Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by progressive cognitive decline, functional impairment, and neuropsychiatric symptoms. It represents the most prevalent form of dementia among the elderly population. Accumulating evidence indicates that oxidative stress plays a pivotal role in the pathogenesis of AD. Notably, elevated levels of oxidative stress have been observed in the brains of AD patients, where excessive reactive oxygen species (ROS) can cause extensive damage to lipids, proteins, and DNA, ultimately compromising neuronal structure and function. Amyloid β‑protein (Aβ) has been shown to induce mitochondrial dysfunction and calcium overload, thereby promoting the generation of ROS. This, in turn, exacerbates Aβ aggregation and enhances tau phosphorylation, leading to the formation of two pathological features of AD: extracellular Aβ plaque deposition and intracellular neurofibrillary tangles (NFTs). These events ultimately culminate in neuronal death, forming a vicious cycle. The interplay between oxidative stress and these pathological processes constitutes a core link in the pathogenesis of AD. The signaling pathways mediating oxidative stress in AD include Nrf2, RCAN1, PP2A, CREB, Notch1, NF‑κB, ApoE, and ferroptosis. Nrf2 signaling pathway serves as a key regulator of cellular redox homeostasis, exerts important antioxidant capacity and protective effects in AD. RCAN1 signaling pathway, as a calcineurin inhibitor, and modulates AD progression through multiple mechanisms. PP2A signaling pathway is involved in regulating tau phosphorylation and neuroinflammation processes. CREB signaling pathway contributes to neuroplasticity and memory formation; activation of CREB improves cognitive function and reduce oxidative stress. Notch1 signaling pathway regulates neuronal development and memory, participates in modulation of Aβ production, and interacts with Nrf2 toco-regulate antioxidant activity. NF‑κB signaling pathway governs immune and inflammatory responses; sustained activation of this pathway forms “inflammatory memory”, thereby exacerbating AD pathology. ApoE signaling pathway is associated with lipid metabolism; among its isoforms, ApoE-ε4 significantly increases the risk of AD, leading to elevated oxidative stress, abnormal lipid metabolism, and neuroinflammation. The ferroptosis signaling pathway is driven by iron-dependent lipid peroxidation, and the subsequent release of lipid peroxidation products and ROS exacerbate oxidative stress and neuronal damage. These interconnected pathways form a complex regulatory network that regulates the progression of AD through oxidative stress and related pathological cascades. In terms of therapeutic strategies targeting oxidative stress, among the drugs currently used in clinical practice for AD treatment, memantine and donepezil demonstrate significant therapeutic efficacy and can improve the level of oxidative stress in AD patients. Some compounds with antioxidant effects (such asα-lipoic acid and melatonin) have shown certain potential in AD treatment research and can be used as dietary supplements to ameliorate AD symptoms. In addition, non-drug interventions such as calorie restriction and exercise have been proven to exerted neuroprotective effects and have a positive effect on the treatment of AD. By comprehensively utilizing the therapeutic characteristics of different signaling pathways, it is expected that more comprehensive multi-target combination therapy regimens and combined nanomolecular delivery systems will be developed in the future to bypass the blood-brain barrier, providing more effective therapeutic strategies for AD.

The mechanisms underlying exercise-induced neuroprotective effects after traumatic brain injury (TBI) remained elusive, and there is a lack of effective treatments for TBI. In this study, we investigated the effects of an integrative approach of exercise and Yisaipu (TNFR-IgG fusion protein, TNF inhibitor) in a mouse TBI model. Male C57BL/6J mice were randomly assigned to a sedentary group or a group that followed a voluntary exercise regimen. The effects of 6-week prophylactic preconditioning exercise (PE) alone or in combination with post-TBI Yisaipu treatment on moderate TBI associated deficits were examined. The results showed that combined treatments of PE and post-TBI Yisaipu were superior to single treatments on reducing sensorimotor and gait dysfunctions in mice. These functional improvements were accompanied by reduced systemic inflammation largely via decreased serum TNF-α, boosted autophagic flux, and mitigated lesion volume after TBI. Given these neuroprotective effects, composite approaches such as a combination of exercise and TNF inhibitor may be a promising strategy for facilitating functional recovery from TBI and are worth further investigation.
Animals ; Brain Injuries, Traumatic/pathology* ; Disease Models, Animal ; Male ; Mice ; Mice, Inbred C57BL ; Neuroprotective Agents/pharmacology* ; Recovery of Function ; Tumor Necrosis Factor Inhibitors

