Acceleration of phosphorus weathering under warm climates.

The release of phosphorous (P) via chemical weathering is a vital process that regulates the global cycling of numerous key elements and shapes the size of the Earth's biosphere. It has long been postulated that global climate should theoretically play a prominent role in governing P weathering rates. Yet, there is currently a lack of direct evidence for this relationship based on empirical data at the global scale. Here, using a compilation of temperature and P content data of global surface soils (0 to 30 cm), we demonstrate that P release does enhance at high mean annual surface temperatures. We propose that this amplification of nutrient supply with warming is a critical component of Earth's natural thermostat, and that this relationship likely caused expanded oceanic anoxia during past climate warming events. The potential acceleration of phosphorus loss from soils due to anthropogenic climate warming may pose threats to agricultural production, terrestrial and marine ecosystems, and alter marine redox landscapes.

Atmospheric oxygenation as a potential trigger for climate cooling.

Secular changes in atmospheric CO2 and consequent global climate variations, are commonly attributed to global outgassing and the efficiency of silicate weathering, which may have been linked to mountain formation, land/arc distribution, and plant colonization through geological time. Although oxidative weathering has been shown to exert a significant role in the propagation of weathering fronts through the oxidation of Fe-bearing minerals, the influence of atmospheric O2 concentration (pO2) on silicate weathering, CO2 consumption, and global climate has not been thoroughly evaluated. This study presents a numerical model aimed at estimating the effects of pO2 on the climate, considering the influence of pO2 on the regolith thickness and thus weathering duration of granitic domains. Our model simulations reveal that an increase in weathering efficiency, through deeper penetration of the oxidative weathering front in the granitic regolith, would independently introduce a steady-state climate cooling of up to ∼8 °C, in step with one-order of magnitude rise in pO2. This temperature change may have repeatedly initiated the runaway ice-albedo feedback, leading to global glacial events (e.g., Neoproterozoic Snowball Earth). Increasing granitic weathering efficiency caused by a substantial pO2 increase may also have contributed to the development of icehouse climate during the Phanerozoic.

Lithium isotopic constraints on the evolution of continental clay mineral factory and marine oxygenation in the earliest Paleozoic Era.

The evolution of oxygen cycles on Earth's surface has been regulated by the balance between molecular oxygen production and consumption. The Neoproterozoic-Paleozoic transition likely marks the second rise in atmospheric and oceanic oxygen levels, widely attributed to enhanced burial of organic carbon. However, it remains disputed how marine organic carbon production and burial respond to global environmental changes and whether these feedbacks trigger global oxygenation during this interval. Here, we report a large lithium isotopic and elemental dataset from marine mudstones spanning the upper Neoproterozoic to middle Cambrian [~660 million years ago (Ma) to 500 Ma]. These data indicate a dramatic increase in continental clay formation after ~525 Ma, likely linked to secular changes in global climate and compositions of the continental crust. Using a global biogeochemical model, we suggest that intensified continental weathering and clay delivery to the oceans could have notably increased the burial efficiency of organic carbon and facilitated greater oxygen accumulation in the earliest Paleozoic oceans.

Revisiting marine redox conditions during the Ediacaran Shuram carbon isotope excursion.

The Neoproterozoic carbonate record contains multiple carbon isotope anomalies, which are the subject of intense debate. The largest of these anomalies, the Shuram excursion (SE), occurred in the mid-Ediacaran (~574-567 Ma). Accurately reconstructing marine redox landscape is a clear path toward making sense of the mechanism that drives this δ13 C anomaly. Here, we report new uranium isotopic data from the shallow-marine carbonates of the Wonoka Formation, Flinders Ranges, South Australia, where the SE is well preserved. Our data indicate that the δ238 U trend during the SE is highly reproducible across globally disparate sections from different depositional settings. Previously, it was proposed that the positive shift of δ238 U values during the SE suggests an extensive, near-modern level of marine oxygenation. However, recent publications suggest that the fractionation of uranium isotopes in ferruginous and anoxic conditions is comparable, opening up the possibility of non-unique interpretations of the carbonate uranium isotopic record. Here, we build on this idea by investigating the SE in conjunction with additional geochemical proxies. Using a revised uranium isotope mass balance model and an inverse stochastic carbon cycle model, we reevaluate models for δ13 C and δ238 U trends during the SE. We suggest that global seawater δ238 U values during the SE could be explained by an expansion of ferruginous conditions and do not require a near-modern level of oxygenation during the mid-Ediacaran.

