Spatiotemporal variations of domoic acid: new findings in the sedimentary environment of a typical nearshore mariculture bay, China.

Domoic acid (DA) is a neurotoxin produced by marine microalgae. It tends to accumulate in marine shellfish and fish, posing a threat to aquaculture and seafood consumers' health. In this study, DA in the surface and bottom seawater, sediment, and porewater of the Jiaozhou Bay, a typical mariculture bay in China, was systematically investigated for the first time over different seasons. Surprisingly, a high concentration of DA was discovered in the marine sediment porewater (maximum detected concentration: 289.49 ng/L) for the first time. DA was found to be extensively distributed in the water body and sedimentary environment of the Jiaozhou Bay. DA in the surface and bottom seawater of Jiaozhou Bay in spring was uniformly distributed, whereas DA showed obvious spatial variations in summer and winter. The high concentration areas of DA are located in the north of Jiaozhou Bay and decreased to the south areas. DA was also distributed in the sediment (spring mean: 316.57 ng/kg; summer mean: 10.22 ng/kg; winter mean: 237.08 ng/kg) and porewater (spring mean: 129.70 ng/L; summer mean: 53.54 ng/L; winter mean: 19.90 ng/L) of Jiaozhou Bay. The DA concentrations in the surface sediment and porewater were higher in the spring than in the winter and summer, contrary to the seasonal variation pattern observed in the surface and bottom seawater. The DA concentration in porewater was significantly higher than in the surface and bottom seawater, indicating that the risk of pollution contamination from DA to benthic fishery organisms may be underestimated. Overall, DA is widely distributed in the seawater and also in the benthic environment of Jiaozhou Bay and exhibited potential harm to fishery organisms varied greatly with seasons. It is an important discovery for marine algae toxins and has important guiding significance and important indicative role for the routine monitoring and management of DA pollution in water and benthic environment.

Near-unity angular anisotropy of circularly polarized luminescence from microspheres of monodispersed chiral conjugated polymers.

A microsphere, assembled from a chiral π-conjugated polymer with narrow polydispersity, features a well-organized twisted-bipolar structure and exhibits highly biased circularly polarized luminescence (CPL). The CPL emitted toward the equatorial direction is 61-fold greater than that emitted along the zenith direction, which is the highest anisotropy among existing microscopic CPL emitters.

Integrated RNA sequencing and biochemical studies reveal endoplasmic reticulum stress and autophagy dysregulation contribute to Tri (2-Ethylhexyl) phosphate (TEHP)-induced cell injury in Sertoli cells.

Tri (2-Ethylhexyl) phosphate (TEHP), widely used as a fire retardant and plasticizer, has been commonly found in the environment. Its potential health-related risks, especially reproductive toxicity, have aroused concern. However, the potential cellular mechanisms remain unexplored. In this study, we aimed to investigate the molecular mechanisms underlying TEHP-caused cell damage in Sertoli cells, which play a crucial role in supporting spermatogenesis. Our findings indicate that TEHP induces apoptosis in 15P-1 mouse Sertoli cells. Subsequently, we conducted RNA sequencing analyses, which suggested that ER stress, autophagy, and MAPK-related pathways may participate in TEHP-induced cytotoxicity. Furthermore, we demonstrated that TEHP triggers ER stress, activates p38 MAPK, and inhibits autophagy flux. Then, we showed that the inhibition of ER stress or p38 MAPK activation attenuates TEHP-induced apoptosis, while the inhibition of autophagy flux is responsible for TEHP-induced apoptosis. These results collectively reveal that TEHP induces ER stress, activates p38, and inhibits autophagy flux, ultimately leading to apoptosis in Sertoli cells. These shed light on the molecular mechanisms underlying TEHP-associated testicular toxicity.

WTAP participates in neuronal damage by protein translation of NLRP3 in an m6A-YTHDF1-dependent manner after traumatic brain injury.