Objective: To develop a nomogram model for the differential diagnosis of benign and malignant breast BI-RADS (Breast Imaging Reporting and Data System) category 4 nodules based on serum tumor specific protein 70 (SP70) and conventional laboratory indicators and validate its predictive efficacy. Methods: A case-control study design was used to retrospectively analyze the data of 429 female patients diagnosed with BI-RADS category 4 breast nodules by breast color doppler flow imaging at the First Affiliated Hospital of Nanjing Medical University from January 2021 to April 2022 with an age range of 16 to 91 years and a median age of 50 years, and the patients were divided into a training cohort (314 patients) and a validation cohort (115 patients) according to the inclusion time successively. Using postoperative pathological findings as the"gold standard", univariate and multivariate logistic regression analyses were used to identify the predictor variables used for the model. The nomogram, receiver operating characteristic (ROC) curves and calibration curves were drawn for the prediction model, and the discrimination and calibration of the model were evaluated using the consistency index (C-index) and calibration plots. Results: The postoperative pathological results showed that 286 (66.7%) were malignant nodules and 143 (33.3%) were benign nodules of 429 breast BI-RADS category 4 nodules. The serum SP70 (OR=1.227,95%CI: 1.033-1.458,P=0.020), NLR (OR=1.545,95%CI: 1.047-2.280,P=0.028), LDL-C (OR=2.215, 95%CI: 1.354-3.622, P=0.002), GLU (OR=2.050,95%CI:1.222-3.438,P=0.007), PT (OR=1.383,95%CI: 1.046-1.828,P=0.023), nodule diameter (OR=1.042, 95%CI: 1.008-1.076, P=0.015) and age (OR=1.062,95%CI: 1.011-1.116,P=0.016) were independent risk factors which could be used to distinguish benign and malignant breast BI-RADS category 4 nodules (P<0.05). The nomogram was plotted by the above seven independent variables, and the concordance index (C-index) for the training cohort and validation cohort were 0.842 (95%CI:0.786-0.898) and 0.787 (95%CI:0.687-0.886), respectively. The sensitivity and specificity of using this model to identify benign and malignant breast BI-RADS category 4 nodules in the training and validation cohort were 83.5%, 72.5% and 79.2%, 73.6%, respectively. The calibration curves showed good agreement between the predicted and actual values in the nomogram. Conclusions: This study combined serum SP70, conventional laboratory indicators and breast color doppler flow imaging to develop a nomogram model for the differential diagnosis of benign and malignant breast BI-RADS category 4 nodules. The model may have good predictive efficacy and may provide a basis for clinical treatment options, which is beneficial for guiding breast cancer screening and prevention.
Female ; Humans ; Middle Aged ; Adolescent ; Young Adult ; Adult ; Aged ; Aged, 80 and over ; Diagnosis, Differential ; Retrospective Studies ; Case-Control Studies ; Breast/pathology* ; Breast Neoplasms/pathology*

Morinda officinalis oligosaccharides (MOO) are an oral drug approved in China for the treatment of depression in China. However, MOO is hardly absorbed so that their anti-depressant mechanism has not been elucidated. Here, we show that oral MOO acted on tryptophan → 5-hydroxytryptophan (5-HTP) → serotonin (5-HT) metabolic pathway in the gut microbiota. MOO could increase tryptophan hydroxylase levels in the gut microbiota which accelerated 5-HTP production from tryptophan; meanwhile, MOO inhibited 5-hydroxytryptophan decarboxylase activity, thus reduced 5-HT generation, and accumulated 5-HTP. The raised 5-HTP from the gut microbiota was absorbed to the blood, and then passed across the blood-brain barrier to improve 5-HT levels in the brain. Additionally, pentasaccharide, as one of the main components in MOO, exerted the significant anti-depressant effect through a mechanism identical to that of MOO. This study reveals for the first time that MOO can alleviate depression via increasing 5-HTP in the gut microbiota.