Salvianolic acid A relieves cognitive disorder after chronic cerebral ischemia: Involvement of Drd2/Cryab/NF-κB pathway.

Chronic cerebral ischemia (CCI) refers to long-term hypoperfusion of cerebral blood flow with the main clinical manifestations of progressive cognitive impairment. The pathological mechanism of CCI is complex, and there is a lack of effective treatments. Salvianolic acid A (SalA) is a neuroprotective extract of Salvia miltiorrhiza with the effects of anti-inflammation and anti-apoptosis. In this study, the effect of SalA on cognitive function and Drd2/Cryab/NF-κB signaling pathway in rats with CCI was investigated. Morris water maze and open field test were used to observe the effects of SalA on the cognitive function of CCI rats. The pathological changes in the brain were observed by HE, Nissl, and LFB staining. TUNEL staining, enzyme-linked immunosorbent assay, and western blot analysis were used to detect the inflammatory and apoptosis in the cortex and hippocampus. The expression of Drd2/Cryab/NF-κB pathway-related molecules and Drd2 localization were detected by western blotting and dual immunofluorescence, respectively. SH-SY5Y cells were exposed to chronic hypoglycemic and hypoxic injury in vitro, and Drd2 inhibitor haloperidol was used to verify the involved pathway. The results showed that SalA could improve the cognitive function of CCI rats, reduce pathological damage of cortex and hippocampus, inhibit neuroinflammation and apoptosis, and suppress the activation of NF-κB by regulating Drd2/Cryab pathway. And SalA inhibited NF-κB activation and nuclear translocation in SH-SY5Y cells by upregulating Drd2/Cryab pathway, which was reversed by haloperidol interference. In conclusion, SalA could relieve CCI-induced cognitive impairment in rats, at least partly through the Drd2/Cryab/NF-κB pathway.

Baicalein alleviates depression-like behavior in rotenone- induced Parkinson's disease model in mice through activating the BDNF/TrkB/CREB pathway.

BACKGROUND: Parkinson's disease (PD) is the second most prevalent neurodegenerative disorder in the world. In addition to motor symptoms, a variety of non-motor symptoms seriously affect the life quality of PD patients. Baicalein, a flavonoid extracted from the herb Scutellaria baicalensis Georgi, exhibits anti-PD activity through alleviation of its motor symptoms. However, its effects on non-motor symptoms were barely reported. This study aimed to investigate the therapeutic effects of baicalein on PD-related depression. METHODS: After a 2-week injection of rotenone, mice with PD-related depression behavior were selected, divided into three groups, and administrated saline, baicalein, or madopar orally for four weeks. Behavior, neuroinflammation, neurotransmitters, and synaptic plasticity were evaluated. RESULTS: Our results showed that 4-week baicalein treatment significantly alleviated the depression-like behavior in the rotenone-induced mice model. Repeated baicalein treatment reduced α-synuclein aggregation, inhibited neuroinflammation, and maintained neurotransmitters homeostasis. Moreover, we found that baicalein treatment could remarkably protect the synaptic plasticity and activate the BDNF/TrkB/CREB pathway in the PD-related depression mice model. As traditional dopamine replacement therapy unleashed few effects on depression-like symptom amelioration and synaptic function protection, baicalein might be a more appropriate choice for PD-related depression. CONCLUSIONS: The current results suggested that baicalein could act as a treatment for PD-related depression.

Xiao-Xu-Ming decoction prevented hemorrhagic transformation induced by acute hyperglycemia through inhibiting AGE-RAGE-mediated neuroinflammation.

