Phenazopyridine promotes RPS23RG1/Rps23rg1 transcription and ameliorates Alzheimer-associated phenotypes in mice.

Alzheimer's disease (AD) is the most common form of dementia with no effective treatment options. A complete elucidation of its underlying molecular mechanisms, including the transcription regulation of genes critically involved in AD, may shed light on new therapeutic development. RPS23RG1 is a newly identified AD-associated gene, whose expression is decreased in AD and restoration can attenuate AD-like phenotypes in animal models. However, the transcription regulation of RPS23RG1 remains unknown. In this study, we explored the promoter of RPS23RG1 and identified its transcription initiation site (TSS) at 1525 bp upstream of the ATG translation start codon. Progressive deletion analysis determined the presence of a negative regulatory region and a positive regulatory region within nucleotide positions +1127 to +1187 and +732 to +1127 relative to the TSS (+1), respectively. We conducted a reporter system to screen for compounds that increase RPS23RG1 expression through antagonizing its negative regulatory elements and identified phenazopyridine. Importantly, we demonstrated that phenazopyridine not only promoted RPS23RG1/Rps23rg1 expression, but also reduced AD-like pathologies and cognitive impairments in the APP/PS1 AD model mice. We also determined a critical negative regulatory domain of RPS23RG1 within nucleotide positions +1177 to +1187 and found that the transcription factor SMAD3 bound to this domain. Inhibition of SMAD3 promoted RPS23RG1 expression. Moreover, phenazopyridine reduced SMAD3 binding to the RPS23RG1 promoter without affecting SMAD3 phosphorylation and nuclear localization. Taken together, our results determine the transcription regulation mechanism of RPS23RG1 and show that phenazopyridine has potential for AD treatment through regulating RPS23RG1 transcription.

Associations between gastro-oesophageal reflux disease and a range of diseases: an umbrella review of systematic reviews and meta-analyses.

OBJECTIVE: Numerous meta-analyses have revealed the association between gastro-oesophageal reflux disease (GORD) and a range of diseases; however, the certainty of the evidence remains unclear. This study aimed to summarise and assess the certainty of evidence derived from meta-analyses. METHODS: Embase, PubMed, Web of Science, Cochrane Databases of Systematic Reviews, CNKI and Wangfang databases from their inception to 22 February 2020 were queried for systematic reviews and meta-analyses on the association between GORD and various diseases. The methodological quality of the included studies was assessed using A Measurement Tool to Assess Systematic Reviews 2 (AMSTAR 2), and evidence certainty was evaluated using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) system. Statistical analysis was conducted using Stata V.15. RESULTS: Ten publications with associations between GORD and different types of diseases were included. There was high heterogeneity (I2 >75%) among seven independent meta-analyses. Evidence for publication bias in two independent meta-analyses was also observed. According to the AMSTAR 2 approach, the methodological quality was high for 20% of meta-analyses, moderate for 10%, low for 40% and critically low for 30%. Based on GRADE approach, the certainty of evidence was high for the association between GORD and higher risk of chronic obstructive pulmonary disease (COPD) exacerbation (OR 5.37; 95% CI 2.71 to 10.64) and higher prevalence of oesophageal adenocarcinoma (OR 4.57; 95% CI 3.89 to 5.36), and it was moderate for the association between GORD and higher chronic rhinosinusitis prevalence (OR 2.16; 95% CI 1.37 to 3.48). CONCLUSION: The association between GORD and a range of diseases was extensively studied, and our findings revealed a high certainty of evidence of the association between GORD and an increased risk of COPD exacerbation as well as increased prevalence of oesophageal adenocarcinoma. Further investigations using systematic reviews and meta-analyses of high methodological quality that include prospective large cohort studies and adjusted confounders are warranted. PROSPERO REGISTRATION NUMBER: CRD42019122264.

Eupatilin prevents behavioral deficits and dopaminergic neuron degeneration in a Parkinson's disease mouse model.