OBJECTIVE: To compare the registration accuracy of three-dimensional (3D) facial scans for the design of full-arch implant supported restoration by five methods and to explore the suitable registration method. METHODS: According to the criteria, ten patients with maxillary edentulous jaw or end-stage dentition requiring implant supported restorations were enrolled in this study. A special rim with individual feature marks reflected appropriate occlusal relationship and esthetic characteristics was made for each patient. Both 3D facial scan data of natural laughter and with opener traction to expose the teeth or occlusal rim of each patient were acquired by facial scan and input to the digital analysis software Geomagic Qualify 2012. The dataset was superimposed by five different methods: seven facial anatomical landmark points alignment, facial immobile area alignment (forehead and nasal area), facial anatomical landmark points and immobile area combining alignment, facial feature points alignment, facial and intraoral feature points alignment with the same local coordinate system. The three-dimensional deviation of the same selected area was calculated, the smaller the deviation, the higher the registration accuracy. The 3D deviation was compared among the three registration methods of facial anatomical landmark points, facial immobile area alignment and the combination of the above two methods. Friedman test was performed to analyze the difference among the three methods (α=0.05). The effect of the aid of the facial and intraoral feature points were evaluated. Paired t test were performed to analyze the difference (P<0.05). RESULTS: The average three-dimensional deviation of the selected area after alignment with the facial anatomical landmarks was (1.501 2±0.406 1) mm, significantly larger than that of the facial immobile area best-fit alignment [(0.629 1±0.150 6) mm] and the combination of the two methods[(0.629 1±0.150 6) mm] (P < 0.001). The aid of the facial feature points could significantly reduce the deviation (t=1.001 3, P < 0.001). There was no significant statistical difference in the remaining groups. CONCLUSION The forehead area of the 3D facial scan can be exposed as much as possible. The establishment of facial characteristic landmark points and the use of the invariant area alignment can improve the accuracy of registration. It should be clinically feasible to apply three-dimensional facial scan to the design of full-arch implant supported restoration with the registration of the immobile area on the face especially the forehead area.
Computer-Aided Design ; Humans ; Imaging, Three-Dimensional ; Jaw, Edentulous/diagnostic imaging* ; Maxilla/diagnostic imaging* ; Radionuclide Imaging

OBJECTIVE: To investigate the oral hygiene status of edentulous patients with locator attachments implant overdentures (IOD) and to analyze the relationship among daily hygiene behavior, oral hygiene status and peri-implant diseases. METHODS: Edentulous patients who received IOD treatment with locator attachments from January 2012 to May 2016 were recruited. Clinical and radiographic examinations were conducted to assess the peri-implant tissue status. Modified plaque index (mPLI), sulcus bleeding index (SBI), gingival index (GI), and probing depth (PD) were recorded and peri-implant marginal bone loss (MBL) was measured using paralleling projection technique. Patients' peri-implant oral hygiene maintainence habits were investigated. The correlation between peri-implant diseases and oral hygiene status and behaviors was analyzed. RESULTS: Fifty patients (125 implants) with an average follow-up time of 22 months (6-54 months) were enrolled. The mean values of mPLI, SBI, and GI were 1.4±1.2, 0.8±0.7, and 0.7± 0.6, respectively. Average PD was (2.2±0.7) mm. Mesial and distal maginal bone resorptions were (1.1±1.1) mm and (0.9±0.9) mm, respectively. The prevalance of mucositis and peri-implantitis of the implants were 49.6% and 0. The prevelance of mucositis in the patients with poor oral hygiene (mPLI≥2) was 11.9 times as much as that of those with adequate oral hygiene (mPLI<1). The patients who performed oral hygiene procedure on attachments at least twice a day achieved much lower mPLI scores than those who cleaned less than twice a day. CONCLUSION Oral hygiene condition in the group of patients with implant overdentures was poor, and it contributed to increased risk of peri-implant mucositis. The prevelance of musositis of the paitients with poor oral hygiene was 11.9 times as much as that of those with proper oral hygiene. Patients wearing IOD should pay more attention to the hygiene of the attachments.
Dental Implants ; Dental Prosthesis, Implant-Supported ; Denture, Overlay ; Humans ; Longitudinal Studies ; Mandible ; Oral Hygiene