BACKGROUND: Traumatic brain injury (TBI) is a common complication of acute and severe neurosurgery. Remodeling of N6-methyladenosine (m6A) stabilization may be an attractive treatment option for neurological dysfunction after TBI. In the present study, we explored the epigenetic methylation of RNA-mediated NLRP3 inflammasome activation after TBI. METHODS: Neurological dysfunction, histopathology, and associated molecules were examined in conditional knockout (CKO) WTAP[flox/flox, Camk2a-cre], WTAPflox/flox, and pAAV-U6-shRNA-YTHDF1-transfected mice. Primary neurons were used in vitro to further explore the molecular mechanisms of action of WTAP/YTHDF1 following neural damage. RESULTS: We found that WTAP and m6A levels were upregulated at an early stage after TBI, and conditional deletion of WTAP in neurons did not affect neurological function but promoted functional recovery after TBI. Conditional deletion of WTAP in neurons suppressed neuroinflammation at the TBI early phase: WTAP could directly act on NLRP3 mRNA, regulate NLRP3 mRNA m6A level, and promote NLRP3 expression after neuronal injury. Further investigation found that YTH domain of YTHDF1 could directly bind to NLRP3 mRNA and regulate NLRP3 protein expression. YTHDF1 mutation or silencing improved neuronal injury, inhibited Caspase-1 activation, and decreased IL-1ß levels. This effect was mediated via suppression of NLRP3 protein translation, which also reversed the stimulative effect of WTAP overexpression on NLRP3 expression and inflammation. CONCLUSION: Our results indicate that WTAP participates in neuronal damage by protein translation of NLRP3 in an m6A-YTHDF1-dependent manner after TBI and that WTAP/m6A/YTHDF1 downregulation therapeutics is a viable and promising approach for preserving neuronal function after TBI, which can provide support for targeted drug development.

A Chinese patent medicine's long-term efficacy on non-dialysis patients with CKD stages 3-5: a retrospective cohort study.

Background: Chinese patent medicine is commonly used in China as an important treatment mechanism to thwart the progression of chronic kidney disease (CKD) stages 3-5, among which Niaoduqing granules are a representative Chinese patent medicine; however, its long-term efficacy on CKD prognosis remains unclear. Methods: Patients were grouped according to Niaoduqing granule prescription duration (non-Niaoduqing granule (non-NDQ) group vs Niaoduqing granule (NDQ) group). Serum creatinine (SCr) variation was compared using a generalized linear mixed model (GLMM). Multivariate Cox regression models were constructed, adjusting for confounding factors, to explore the risk of composite outcomes (receiving renal replacement therapy (RRT) or having an estimated glomerular filtration rate (eGFR)<5 mL/min/1.73 m2, ≥50% decline in the eGFR from the baseline, and doubling of SCr) in individuals consuming Niaoduqing granules. Results: A total of 1,271 patients were included, with a median follow-up duration of 29.71 (12.10, 56.07) months. The mean SCr Z-scores for the non-NDQ group and NDQ group were -0.175 and 0.153, respectively, at baseline (p = 0.015). The coefficients of the NDQ group from visit 1 to visit 5 were -0.207 (95% CI: -0.346, -0.068, p = 0.004), -0.214 (95% CI: 0.389, -0.039, p = 0.017), -0.324 (95% CI: 0.538, -0.109, p = 0.003), -0.502 (95% CI: 0.761, -0.243, p = 0.000), and -0.252 (95% CI: 0.569, 0.065, p = 0.119), respectively. The survival probability was significantly higher in the NDQ group (p = 0.0039). Taking Niaoduqing granules was a significant protective factor for thwarting disease progression (model 1: HR 0.654 (95% CI 0.489-0.875, p = 0.004); model 2: HR 0.646 (95% CI 0.476, 0.877, p = 0.005); and model 3: HR 0.602 (95% CI 0.442, 0.820, p = 0.001)). Conclusion: The long-term use of Niaoduqing granules improved SCr variation and lowered the risk of CKD progression by 39.8%.

