaviors, such as social defects, increased repetitive behaviors, and cognitive impairments. Multifaceted transcriptome analyses revealed that Foxg1 signaling is predominantly altered in Men1 deficiency mice, through its regulation of the Alpha Thalassemia/Mental Retardation Syndrome X-Linked (Atrx) factor. Atrx recruits menin to bind to the transcriptional start region of Foxg1 and mediates the regulation of Foxg1 expression by H3K4me3 (Trimethylation of histone H3 lysine 4) modification. The deficits observed in menin deficient mice are rescued by the over-expression of Foxg1, leading to normalized spine growth and restoration of hippocampal synaptic plasticity. These findings suggest that menin may have a putative role in the maintenance of Foxg1 expression, highlighting menin signaling as a potential therapeutic target for Foxg1-related encephalopathy.

Dexmedetomidine and acute kidney injury after non-cardiac surgery: A meta-analysis with trial sequential analysis.

BACKGROUND: Acute kidney injury (AKI) is a common complication after surgery and is associated with detrimental outcomes. This systematic review and meta-analysis evaluated perioperative dexmedetomidine on AKI and renal function after non-cardiac surgery. METHODS: PubMed, Embase, and Cochrane Library databases were searched until August 2023 for randomised trials comparing dexmedetomidine with normal saline on AKI and renal function in adults undergoing non-cardiac surgery. The primary outcome was the incidence of AKI (according to Kidney Disease Improving Global Outcomes or Acute Kidney Injury Network criteria). Meta-analysis was performed using a random-effect model. We conducted sensitivity analysis, trial sequential analysis (TSA), and Grading of Recommendations Assessment, Development and Evaluation level of evidence. RESULTS: Twenty-three trials involving 2440 patients were included. Dexmedetomidine administration, as compared to normal saline, significantly reduced the incidence of AKI (7.4% vs. 13.2%; risk ratio = 0.57, 95% CI = 0.40-0.83, P = 0.003, I2 = 0%; a high level of evidence); TSA and sensitivity analyses suggested the robustness of this outcome. For the renal function and inflammation parameters, dexmedetomidine decreased serum creatinine, blood urea nitrogen, cystatin C, tumour necrosis factor-α, and interleukin-6, and increased urine output and estimated glomerular filtration rate. Additionally, dexmedetomidine reduced postoperative nausea and vomiting and length of hospital stay. Dexmedetomidine was associated with an increased rate of bradycardia, but not hypotension. CONCLUSION: Dexmedetomidine administration reduced the incidence of AKI and improved renal function after non-cardiac surgery. Based on a high level of evidence, dexmedetomidine is recommended as a component of perioperative renoprotection. REGISTRATION: International Prospective Register of Systematic Reviews; Registration number: CRD42022299252.

Local Renal Treatments for Acute Kidney Injury: A Review of Current Progress and Future Translational Opportunities.

Acute kidney injury (AKI) constitutes a significant public health concern, with limited therapeutic options to mitigate injury or expedite recovery. A novel therapeutic approach, local renal treatment, encompassing pharmacotherapy and surgical interventions, has exhibited positive outcomes in AKI management. Peri-renal administration, employing various delivery routes, such as the renal artery, intrarenal, and subcapsular sites, has demonstrated superiority over peripheral intravenous infusion. This review evaluates different drug delivery methods, analyzing their benefits and limitations, and proposes potential improvements. Renal decapsulation, particularly with the availability of minimally invasive techniques, emerges as an effective procedure warranting renewed consideration for AKI treatment. The potential synergistic effects of combined drug delivery and renal decapsulation could further advance AKI therapies. Clinical studies have already begun to leverage the benefits of local renal treatments, and with ongoing technological advancements, these modalities are expected to increasingly outperform systemic intravenous therapy.

Design, synthesis, and anti-cancer evaluation of C-14 arylcarbamate derivatives of andrographolide.

In this study, we explored a concise and mild synthetic route to produce novel C-14 arylcarbamate derivatives of andrographolide, a known anti-inflammatory and anticancer natural product. Upon assessing their anti-cancer efficacy against pancreatic ductal adenocarcinoma (PDAC) cells, some derivatives showed stronger cytotoxicity against PANC-1 cells than andrographolide. In addition, we demonstrated one derivative, compound 3m, effectively reduced the expression of oncogenic p53 mutant proteins (p53R273H and p53R248W), proliferation, and migration in PDAC lines, PANC-1 and MIA PaCa-2. Accordingly, the novel derivative holds promise as an anti-cancer agent against pancreatic cancer. In summary, our study broadens the derivative library of andrographolide and develops an arylcarbamate derivative of andrographolide with promising anticancer activity against PDAC.