Shengmai San was first recorded in Medical Origin and Insights, a medical book written by ZHANG Yuan\|su. Shengmai San composed of Ginseng Radix et Rhizoma, Ophiopogonis Radix and Schiandrae Chinensisin Fructus. Ginseng Radix et Rhizoma as the monarch drug in the prescription has effects in invigorating vigour potently, and promoting production of body fluid to quench thirst. Ophiopogonis Radix as a sweet-cold minister drug has effects in nourishing yin, clearing heat and generating fluid and moistening lung to stop cough in the prescription. Both medicines are combined to have a good effect in replenishing Qi. Schiandrae Chinensisin Fructus is an adjuvant medicine, with effects in acid astringency, retaining Yin with astringent and hidroschesis. Ginseng Radix et Rhizoma has effects in strengthening the healthy energy, and Ophiopogonis Radix has a effect in retaining yin with astringent. It is a classic prescription for treating deficiency of Qi and Yin. With the in-depth research of modern medical experts, it is found that Shengmai San not only has a significant therapeutic effect on cardiovascular diseases, central nervous system diseases and endocrine system diseases, but also a good effect on digestive system diseases, immune system and hematopoietic system diseases and shock. As China's aging population, irregular diet and other problems become increasingly serious, the incidences of cardiovascular diseases, senile dementia, cerebral infarction, diabetes, liver dysfunction and other diseases have become higher and younger, which is a serious threat to human health. Therefore, by consulting a large number of domestic literatures, the authors respectively elaborated the therapeutic effect and mechanism of Shengmai San and its modified prescriptions on the above diseases, with the aim to reveal the target and mechanism of this prescription on the above diseases, provide theoretical basis for better treatment of the above diseases and promote the clinical application of this prescription. In addition, it provides reference ideas for the research of other classical famous formula.

Objective To explore the significance of signal classification by multimodal magnetic resonance imaging(MRI)(including conventional MRI,diffusion imaging,and susceptibility-weighted imaging)on neonatal punctate white matter lesions(PWML).Methods Between March 2011 and February 2013,neonates with PWML who underwent 3.0T MRI examination were recruited.The routine protocols included T1 weighted imaging (T1WI),T2 weighted imaging(T2WI),diffusion tensor imaging(DTI),and 3D-enhanced susceptibility-weighted angiography(ESWAN).Apparent diffusion coefficient(ADC)map,magnitude image,and phase image were obtained from DTI and ESWAN,respectively.The signal of PWML was one-to-one observed on T1WI,T2WI, ADC map and magnitude image.The combined signals were classified and the number of cases of each type was counted.Results Totally 84 neonates with PWML were included(preterm/term,47/37).Seven signal types were found and classified into three groups: ① Type Ⅰ was the most,59 cases,accounting for 70.24%,with the performance of high-signal intensity on T1WI,low-signal intensity on T2WI,low-signal intensity on ADC map,and high-signal intensity on magnitude image. ② Type Ⅱ,7 cases,accounting for 8.33%,high-signal intensity on T1WI,low-signal intensity on T2WI,low-signal intensity on ADC map,and low-signal intensity on magnitude image.③ Type Ⅲ - Ⅶ,26 cases,accounting for 30.95%,high-signal intensity on T1WI,low/iso-signal intensity on T2WI,low/iso-signal intensity on ADC map,high/iso-signal intensity on magnitude image.There was no significant difference in the incidence of different signal types between preterm and full-term PWML neonates. Conclusion Magnetic resonance signal may reflect the characteristics of PWML lesions.Signal classification of PWML by multimodal magnetic resonance imaging is helpful in determining injury type and has certain significance in guiding clinical treatment.