Renal protective effects and mechanisms of Astragalus membranaceus for diabetic kidney disease in animal models: An updated systematic review and meta-analysis.

BACKGROUND: Astragalus membranaceus (AM) shows potential therapeutic benefits for managing diabetic kidney disease (DKD), a leading cause of kidney failure with no cure. However, its comprehensive effects on renal outcomes and plausible mechanisms remain unclear. PURPOSE: This systematic review and meta-analysis aimed to synthesize the effects and mechanisms of AM on renal outcomes in DKD animal models. METHODS: Seven electronic databases were searched for animal studies until September 2023. Risk of bias was assessed based on SYRCLE's Risk of Bias tool. Standardized mean difference (SMD) or mean difference (MD) were estimated for the effects of AM on serum creatinine (SCr), blood urea nitrogen (BUN), albuminuria, histological changes, oxidative stress, inflammation, fibrosis and glucolipids. Effects were pooled using random-effects models. Heterogeneity was presented as I2. Subgroup analysis investigated treatment- and animal-related factors for renal outcomes. Publication bias was assessed using funnel plots and Egger's test. Sensitivity analysis was performed to assess the results' robustness. RevMan 5.3 and Stata MP 15 software were used for statistical analysis. RESULTS: Forty studies involving 1543 animals were identified for analysis. AM treatment significantly decreased SCr (MD = -19.12 µmol/l, 95 % CI: -25.02 to -13.23), BUN (MD = -6.72 mmol/l, 95 % CI: -9.32 to -4.12), urinary albumin excretion rate (SMD = -2.74, 95 % CI: -3.57, -1.90), histological changes (SMD = -2.25, 95 % CI: -3.19 to -1.32). AM treatment significantly improved anti-oxidative stress expression (SMD = 1.69, 95 % CI: 0.97 to 2.41), and decreased inflammation biomarkers (SMD = -3.58, 95 % CI: -5.21 to -1.95). AM treatment also decreased fibrosis markers (i.e. TGF-ß1, CTGF, collagen IV, Wnt4 and ß-catenin) and increased anti-fibrosis marker BMP-7. Blood glucose, lipids and kidney size were also improved compared with the DM control group. CONCLUSION: AM could improve renal outcomes and alleviate injury through multiple signaling pathways. This indicates AM may be an option to consider for the development of future DKD therapeutics.

Oroxin A alleviates early brain injury after subarachnoid hemorrhage by regulating ferroptosis and neuroinflammation.

BACKGROUND: Subarachnoid hemorrhage (SAH), a severe subtype of stroke, is characterized by notably high mortality and morbidity, largely due to the lack of effective therapeutic options. Although the neuroprotective potential of PPARg and Nrf2 has been recognized, investigative efforts into oroxin A (OA), remain limited in preclinical studies. METHODS: SAH was modeled in vivo through filament perforation in male C57BL/6 mice and in vitro by exposing HT22 cells to hemin to induce neuronal damage. Following the administration of OA, a series of methods were employed to assess neurological behaviors, brain water content, neuronal damage, cell ferroptosis, and the extent of neuroinflammation. RESULTS: The findings indicated that OA treatment markedly improved survival rates, enhanced neurological functions, mitigated neuronal death and brain edema, and attenuated the inflammatory response. These effects of OA were linked to the suppression of microglial activation. Moreover, OA administration was found to diminish ferroptosis in neuronal cells, a critical factor in early brain injury (EBI) following SAH. Further mechanistic investigations uncovered that OA facilitated the translocation of nuclear factor erythroid 2-related factor 2 (Nrf-2) from the cytoplasm to the nucleus, thereby activating the Nrf2/GPX4 pathway. Importantly, OA also upregulated the expression of FSP1, suggesting a significant and parallel protective effect against ferroptosis in EBI following SAH in synergy with GPX4. CONCLUSION: In summary, this research indicated that the PPARg activator OA augmented the neurological results in rodent models and diminished neuronal death. This neuroprotection was achieved primarily by suppressing neuronal ferroptosis. The underlying mechanism was associated with the alleviation of cellular death through the Nrf2/GPX4 and FSP1/CoQ10 pathways.