AIMS: Neuroinflammation and apoptosis play a crucial role in Parkinson's disease (PD) pathogenesis. Eupatilin is a lipophilic flavonoid isolated from Artemisia species and exerts anti-apoptotic and anti-inflammatory activities. In this study, we investigated the effects of Eupatilin on a mouse model of PD induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). MAIN METHODS: The rotarod test and traction test were constructed to examine the motor function. Immunofluorescent staining was performed to detect the expression of TH, Iba-1 and GFAP. Apoptosis was examined by the TUNEL assay. Real-time PCR was used to determine the mRNA expression and Western blot and ELISA were used to determine the protein expression. KEY FINDINGS: Eupatilin improved behavioral impairment caused by MPTP. A loss of TH positive neurons was observed in the substantia nigra pars compacta of MPTP-lesioned brain, while it was rescued by Eupatilin. Moreover, MPTP administration increased the cell number of microglia and astrocytes and the expression of inflammatory factors TNF-α, IL-1ß, and IL-6. Whereas Eupatilin suppressed the activation of neuroinflammation. Eupatilin also decreased cell apoptosis enhanced by MPTP/MPP+ exposure in vivo and in vitro. We further revealed that Eupatilin abolished MPTP-induced downregulation of IκBα expression and accumulation of p65 in the nuclear compartment. Besides, MPTP administration led to dephosphorylation of Akt and GSK-3ß, but it was restored by Eupatilin. SIGNIFICANCE: We demonstrate that Eupatilin alleviates behavioral impairment and dopaminergic neuron loss induced by MPTP through inhibition of neuroinflammation and apoptosis. Our research provides more evidence for Eupatilin as a potential preventative drug for PD.

Association between H. pylori infection and health Outcomes: an umbrella review of systematic reviews and meta-analyses.

OBJECTIVE: Systematic reviews and meta-analyses have revealed the associations between H. pylori infection and various health outcomes. We aimed to evaluate the strength and breadth of evidence on the associations. DESIGN: Umbrella review of systematic reviews and meta-analyses. SETTING: No settings. PARTICIPANTS: No patients involved. DATA SOURCES: Embase, PubMed, Web of Science, Cochrane Library Databases, CNKI, VIP database and Wangfang database from inception to February 1, 2019. OUTCOMES MEASURES: Diverse diseases (such as cancer and ischaemic heart disease). RESULTS: Sixty articles reporting 88 unique outcomes met the eligible criteria. 74 unique outcomes had nominal significance (p<0.05). Of the outcomes with significance, 61 had harmful associations and 13 had beneficial associations. Furthermore, 73% (64) of the outcomes exhibited significant heterogeneity . Of the these meta-analyses, 32 had moderate to high heterogeneity (I2=50%-75%) and 24 had high heterogeneity (I2>75%). Moreover, 20% exhibited publication bias (p<0.1). In addition, 97% of the methodological qualities were rated 'critically low'. 36% of the evidence qualities of outcomes were rated 'low', 56% of the evidence qualities were rated 'very low' and 8% of the evidence qualities were rated 'moderate'. H. pylori infection may be associated with an increased risk of five diseases and a decreased risk of irritable bowel syndrome. CONCLUSION: Although 60 meta-analyses explored 88 unique outcomes, moderate quality evidence only existed for six outcomes with statistical significance. H. pylori infection may be associated with a decreased risk of irritable bowel syndrome and an increased risk of hypertriglyceridemia, chronic cholecystitis and cholelithiasis, gestational diabetes mellitus, gastric cancer and systemic sclerosis. TRIAL REGISTRATION: CRD42019124680.

[Real-Time Monitoring Method for Pedicle Screw Fixation Surgery Based on Near-Infrared Spectrum and Computer Tomography Images].

Spine is one of the most important organs in the human body. One of the most commonly used method for the treatment of spinal diseases is the internal fixation and accurate placement of pedicle screw, which is a key factor of spinal surgery. However, due to the large differences as to the appearance of pedicles, it is hard to place the pedicle screw precisely, which will cause complication. Therefore, to find a new real-time intra-operative monitoring method with navigation is the direction of clinical application research. In this paper, a new method was firstly proposed. This method combined computer tomography (CT) values and near-infrared spectroscopy (NIRs) measurement data to guide the PS placement, and the relationship between NIRs parameters and CT values along the PS trajectory in vertebrae was investigated. First, we took pig vertebrae as samples and different puncture paths were planned. Second, a near-infrared monitoring device was utilized in experiments of fresh pig vertebrae to acquire the best NIRs monitoring pattern factors. Finally, the correlation function between NIRs data and CT values pattern factors was obtained. The results showed that CT values have a linear relationship with NIRs monitoring pattern factors, which provide references for real-time monitoring method in pedicle screw fixation surgery. This model can be applied in monitoring the pedicle screw implantation and alarming. The proposed method will be potential in improving the accuracy of PS placement and reduce the risk caused by the misplacement of pedicle screw.

[Research on Optical Parameter along Puncture Path in Spinal Surgery Navigation Based on Near Infrared Spectroscopy].

