Association evaluations of oral anticoagulants with dementia risk based on genomic and real-world data.

BACKGROUND: Several observational studies have suggested that oral anticoagulants (OACs) might reduce the risk of dementia in the elderly, but the evidence is inconclusive. And the consistency of this relationship across different OAC classes and dementia subtypes is still uncertain. METHODS: To comprehensively evaluate this association, we applied Mendelian randomization (MR) combined with pharmacovigilance analysis. MR was used to assess the associations between genetic proxies for three target genes of OACs (VKORC1, F2, and F10) and dementia, including Alzheimer's disease (AD) and vascular dementia (VaD). This genetic analysis was supplemented with real-world pharmacovigilance data, employing disproportionality analysis for more reliable causal inference. RESULTS: Increased expression of the VKORC1 gene was strongly associated with increased risk of dementia, especially for AD (OR = 1.28, 95% CI = 1.14-1.43; p value < 0.001). Based on pharmacovigilance data, vitamin K antagonists (VKAs, inhibitors targeting VKORC1) exhibited a protective effect against dementia risk (ROR = 0.43, 95% CI = 0.28-0.67). Additional sensitivity analyses, including different MR models and cohorts, supported these results. Conversely, no strong causal associations of genetically proxied F2 and F10 target genes with dementia and its subtypes were found. CONCLUSIONS: This study reveals that the inhibition of genetically proxied VKORC1 expression or VKAs exposure is associated with a reduced risk of Alzheimer's dementia. However, there is little evidence to support similar associations with direct oral anticoagulants (F2 inhibitors and F10 inhibitors). Further research is warranted to clinically validate our findings.

The Effect of Yiqi Huoxue Tongluo Decoction on Spinal Cord Microglia Activation and ASK1-MKK3-p38 Signal Pathway in Rats with Diabetic Neuropathic Pain.

Diabetic neuropathic pain (DNP) is one of the most common chronic peripheral neuropathies in diabetes mellitus (DM). Objective. To observe the underlying mechanism of the effects of Yiqi Huoxue Tongluo Decoction (YQHX) on DNP rats. Methods. SD rats were intraperitoneally injected with 35 mg/kg streptozotocin (STZ) to prepare DNP models and were treated with YQHX for 8 weeks. Results. Studies have shown that the drug restores some levels of MWT, TWL, and MNCV, downregulates the levels of inflammatory factors IL-6, IL-1ß, and TNF-α, downregulates the levels of ASK1-MKK3-p38, and weakens the level of OX42 activation. Conclusion. Yiqi Huoxue Tongluo Decoction can relieve DNP by affecting the activity of spinal cord microglia and the ASK1-MKK3-p38 signaling pathway, thereby reducing the central sensitization caused by the inflammatory response of DNP rats.

[Tetrahydropalmatine alleviated diabetic neuropathic pain by inhibiting activation of microglia via p38 MAPK signaling pathway].