Tris(2-ethylhexyl) phosphate induces cytotoxicity in TM3 Leydig cells by modulating autophagy and endoplasmic reticulum stress.

Tris (2-ethylhexyl) phosphate (TEHP) is a frequently used organophosphorus flame retardant with significant ecotoxicity and widespread human exposure. Recent research indicates that TEHP has reproductive toxicity. However, the precise cell mechanism is not enough understood. Here, by using testicular mesenchymal stromal TM3 cells as a model, we reveal that TEHP induces apoptosis. Then RNA sequencing analysis, immunofluorescence, and western blotting results show that THEP inhibits autophagy flux and enhances endoplasmic reticulum (ER) stress. Moreover, the activation of the ER stress is critical for TEHP-induced cell injury. Interestingly, TEHP-induced ER stress is contributed to autophagic flux inhibition. Furthermore, pharmacological inhibition of autophagy aggravates, and activation of autophagy attenuates TEHP-induced apoptosis. In summary, these findings indicate that TEHP triggers apoptosis in mouse TM3 cells through ER stress activation and autophagy flux inhibition, offering a new perspective on the mechanisms underlying TEHP-induced interstitial cytotoxicity in the mouse testis.

Occurrence and prevalence of per- and polyfluoroalkyl substances in the sediment pore water of mariculture sites: Novel findings of PFASs from the Bohai and Yellow Seas using a newly established analytical method.

A new method for the determination of 26 legacy and emerging per- and polyfluoroalkyl substances (PFASs) in marine sediment pore water was developed using online solid phase extraction coupled with liquid chromatography-tandem mass spectrometry. The proposed method requires only about 1 mL of pore water samples. Satisfactory recoveries of most target PFASs (83.55-125.30 %) were achieved, with good precision (RSD of 1.09-16.53 %), linearity (R2 ≥ 0.990), and sensitivity (MDLs: 0.05 ng/L-5.00 ng/L for most PFASs). Subsequently, the method was applied to determine PFASs in the sediment pore water of five mariculture bays in the Bohai and Yellow Seas of China for the first time. Fifteen PFASs were detected with total concentrations ranging from 150.23 ng/L to 1838.48 ng/L (mean = 636.80 ng/L). The ∑PFASs and PFOA concentrations in sediment pore water were remarkably higher than those in surface seawater (tens of ng/L), indicating that the potential toxic effect of PFASs on benthic organisms may be underestimated. PFPeA was mainly distributed in pore water, and the partition of PFHpA (50.99 %) and PFOA (49.01 %) was almost equal in the solid and liquid phases. The proportions of all other PFASs partitioned in marine sediments were significantly higher than those in pore water.

Single-cell transcriptomics reveals the ameliorative effect of rosmarinic acid on diabetic nephropathy-induced kidney injury by modulating oxidative stress and inflammation.

Diabetic nephropathy (DN) is a severe complication of diabetes, characterized by changes in kidney structure and function. The natural product rosmarinic acid (RA) has demonstrated therapeutic effects, including anti-inflammation and anti-oxidative-stress, in renal damage or dysfunction. In this study, we characterized the heterogeneity of the cellular response in kidneys to DN-induced injury and RA treatment at single cell levels. Our results demonstrated that RA significantly alleviated renal tubular epithelial injury, particularly in the proximal tubular S1 segment and on glomerular epithelial cells known as podocytes, while attenuating the inflammatory response of macrophages, oxidative stress, and cytotoxicity of natural killer cells. These findings provide a comprehensive understanding of the mechanisms by which RA alleviates kidney damage, oxidative stress, and inflammation, offering valuable guidance for the clinical application of RA in the treatment of DN.