OBJECTIVETo investigate the apoptotic effects of Hsp90 selective inhibitor 17-AAG on human leukemia HL-60 and NB4 cells and analyse its possible mechanism.

METHODSCCK-8 assay was used to quantify the growth inhibition of cells after exposure to 17-AAG for 24 hours. Flow cytometrve with annexin V/propidium iodide staining was used to detect apoptosis of leukemia cells. Then Western blot was used to detect the activation of apoptosis related protein caspase-3 and PARP level. Gene expression profile of NB4 cells treated with 17-AAG was analyzed with real-time PCR arrays.

RESULTSThe inhibition of leukemia cell proliferation displayed a dose-dependent manner. Annexin V assay, cell cycle analysis and activation of PARP demonstrate that 17-AAG induced apoptosis leukemia cells. Real-time PCR array analysis showed that expression of 56 genes significantly up-regulated and expression of 23 genes were significantly down-regulated after 17-AAG treatment.

CONCLUSIONThe 17-AAG can inhibit the proliferation and induce the apoptosis of leukemia cells. After leukemia cells are treated with 17-AAG, the significant changes of apoptosis-related genes occured, and the cell apoptosis occurs via activating apoptosis related signaling pathway.

Apoptosis ; Benzoquinones ; pharmacology ; Caspase 3 ; metabolism ; Cell Cycle ; Cell Line, Tumor ; Cell Proliferation ; Down-Regulation ; HL-60 Cells ; HSP90 Heat-Shock Proteins ; antagonists & inhibitors ; Humans ; Lactams, Macrocyclic ; pharmacology ; Leukemia ; metabolism ; Poly(ADP-ribose) Polymerases ; metabolism ; Real-Time Polymerase Chain Reaction ; Signal Transduction ; Transcriptome

OBJECTIVE: To explore the correlation between postmortem interval (PMI) and five RNA markers of rat's skin--β-actin, glyceraldehyde-3-phosphate dehydrogenase (GAPDH), 18S ribosomal RNA(18S rRNA), 5S ribosomal RNA (5S rRNA), and microRNA-203 (miR-203), at different temperatures. METHODS: Eighteen SD rats were randomly divided into three environmental temperature groups: 4 °C, 15 °C and 35 °C, respectively. Skin samples were taken at 11 time points from 0 h to 120 h post-mortem. The total RNA was extracted from the skin samples and the five RNA levels were detected by real-time fluorescent quantitative PCR. Proper internal reference was selected by geNorm software. Regression analysis of the RNA markers was conducted by GraphPad software. RESULTS: 5S rRNA and miR-203 were most suitable internal references. A good linear relationship between PMI and RNA levels (β-actin and GAPDH) was observed in two groups (4 °C and 15 °C), whereas the S type curve relationship between the expression levels of the two markers (β-actin and GAPDH) and PMI was observed in the 35 °C group. The partial linear relationship between 18S rRNA and PMI was observed in the groups (15 °C and 35 °C). CONCLUSION Skin could be a suitable material for extracting RNA. The RNA expression levels of β-actin and GAPDH correlate well with PMI, and these RNA markers of skin tissue could be additional indice for the estimation of PMI.
Actins ; Animals ; Autopsy ; Glyceraldehyde-3-Phosphate Dehydrogenases/genetics* ; Postmortem Changes ; RNA ; RNA Stability ; RNA, Ribosomal, 18S ; Rats ; Real-Time Polymerase Chain Reaction ; Regression Analysis ; Skin ; Temperature