Neuropathic pain is one of the common complications of diabetes. Tetrahydropalmatine(THP) is a main active component of Corydalis Rhizoma with excellent anti-inflammatory and pain-alleviating properties. This study aims to investigate the therapeutic effect of THP on diabetic neuropathic pain(DNP) and the underlying mechanism. High-fat and high-sugar diet(4 weeks) and streptozotocin(STZ, 35 mg·kg~(-1), single intraperitoneal injection) were employed to induce type-2 DNP in rats. Moreover, lipopolysaccharide(LPS) was used to induce the activation of BV2 microglia in vitro to establish an inflammatory cellular model. Fasting blood glucose(FBG) was measured by a blood glucose meter. Mechanical withdrawal threshold(MWT) was assessed with von Frey filaments, and thermal withdrawal latency(TWL) with hot plate apparatus. The protein expression levels of OX42, inducible nitric oxide synthase(iNOS), CD206, p38, and p-p38 were determined by Western blot, the fluorescence expression levels of OX42 and p-p38 in the dorsal horn of the rat spinal cord by immunofluorescence, the mRNA content of p38 and OX42 in rat spinal cord tissue by qRT-PCR, and levels of nitric oxide(NO), interleukin-1ß(IL-1ß), interleukin-6(IL-6), tumor necrosis factor-α(TNF-α), interleukin-10(IL-10), and serum fasting insulin(FINS) by enzyme-linked immunosorbent assay(ELISA). RESULTS:: showed that the mo-del group demonstrated significant decrease in MWT and TWL, with pain symptoms. THP significantly improved the MWT and TWL of DNP rats, inhibited the activation of microglia and p38 MAPK signaling pathway in rat spinal cord, and ameliorated its inflammatory response. Meanwhile, THP promoted the change of LPS-induced BV2 microglia from the pro-inflammatory M1 phenotype to the anti-inflammatory M2 phenotype, suppressed the activation of the p38 MAPK signaling pathway, decreased the expression levels of inflammatory factors NO, IL-1ß, IL-6, and TNF-α, and increased the expression level of anti-inflammatory factor IL-10. The findings suggested that THP can significantly ameliorate the pain symptoms of DNP rats possibly by inhibiting the inflammatory response caused by M1 polarization of microglia via the p38 MAPK pathway.

Acupuncture attenuates the development of diabetic peripheral neuralgia by regulating P2X4 expression and inflammation in rat spinal microglia.

Diabetic peripheral neuropathy (DPN) is a chronic microvascular complication of diabetes. The purpose of this study is to find the underlying mechanism for the effects of acupuncture in DPN rats. Rats were rendered diabetic with a single injection of 35 mg/kg streptozotocin (STZ). These STZ-diabetic rats were treated with acupuncture for 20 min once daily. The therapeutic efficacy of acupuncture was assessed using mechanical withdrawal threshold (MWT) and thermal withdrawal latency (TWL) evaluations. After 14 days treatment, acupuncture markedly reduced the pathological injury in STZ-diabetic rats. Moreover, it significantly down-regulated P2X4 and OX42 expression along with the reduced levels of inflammatory factors (CXCR3, TNF-α, IL-1ß, IL-6), GSP and lipid metabolisms in the spinal cord of the DPN rats. Acupuncture could relieve DPN in rats by regulating P2X4 expression and inflammation in spinal microglia.

Particle-enhanced turbidimetric immunoassay for determination of serum neutrophil gelatinase-associated lipocalin on the Roche Cobas c501 analyzer.

OBJECTIVE: Neutrophil gelatinase-associated lipocalin (NGAL) has been reported to be a good marker for tubular damage and acute kidney injury. The aim of this study was to develop a high throughput assay for the quantification of serum NGAL (sNGAL). METHODS: Imprecision, interference, linearity, recovery, and reference values were evaluated on Cobas c501. RESULTS: The assay was linear over the dynamic range of the study (R(2)=0.9988). The total assay imprecision was below 5%. The assay recovery was estimated at 98.89%-102.61%. The assay displayed a good linearity over the range from 35 µg/L to 4250 µg/L. A typical high-dose hook effect was observed for the assay at NGAL concentration>28,800 µg/L. No interference was observed with hemoglobin ≤ 5 g/L, bilirubin ≤ 0.3g/L, vitamin C ≤ 0.5 g/L, sodium heparin≤ 5 g/L and intralipid ≤ 1%. The 95th centile for serum NGAL was <122.57 µg/L from 454 healthy donors. There were no gender-related differences for serum NGAL. There were significant age-related differences between the 21-44 and 45-75 year categories for serum NGAL. The reference value for sNGAL was <116.52 µg/L in the 21-44 year group and <126.9 µg/L in the 45-75 year group. CONCLUSIONS: The NGAL assay verified to be a reliable assay with convenient performance characteristics. The assay improves and simplifies the laboratory workload.