Depletion of regulatory T cells enhancing the anti-tumor effect of in situ vaccination in solid tumors.

The emergence of immune checkpoint inhibitors (ICIs) has revolutionized the clinical treatment for tumor. However, the low response rate of ICIs remains the major obstacle for curing patients and effective approaches for patients with primary or secondary resistance to ICIs remain lacking. In this study, immune stimulating agent unmethylated CG-enriched (CpG) oligodeoxynucleotide (ODN) was locally injected into the tumor to trigger a robust immune response to eradicate cancer cells, while anti-CD25 antibody was applied to remove immunosuppressive regulatory T cells, which further enhanced the host immune activity to attack tumor systematically. The combination of CpG and anti-CD25 antibody obtained notable regression in mouse melanoma model. Furthermore, rechallenge of tumor cells in the xenograft model has resulted in smaller tumor volume, which demonstrated that the combinational treatment enhanced the activity of memory T cells. Remarkably, this combinational therapy presented significant efficacy on multiple types of tumors as well and was able to prevent relapse of tumor partially. Taken together, our combinational immunotherapy provides a new avenue to enhance the clinical outcomes of patients who are insensitive or resistant to ICIs treatments.

vEpiNet: A multimodal interictal epileptiform discharge detection method based on video and electroencephalogram data.

To enhance deep learning-based automated interictal epileptiform discharge (IED) detection, this study proposes a multimodal method, vEpiNet, that leverages video and electroencephalogram (EEG) data. Datasets comprise 24 931 IED (from 484 patients) and 166 094 non-IED 4-second video-EEG segments. The video data is processed by the proposed patient detection method, with frame difference and Simple Keypoints (SKPS) capturing patients' movements. EEG data is processed with EfficientNetV2. The video and EEG features are fused via a multilayer perceptron. We developed a comparative model, termed nEpiNet, to test the effectiveness of the video feature in vEpiNet. The 10-fold cross-validation was used for testing. The 10-fold cross-validation showed high areas under the receiver operating characteristic curve (AUROC) in both models, with a slightly superior AUROC (0.9902) in vEpiNet compared to nEpiNet (0.9878). Moreover, to test the model performance in real-world scenarios, we set a prospective test dataset, containing 215 h of raw video-EEG data from 50 patients. The result shows that the vEpiNet achieves an area under the precision-recall curve (AUPRC) of 0.8623, surpassing nEpiNet's 0.8316. Incorporating video data raises precision from 70% (95% CI, 69.8%-70.2%) to 76.6% (95% CI, 74.9%-78.2%) at 80% sensitivity and reduces false positives by nearly a third, with vEpiNet processing one-hour video-EEG data in 5.7 min on average. Our findings indicate that video data can significantly improve the performance and precision of IED detection, especially in prospective real clinic testing. It suggests that vEpiNet is a clinically viable and effective tool for IED analysis in real-world applications.

Occurrence and distribution of phycotoxins in the Antarctic Ocean.

Lipophilic phycotoxins (LPTs) and domoic acid (DA) in Antarctic seawater, as well as parts of the South Pacific and the Southern Indian Oceans were systematically investigated. DA and six LPTs, namely pectenotoxin-2 (PTX2), okadaic acid (OA), yessotoxin (YTX), homo-yessotoxin (h-YTX), 13-desmethyl spirolide C (SPX1), and gymnodimine (GYM), were detected. PTX2, as the dominant LPTs, was widely distributed in seawater surrounding Antarctica, whereas OA, YTX, and h-YTX were irregularly distributed across the region. The total concentration of LPTs in surface seawater ranged from 0.10 to 13.57 ng/L (mean = 2.20 ng/L). ∑LPT levels were relatively higher in the eastern sea areas of Antarctica than in the western sea areas. PTX2 was the main LPT in the vertical profiles, and the PTX2 concentration was significantly higher in the epipelagic zone than water depths below 200 m. The predominant sources of PTX2 and OA in Antarctic sea areas are likely to be Dinophysis.