Menin Reduces Parvalbumin Expression and is Required for the Anti-Depressant Function of Ketamine.

Dysfunction of parvalbumin (PV) neurons is closely involved in depression, however, the detailed mechanism remains unclear. Based on the previous finding that multiple endocrine neoplasia type 1 (Protein: Menin; Gene: Men1) mutation (G503D) is associated with a higher risk of depression, a Menin-G503D mouse model is generated that exhibits heritable depressive-like phenotypes and increases PV expression in brain. This study generates and screens a serial of neuronal specific Men1 deletion mice, and found that PV interneuron Men1 deletion mice (PcKO) exhibit increased cortical PV levels and depressive-like behaviors. Restoration of Menin, knockdown PV expression or inhibition of PV neuronal activity in PV neurons all can ameliorate the depressive-like behaviors of PcKO mice. This study next found that ketamine stabilizes Menin by inhibiting protein kinase A (PKA) activity, which mediates the anti-depressant function of ketamine. These results demonstrate a critical role for Menin in depression, and prove that Menin is key to the antidepressant function of ketamine.

Dexmedetomidine Infusion Versus Placebo During Light or Deep Anesthesia on Postoperative Delirium in Older Patients Undergoing Major Noncardiac Surgery: A Pilot Randomized Factorial Trial.

BACKGROUND: Postoperative delirium (POD) is common among older surgical patients and may be affected by dexmedetomidine and depth of anesthesia. We designed this pilot study to assess the feasibility of comparing dexmedetomidine with normal saline during light versus deep anesthesia on POD in older patients undergoing major noncardiac surgery. METHODS: In this pilot randomized factorial study, 80 patients aged 60 years or older undergoing major noncardiac surgery were randomized (1:1:1:1) to receive dexmedetomidine infusion 0.5 µg/kg/h or normal saline placebo during light (bispectral index [BIS] target 55) or deep (BIS target 40) anesthesia. Feasibility end points included consent rate and dropout rate, timely enrollment, blinded study drug administration throughout surgery, no inadvertent unmasking, achieving BIS target throughout >70% of surgery duration, and the process of twice-daily POD screening. In addition, we estimated the POD incidences in the 2 control groups (placebo and deep anesthesia) and treatment effects of dexmedetomidine and light anesthesia. RESULTS: Between November 1, 2021, and June 30, 2022, 78 patients completed the trial (mean [standard deviation, SD] age, 69.6 [4.6] years; 48 male patients [62%]; dexmedetomidine-deep, n = 19; dexmedetomidine-light, n = 20; placebo-deep, n = 19; placebo-light, n = 20). This study had a high consent rate (86%) and a low dropout rate (2.5%). Average recruitment was 5 patients at each center per month. Dexmedetomidine and normal saline were administered in a blinded fashion in all patients. Unmasking did not occur in either group. Approximately 99% of patients received the scheduled study drug infusion throughout the surgery. Approximately 81% of patients achieved the BIS targets throughout >70% of the surgery duration. The scheduled twice-daily POD screening was completed without exception. Overall, 10 of the 78 patients (13%; 95% confidence interval [CI], 7%-22%) developed POD. For the 2 reference groups, POD was observed in 7 of the 39 patients (17.9%; 95% CI, 9%-32.7%) in the placebo group and 7 of the 38 patients (18.4%; 95% CI, 9.2%-33.4%) in the deep anesthesia group. Regarding the treatment effects on POD, the estimated between-group difference was -10% (95% CI, -28% to 7%) for dexmedetomidine versus placebo, and -11% (95% CI, -28% to 6%) for light versus deep anesthesia. CONCLUSIONS: The findings of this pilot study demonstrate the feasibility of assessing dexmedetomidine versus placebo during light versus deep anesthesia on POD among older patients undergoing major noncardiac surgery, and justify a multicenter randomized factorial trial.

Hypericum sampsonii exhibits anti-inflammatory activity in a lipopolysaccharide-induced sepsis mouse model.