Accurate placement of pedicle screws is a key factor of spinal surgery. Investigation of a new real-time intra-operative monitoring method is an important area of clinical application research which makes a contribution to planting pedicle screw accurately. Porcine spines were chosen as experimental objects. The changes of reduced scattering coefficient (µ'(s)) along normal puncture path, medial perforation path and lateral perforation path were measured and studied. A conclusion is drawn that there are two distinct peaks throughout the puncture process, appearing at the junction of cancellous bone and cortical bone, at the beginning and at the end, respectively. The reduced scattering coefficient is proved to be a good monitoring factor which can identify whether the screw is about to reach the critical position of the spine puncture. Moreover, the variation provides an important reference for spinal surgical navigation process.

[Study on real-time monitoring and assessment of near-infrared in the dehydration treatment of traumatic brain injury].

We used near-infrared spectroscopy technology to monitor and assess the treatment effect of dehydrating agent in injured rat brain in real time style. We employed the brain edema model in rats resulting from Feeney' s freefall damage, then treated with different doses of mannitol, and collected reduced scattering coefficient (p',) and intracranial pressure (ICP) values after the injury and during the treatment. The results showed that brain edema happened 1 h after the injury in rats' brain tissue, peaked around 72 h after injury, and then began to decrease gradually. The reduced scattering coefficient and ICP values of the treatment group injected with mannitol all decreased after administration. Compared with the effect of low-dose mannitol treatment, that of high-dose mannitol treatment was much better. The duration of the plateau was longer and most experiments results declined significantly. From this we conclude that the reduced scattering coefficient and ICP are consistent with the trend changes, and the reduced scattering coefficient could be used as an indicator for monitoring cerebral edema.

[Applications and progress of Fourier transform infrared spectroscopic microimaging in bone disease research].

Fourier transform infrared spectroscopy (FTIRS) and microimaging technique have been integrated together to evolve into Fourier transform infrared spectroscopic imaging (FTIRI) system. This system can provide not only the morphological information of the sample by visible image and FTIR image, but also the abundant information on the spectral, component and structure of specimen by FTIRS, especially of the heterogeneous solid mixture. The richer and more visualized information obtained by FTIRI greatly raised the research efficiency and usability of the spectral technique in biomedicine, pharmacology, forensic medicine, material science and chemistry, etc. The present paper depicts FTIRI development process, system structure, imaging principle and mode selection; and then introduces that FTIRI opened a new area of investigation for biomedicine, namely, research on bone disease by FTIRI. Then the paper illustrates the related research findings and progress in FTIRI use for osteopetrosis, osteogenesis imperfecta, osteoporosis and osteomalacia, as well as a couple of limitations. The prospective study for FTIRI in biomedical research field is also addressed.

Minimally invasive assessment of the effect of mannitol and hypertonic saline therapy on traumatic brain edema using measurements of reduced scattering coefficient (µs').

Minimally invasive functional near infrared spectroscopy (fNIRs) technology was utilized to assess the effects of mannitol and hypertonic saline (HS) in treating traumatic brain edema (TBE). Rats with TBE models were given mannitol or HS in different dosages for different groups. The reduced scattering coefficient (µ(s)') of the local cortex of rats was simultaneously monitored and recorded in vivo and real time by the minimally invasive fNIRs system. Brain water content (BWC) was measured by the wet and dry weight method at 1, 6, 24, 72, and 120 h after injury and treatment. Effects of treating TBE with different dehydration agents were then assessed by recording µ(s)' and BWC before and after administration of dehydration. In this study, the dynamic changes of brain edema and the effects of dehydration therapy were continuously monitored. Results implied that µ(s)' of the local cortex in rats is a good indicator for assessing effects of treatment of TBE. By recording changes in the value of µ(s)', the following conclusions were obtained: HS is more effective than mannitol in reducing cerebral edema. The effect of dehydration of HS is only related to osmotic gradient and has no correlation with concentration.

[Study on assessment of effects of mannitol on treatment of TBE based on measurement of mini-invasive optical parameter (micro'(s))].

Near infrared spectroscopy (NIRs) technology was utilized for assessing effects in treating traumatic brain edema (TBE). Firstly, models for rats with traumatic brain edema were copied according to Feeney's apparatus. Then rats were given mannitol with different dosages (large and little) according to their groups. Simultaneously rat's brain tissues were monitored in vivo and real-time by NIRs mini-invasive detector developed by the authors' laboratory. And the water content of the brain tissues was measured by the wet and dry weight method at 1, 6, 24, 72 and 120 h after the injury and the treatment. Then, effects in treating TBE with different dosages were assessed by analyzing reduced scattering coefficient (micro'(s)) data measured by NIRs and brain water content (BWC) before and after injecting dehydration. Finally, the authors found that reduced scattering coefficient (micro'(s)) of rat's local cortex is a good indicator of assessing effects of treatment of TBE and that may be a preferable approach to assessing effects in vivo and real-time in treatment of brain injury.