Mechanical and chemical itch regulated by neuropeptide Y-Y1 signaling.

Itch is a somatosensory sensation to remove potential harmful stimulation with a scratching desire, which could be divided into mechanical and chemical itch according to diverse stimuli, such as wool fiber and insect biting. It has been reported that neuropeptide Y (NPY) neurons, a population of spinal inhibitory interneurons, could gate the transmission of mechanical itch, with no effect on chemical itch. In our study, we verified that chemogenetic activation of NPY neurons could inhibit the mechanical itch as well as the chemical itch, which also attenuated the alloknesis phenomenon in the chronic dry skin model. Afterwards, intrathecal administration of NPY1R agonist, [Leu31, Pro34]-NPY (LP-NPY), showed the similar inhibition effect on mechanical itch, chemical itch and alloknesis as chemo-activation of NPY neurons. Whereas, intrathecal administration of NPY1R antagonist BIBO 3304 enhanced mechanical itch and reversed the alloknesis phenomenon inhibited by LP-NPY treatment. Moreover, selectively knocking down NPY1R by intrathecal injection of Npy1r siRNA enhanced mechanical and chemical itch behavior as well. These results indicate that NPY neurons in spinal cord regulate mechanical and chemical itch, and alloknesis in dry skin model through NPY1 receptors.

Investigating organic sulfur in estuarine and offshore environments: A combined field and cultivation approach.

Estuarine-offshore sediments accumulate substantial particulate organic matter, containing organic sulfur as a key component. However, the distribution and sources of organic sulfur in such environments remain poorly understood. This study investigated organic sulfur in the Yangtze River Estuary and adjacent East China Sea. Dissolved organic sulfur varied from 0.65 to 1.99 µmol/L (molar S:C 0.006-0.018), while particulate organic sulfur ranged from 0.42 to 2.69 µmol/L (molar S:C 0.007-0.082). Sedimentary organic sulfur exhibited a similar molar S:C ratio (0.014-0.071) to particulate organic sulfur in bottom water, implying that particulate matter deposition is a potential source. Furthermore, sediments exposed to frequent hypoxia harbored significantly higher organic sulfur and S:C values compared to non-hypoxic areas. Laboratory incubation experiments revealed the underlying mechanism: sustained activity of sulfate-reducing bacteria in hypoxic sediments led to a substantial increase in sedimentary organic sulfur (from 15 to 53 µmol/g) within 600 days. This microbially driven sulfurization rendered over 90 % of the organic sulfur resistant to acid hydrolysis. Therefore, this study demonstrates that, alongside particle deposition, microbial sulfurization significantly contributes to organic sulfur enrichment and likely promotes organic matter preservation in estuarine-offshore sediments, particularly under hypoxic conditions. This finding advances our understanding of organic sulfur sources in these vital ecosystems.

Magnetic biochar accelerates microbial succession and enhances assimilatory nitrate reduction during pig manure composting.

Biochar promotes microbial metabolic activities and reduces N2O on aerobic composting. However, the effects of magnetic biochar (MBC) on the microbial succession and N2O emissions during pig manure composting remain unclear. Herein, a 42-day composting experiment was conducted with five treatment regimes: pig manure without biochar (CK), 5 % pig manure-based biochar (5 % PBC), 2 % MBC (2 % MBC), 5 % MBC (5 % MBC) and 7.5 % MBC (7.5 % MBC)), to clarify the variation in functional microorganisms and genes associated with nitrogen and direct interspecies electron transfer via metagenomics. Fourier-transform infrared spectroscopy showed that MBC possessed more stable aromatic structures than pig manure-based biochar (PBC), indicating its greater potential for nitrous oxide reduction. MBC treatments were more effective in composting organic matter and improving the carbon/nitrogen ratio than PBC. The microbial composition during composting varied significantly, with the dominant phyla shifting from Firmicutes to Proteobacteria, Actinobacteria, and Bacteroidota. Network and hierarchical clustering analyses showed that the MBC treatment enhanced the interactions of dominant microbes (Proteobacteria and Bacteroidota) and accelerated the composting process. The biochar addition accelerated assimilatory nitrate reduction and slowed dissimilatory nitrate reduction and denitrification. The Mantel test demonstrated that magnetic biochar potentially helped regulate composting nutrients and affected functional nitrogen genes. These findings shed light on the role of MBC in mitigating greenhouse gas emissions during aerobic composting.