Background and aim: Sepsis causes an uncontrolled systemic response characterized by excessive inflammation and immune suppression, leading to multiple organ failure and death. An effective therapeutic strategy for sepsis-related syndromes is urgently needed. Hypericum sampsonii Hance (HS) is a folk herbal plant used to treat arthritis and dermatitis, but the anti-inflammatory properties of HS and its related compounds have rarely been investigated. In this study, we aimed to explore the anti-inflammatory effects of HS. Experimental procedure: Models of bacterial lipopolysaccharide (LPS)-induced activated macrophages and endotoxemia mice were used, in which the TLR4/NF-κB signaling pathway is upregulated to trigger inflammatory responses. The HS extract (HSE) was delivered into LPS-induced endotoxemia mice via oral administration. Three compounds were purified using column chromatography and preparative thin layer chromatography and were validated by physical and spectroscopic data. Results: HSE suppressed NF-κB activation and proinflammatory molecules (TNF-α, IL-6, iNOS) in LPS-activated RAW 264.7 macrophages. Furthermore, oral administration of HSE (200 mg/kg) to LPS-treated mice improved the survival rate, restored body temperature, decreased TNF-α and IL-6 in serum, and reduced IL-6 expression in bronchoalveolar lavage fluid (BALF). In lung tissues, HSE reduced LPS-induced leukocyte infiltration and the expression of proinflammatory molecules (TNF-α, IL-6, iNOS, CCL4 and CCL5). Three pure compounds isolated from HSE, including 2,4,6-trihydroxybenzophenone-4-O-geranyl ether, 1-hydroxy-7 methoxyxanthone and euxanthone, were demonstrated to exhibit anti-inflammatory activities in LPS-stimulated RAW 264.7 macrophages. Conclusion: The present study demonstrated the anti-inflammatory effects of HS in vitro and in vivo. Further clinical studies of HS in human sepsis are warranted.

Targeting transient receptor potential canonical 1 reduces non­small cell lung cancer chemoresistance and stemness via inhibition of PI3K/AKT signaling.

TRPC1 enhances cell proliferation and migration in non-small cell lung cancer (NSCLC); however, its effect on NSCLC chemoresistance and stemness remains to be determined. The aim of the current study was to investigate the effect of TRPC1 on NSCLC chemoresistance and stemness and to determine the underlying mechanism of action. Cisplatin-resistant A549 (A549/CDDP) and H460 (H460/CDDP) cells were first established and were then transfected with negative control small interfering (si)RNA (si-NC) or TRPC1 siRNA (si-TRPC1). Cells were then treated with 740 Y-P, a PI3K/Akt agonist. Subsequently, the sensitivity of A549/CDDP and H460/CDDP cells to CDDP was evaluated. Furthermore, the expression levels of CD133 and CD44, and sphere formation ability were also determined. The results showed that the half-maximal inhibitory concentration (IC50) of CDDP was significantly higher in A549/CDDP cells compared with A549 cells and in H460/CDDP cells compared with H460 cells. TRPC1 silencing decreased the IC50 value of CDDP compared with the si-NC group in A549/CDDP (11.78 vs. 21.58 µM; P<0.01) and H460/CDDP (23.76 vs. 43.11 µM; P<0.05) cells. Additionally, TRPC1 knockdown in both cell lines decreased the number of spheres formed compared with the si-NC group. Furthermore, compared with the si-NC group, A549/CDDP cells transfected with si-TRPC1 exhibited decreased levels of both CD133 (P<0.01) and CD44 (P<0.05). However, only CD133 (P<0.05) was downregulated in TRPC1-depleted H460/CDDP cells compared with the si-NC group. In addition, TRPC1 knockdown repressed PI3K/AKT signaling compared with the si-NC group in both A549/CDDP and H460/CDDP cells (all P<0.05). Finally, cell treatment with 740 Y-P reversed the effect of TRPC1 knockdown on PI3K/AKT signaling, chemoresistance, and cancer stemness in A549/CDDP and H460/CDDP cells (all P<0.05). In conclusion, the results of the current study suggested that targeting TRPC1 could attenuate cancer stemness and chemoresistance via suppression of PI3K/AKT signaling in NSCLC.

Hypothalamic Menin regulates systemic aging and cognitive decline.

Aging is a systemic process, which is a risk factor for impaired physiological functions, and finally death. The molecular mechanisms driving aging process and the associated cognitive decline are not fully understood. The hypothalamus acts as the arbiter that orchestrates systemic aging through neuroinflammatory signaling. Our recent findings revealed that Menin plays important roles in neuroinflammation and brain development. Here, we found that the hypothalamic Menin signaling diminished in aged mice, which correlates with systemic aging and cognitive deficits. Restoring Menin expression in ventromedial nucleus of hypothalamus (VMH) of aged mice extended lifespan, improved learning and memory, and ameliorated aging biomarkers, while inhibiting Menin in VMH of middle-aged mice induced premature aging and accelerated cognitive decline. We further found that Menin epigenetically regulates neuroinflammatory and metabolic pathways, including D-serine metabolism. Aging-associated Menin reduction led to impaired D-serine release by VMH-hippocampus neural circuit, while D-serine supplement rescued cognitive decline in aged mice. Collectively, VMH Menin serves as a key regulator of systemic aging and aging-related cognitive decline.

Hydrodynamic cavitation-enhanced photocatalytic activity of P-doped TiO2 for degradation of ciprofloxacin: Synergetic effect and mechanism.

Hybrid methods with an enhanced oxidation capacity have been proposed for the removal of organic contaminants based on combining hydrodynamic cavitation (HC) with advanced oxidation processes (AOPs). In this study, we utilize the synergetic effect between photocatalytic processes and HC to strengthen ciprofloxacin (CIP) degradation by P-doped TiO2 catalysts. In comparison to a degradation ratio of 20.37 % in HC and 55.7 % in P-TiO2-based photocatalytic processes alone, the CIP degradation ratio reached as high as 90.63 % in HC-assisted photocatalytic processes with the optimal experimental parameters. The mechanic microjets treatment originated from HC make P-TiO2 nano photocatalysts with significantly increased surface area, smaller particle sizes, cleaner surface and improved dispersion, which were found using SEM, TEM, and BET analysis. Possible degradation mechanisms and reaction pathways of CIP during hybrid HC + photocatalytic processes were explored by coupling free radical capture experiments and liquid chromatography-mass spectrometry . This hybrid HC + photocatalytic technique has a potential application in the treatment of antibiotic sewage at the industrial level.

HDAC Inhibitor SAHA Alleviates Pyroptosis by up-regulating miR-340 to Inhibit NEK7 Signaling in Subarachnoid Hemorrhage.

BACKGROUND: Subarachnoid hemorrhage (SAH) is a cerebral hemorrhagic disease with a high disability and fatality rate. Cell pyroptosis is involved in the brain injury following SAH. Here, we explored the effect of HDAC inhibitor SAHA against cell pyroptosis after SAH. METHODS: The rat SAH model was established by endovascular perforation and the rat microglia were treated with 25 µm oxyhemoglobin (OxyHb) for 24 h to mimic SAH model in vitro. Neurological score and brain edema were assessed in rat SAH model. TUNEL staining detected apoptosis. qRT-PCR and western blotting were employed to detect expression levels of miR-340, NEK7 and inflammatory cytokines. ELISA assay determined the secretion of IL-1ß and IL-18 in rat serum and cell supernatant. A lactate dehydrogenase (LDH) kit measured the LDH activity in rat primary microglia. Microglia pyroptosis was detected by flow cytometry. RIP and dual luciferase reporter assays confirmed the binding relationship between miR-340 and NEK7. RESULTS: SAHA alleviated neurological dysfunction, inflammatory injury and microglia pyroptosis in SAH rats. SAHA suppressed LDH release, inflammatory factor expression and pyroptosis in microglia treated with OxyHb. Meanwhile, SAHA increased miR-340 expression and inhibited NEK7 level in vivo and in vitro SAH models. Further, miR-340 directly targeted NEK7 to inhibit the NLRP3 signaling pathway. Knockdown of miR-340 or overexpression of NEK7 reversed the suppressive effects of SAHA on microglia inflammation and pyroptosis. Additionally, knockdown of NEK7 impaired microglia inflammation and pyroptosis induced by miR-340 inhibitor. CONCLUSION: HDAC inhibitor SAHA ameliorates microglia pyroptosis in SAH through triggering miR-340 expression to suppress NEK7 signaling. This novel mechanism provides promise for SAHA in SAH treatment.

Microglial hexokinase 2 deficiency increases ATP generation through lipid metabolism leading to ß-amyloid clearance.

Microglial cells consume adenosine triphosphate (ATP) during phagocytosis to clear neurotoxic ß-amyloid in Alzheimer's disease (AD). However, the contribution of energy metabolism to microglial function in AD remains unclear. Here, we demonstrate that hexokinase 2 (HK2) is elevated in microglia from an AD mouse model (5xFAD) and AD patients. Genetic deletion or pharmacological inhibition of HK2 significantly promotes microglial phagocytosis, lowers the amyloid plaque burden and attenuates cognitive impairment in male AD mice. Notably, the ATP level is dramatically increased in HK2-deficient or inactive microglia, which can be attributed to a marked upregulation in lipoprotein lipase (LPL) expression and subsequent increase in lipid metabolism. We further show that two downstream metabolites of HK2, glucose-6-phosphate and fructose-6-phosphate, can reverse HK2-deficiency-induced upregulation of LPL, thus supporting ATP production and microglial phagocytosis. Our findings uncover a crucial role for HK2 in phagocytosis through regulation of microglial energy metabolism, suggesting a potential therapeutic strategy for AD by targeting HK2.