Single-Cell Transcriptomics Reveals the Ameliorative Effect of Oridonin on Septic Liver Injury.

Sepsis is a life-threatening syndrome leading to hemodynamic instability and potential organ dysfunction. Oridonin, commonly used in Traditional Chinese Medicine (TCM), exhibits significant anti-inflammation activity. To explore the protective mechanisms of oridonin against the pathophysiological changes, the authors conducted single-cell transcriptome (scRNA-seq) analysis on septic liver models induced by cecal ligation and puncture (CLP). They obtained a total of 63,486 cells, distributed across 11 major cell clusters, and concentrated their analysis on four specific clusters (hepatocytes/Heps, macrophages, endothelial/Endos and T/NK) based on their changes in proportion during sepsis and under oridonin treatment. Firstly, biological changes in Hep, which are related to metabolic dysregulation and pro-inflammatory signaling, are observed during sepsis. Secondly, they uncovered the dynamic profiles of macrophage's phenotype, indicating that a substantial number of macrophages exhibited a M1-skewed phenotype associated with pro-inflammatory characteristics in septic model. Thirdly, they detected an upregulation of both inflammatory cytokines and transcriptomic factor Nfkb1 expression within Endo, along with slight capillarization during sepsis. Moreover, excessive accumulation of cytotoxic NK led to an immune imbalance. Though, oridonin ameliorated inflammatory-related responses and improved the liver dysfunction in septic mice. This study provides fundamental evidence of the protective effects of oridonin against sepsis-induced cytokine storm.

Oral Chinese Herbal Medicine plus usual care for diabetic kidney disease: study protocol for a randomized, double-blind, placebo-controlled pilot trial.

Background: Diabetic kidney disease (DKD) has become the leading cause of kidney failure, causing a significant socioeconomic burden worldwide. The usual care for DKD fails to achieve satisfactory effects in delaying the persistent loss of renal function. A Chinese herbal medicine, Tangshen Qushi Formula (TQF), showed preliminary clinical benefits with a sound safety profile for people with stage 2-4 DKD. We present the protocol of an ongoing clinical trial investigating the feasibility, efficacy, and safety of TQF compared to placebo in delaying the progressive decline of renal function for people with stage 2-4 DKD. Methods: A mixed methods research design will be used in this study. A randomized, double-blind, placebo-controlled pilot trial will evaluate the feasibility, efficacy, and safety of TQF compared to placebo on kidney function for people with stage 2-4 DKD. An embedded semi-structured interview will explore the acceptability of TQF granules and trial procedures from the participant's perspective. Sixty eligible participants with stage 2-4 DKD will be randomly allocated to the treatment group (TQF plus usual care) or the control group (TQF placebo plus usual care) at a 1:1 ratio for 48-week treatment and 12-week follow-up. Participants will be assessed every 12 weeks. The feasibility will be assessed as the primary outcome. The changes in the estimated glomerular filtration rate, urinary protein/albumin, renal function, glycemic and lipid markers, renal composite endpoint events, and dampness syndrome of Chinese medicine will be assessed as the efficacy outcomes. Safety outcomes such as liver function, serum potassium, and adverse events will also be evaluated. The data and safety monitoring board will be responsible for the participants' benefits, the data's credibility, and the results' validity. The intent-to-treat and per-protocol analysis will be performed as the primary statistical strategy. Discussion: Conducting a rigorously designed pilot trial will be a significant step toward establishing the feasibility and acceptability of TQF and trial design. The study will also provide critical information for future full-scale trial design to further generate new evidence supporting clinical practice for people with stage 2-4 DKD. Trial registration number: https://www.chictr.org.cn/, identifier ChiCTR2200062786.