Theoretical Study of Adsorption Behavior of Dimethylamine and Ammonia on Al- and Ga-Doped BN Monolayer Surfaces Based on DFT.

Endogenous volatile organic compounds (VOCs) can reflect human health status and be used for clinical diagnosis and health monitoring. Dimethylamine and ammonia are the signature VOC gases of nephropathy. In order to find a potential gas sensitivity material for the detection of both signature VOC gases of nephropathy, this paper investigated the adsorption properties of dimethylamine and ammonia on Al- and Ga-doped BN monolayers based on density functional theory. Through analyzing the adsorption energy, adsorption distance, charge transfer, density of states, and HOMO/LUMO, the results indicated that the adsorption effect of Al- and Ga-doped BN monolayers to dimethylamine and ammonia is probably good, and these nanomaterials have the potential to be applied for nephropathy monitoring and clinical diagnosis.

Comparison of EGFR mutations detected by LNA-ARMS PCR in plasma ctDNA samples and matched tissue sample in non-small cell lung cancer patients.

BACKGROUND: Screening for epidermal growth factor receptor (EGFR) mutations is the key to select suitable patients with non-small cell lung cancer (NSCLC) for EGFR-TKI therapy in clinical practice. Nevertheless, tumor tissue that needed for mutation analysis is frequently unavailable, especially for patients with recurrence after operation. Therefore, detection of EGFR from circulating tumor DNA (ctDNA) in patients with NSCLC is a sensitive and convenient method to direct patient sequential treatment strategy. METHODS: One hundred and seventy-nine NSCLC patients with both tumor tissue samples and paired plasma samples were recruited. EGFR mutations were detected in 68 tumor tissue samples and 179 plasma samples using Anlongen Locked Nucleic Acid-Amplification Refractory Mutation System (LNA-ARMS) EGFR Mutation Detection Kit. The remaining 111 tumor tissue samples were detected with the use of multiplex PCR-Based NGS sequence. We calculated the sensitivity, specificity, positive prediction value (PPV) and negative prediction value (NPV) of LAN-ARMS PCR. The objective response rate (ORR) of patients received TKIs therapy was calculated. RESULTS: Of the 179 patients, EGFR mutations were detected in 77 of the 179 tumor tissue samples, with a positive rate of 43.01% (77/179). In addition, EGFR mutations were detected in 42 of the 179 plasma samples. The sensitivity and specificity of LAN-ARMS in detecting EGFR mutations were 57.18% and 98.04% respectively compared to tissue results. The PPV was 95.24%, and NPV was 72.99%. Of the 179 pair of samples, EGFR mutations were inconsistent in 39 pairs of tissue and plasma. The overall agreement of EGFR mutation detection was 78.21% (140/179). The ORR was higher in patients with both tissue and plasma EGFR mutations compared with that in patients with only tissue EGFR mutations (73.33% vs. 68.29%), but the difference was not significant. It was suggested that tissue detection combined with plasma detection could improve the mutation rate. CONCLUSION: In plasma samples, Anlongen LAN-ARMS EGFR Mutation Detection Kit had a high sensitivity and specificity for the detection of EGFR mutations. Anlongen LAN-ARMS EGFR Mutation Detection Kit had the advantages of easy-to-operate and high sensitivity in clinical application.

CEND1 deficiency induces mitochondrial dysfunction and cognitive impairment in Alzheimer's disease.

Alzheimer's disease (AD) is the most common form of neurodegenerative disease featured with memory loss and cognitive function impairments. Chronic mitochondrial stress is a vital pathogenic factor for AD and finally leads to massive neuronal death. However, the underlying mechanism is unclear. By proteomic analysis, we identified a new mitochondrial protein, cell-cycle exit and neuronal differentiation 1 (CEND1), which was decreased significantly in the brain of 5xFAD mice. CEND1 is a neuronal specific protein and locates in the presynaptic mitochondria. Depletion of CEND1 leads to increased mitochondrial fission mediated by upregulation of dynamin related protein 1 (Drp1), resulting in abnormal mitochondrial functions. CEND1 deficiency leads to cognitive impairments in mice. Overexpression of CEND1 in the hippocampus of 5xFAD mice rescued cognitive deficits. Moreover, we identified that CDK5/p25 interacted with and phosphorylated CEND1 which promoted its degradation. Our study provides new mechanistic insights in mitochondrial function regulations by CEND1 in Alzheimer's disease.