The neuroprotection of controlled decompression after traumatic epidural intracranial hypertension through suppression of autophagy via PI3K/Akt signaling pathway.

Acute intracranial hypertension (AIH) is a common and tricky symptom that inflicts upon patients after traumatic brain injury (TBI). A variety of clinical options have been applied for the management of AIH, such as physiotherapy, medication, surgery and combination therapy. Specifically, controlled decompression (CDC) alleviates the extent of brain injury and reduces the incidence of a series of post-TBI complications, thereby enhancing the prognosis of patients suffering from acute intracranial hypertension. The objective of the present project is to illuminate the potential molecular mechanism that underlies the neuroprotective effects of CDC in a rat model of traumatic epidural intracranial hypertension (TEIH). Herein, we observed the functional recovery, the degree of brain edema, the level of apoptosis, the expressions of neuronal cell autophagy-related signaling pathway proteins (including Akt, p-Akt, LC3 and Beclin-1) in rat TEIH model at 24 h post-surgery. The results showed in comparison with rapid decompression (RDC), CDC reduced the degree of brain edema, diminished the level of cellular apoptosis and enhanced neurological function, and whereas the neuroprotective effect of CDC could be reversed by rapamycin (Rap). The expressions of Beclin-1 and LC3 in CDC group were significantly lower than those of RDC group, and the expression levels of these two proteins were significantly elevated after the addition of Rap. The expression of p-Akt in CDC group was considerably enhanced than RDC group. After the addition of LY294002, a PI3K/Akt pathway inhibitor, p-Akt protein expression was reduced, and the neuroprotective effect of the rats was markedly inhibited. Taken together, our data demonstrate the superior neuroprotective effect of CDC with regard to alleviating early brain edema, improving the neurological status, suppressing apoptosis and inhibiting neuronal autophagy via triggering PI3K/Akt signaling pathway.

The value of computed tomography angiography in predicting the surgical effect and prognosis of severe traumatic brain injury.

It is difficult to predict the surgical effect and outcome of severe traumatic brain injury (TBI) before surgery. This study aims to approve an evaluation method of computed tomography angiography (CTA) to predict the effect of surgery and outcome in severe TBI. Between January 2010 and January 2020, we retrospectively reviewed 358 severe TBI patients who underwent CTA at admission and reexamination. CTA data were evaluated for the presence of cerebrovascular changes, including cerebrovascular shift (CS), cerebral vasospasm (CVS), large artery occlusion (LAO), and deep venous system occlusion (DVSO). Medical records were reviewed for baseline clinical characteristics and the relationship between CTA changes and outcomes. Cerebrovascular changes were identified in 247 (69.0%) of 358 severe TBI patients; only 25 (10.12%) of them had poor outcomes, and 162 (65.6%) patients had a good recovery. Eighty-three (23.18%) patients were diagnosed with CVS, 10 (12.05%) had a good outcome, 57 (68.67%) had severe disability and 16 (19.28%) had a poor outcome. There were twenty-six (7.3%) patients who had LAO and thirty-one (8.7%) patients who had DVSO; no patients had good recovery regardless of whether they had the operation or not. Cerebrovascular injuries and changes are frequent after severe TBI and correlate closely with prognosis. CTA is an important tool in evaluating the severity, predicting the operation effect and prognosis, and guiding therapy for severe TBI. Well-designed, multicenter, randomized controlled trials are needed to evaluate the value of CTA for severe TBI in the future.