Stroke is one of the leading causes of death worldwide. Hemorrhagic transformation (HT) is a common serious complication of ischemic stroke (IS) and is related to poor prognosis. Hyperglycemia after stroke is associated with the occurrence of HT and seriously affects the clinical treatment of stroke. Our previous experiments demonstrated that the Xiao-Xu-Ming decoction effective components group (XXMD), which is a Chinese medicine formula reconstituted by active ingredients, has multiple pharmacological effects in the treatment of IS. However, the effects of XXMD on HT after IS remain unclear. Thus, we investigated the preventive effects of XXMD on hyperglycemia-induced HT and further explored the underlying mechanism. Acute hyperglycemia combined with the electrocoagulation cerebral ischemia model was used to establish the HT model. XXMD (37.5, 75, 150 mg/kg/d) was given by gavage for 5 days. Network pharmacology was used to predict potential targets and pathways of XXMD in HT occurrence, and further studies confirmed the related targets. The results showed that hyperglycemia aggravated neurological deficits and blood-brain barrier (BBB) disruption, leading to intracerebral hemorrhage. Pretreatment with XXMD improved neurological function and BBB integrity and inhibited HT occurrence. Network pharmacology revealed that AGE-RAGE-mediated neuroinflammation may be associated with hyperglycemia-induced HT. Further studies confirmed that hyperglycemia activated the AGE-RAGE signaling pathway, increased the expression of HMGB1, TLR4 and p-p65, and induced the release of inflammatory factors and neutrophil infiltration, leading to HT. XXMD could inhibit AGE-RAGE-mediated neuroinflammation. These findings indicated that pretreatment with XXMD alleviated hyperglycemia-induced HT, which may be associated with the inhibition of AGE-RAGE-mediated neuroinflammation. Therefore, XXMD may be a potential therapeutic drug for HT.

Cryptotanshinone alleviates chemotherapy-induced colitis in mice with colon cancer via regulating fecal-bacteria-related lipid metabolism.

Patients with colorectal cancer treated with 5-fluorouracil (5-FU) and irinotecan (CPT-11) exhibit a risk for chemotherapy-induced colitis (CIC) that may lead to fatal consequences. Cryptotanshinone (CTS) is a natural compound extracted from the root of Salvia miltiorrhiza Bunge that shows potent antitumor activities. We previously reported CTS relieved 5-FU/ CPT-11 induced colitis in tumor-free mice. In this study, we studied the effect of CTS on 5-FU/ CPT-11 induced colitis in mice with colitis associated colon cancer (CAC). The effects of CTS on CIC were evaluated by disease activity index (DAI) and histological assessment via hematoxylin-and-eosin staining. Serum lipids and lipid-metabolic enzymes were detected by commercial kits. Fecal microbial diversity was detected by 16S ribosomal RNA gene sequencing. To find the role of fecal bacteria in CAC mice with 5-FU/ CPT-11 induced colitis, pseudo-germ-free mice were established by intragastric administration of mixed antibiotics. Except for decreasing tumor number (3 ± 1 vs 6 ± 1, p < 0.05), CTS significantly alleviated DAI (1.9 ± 0.6 vs 2.6 ± 0.5, p < 0.05) and regulated serum lipids in CAC mice with 5-FU/ CPT-11induced colitis. Compared with model group, CTS significantly increased serum triglycerides (TG) (1.13 ± 0.26 mM vs 0.79 ± 0.03 mM, p < 0.05), high density lipoprotein (HDL) (3.88 ± 0.1 mM vs 3.28 ± 0.05 mM, p < 0.001) and oxidized low-density lipoprotein (oxLDL) (288.12 ± 65.92 ng/mL vs 150.72 ± 42.13 ng/mL, p < 0.05) level but decreased serum adiponectin level (1177.47 ± 179.2 pg/mL vs 1523.43 ± 91.8 pg/mL, p < 0.05). Among fecal bacteria significantly correlated with lipid metabolism, CTS significantly decreased the abundance of g__norank_f__Muribaculaceae (21.15 % ± 5.7 % vs 41.84 ± 12.0 %, p < 0.01) but increased that of g_Lactobacillus (11.13 % ± 6.6 % vs 5.7 % ± 4.6 %, p < 0.05), g__Alistipes (3.66 % ± 0.7 % vs 1.47 % ± 1,0%, p < 0.01) and g__Odoribacter (1.31 % ± 0.7 % vs 0.30 % ± 0.2 %, p < 0.01). In addition, the development of CIC and abnormal lipid metabolism were significantly prevented in pseudo-germ-free mice. Therefore, we concluded CTS alleviated 5FU/CPT-11 induced colitis in CAC mice via regulating fecal flora associated lipid metabolism.

Dihydrotanshinone attenuates chemotherapy-induced intestinal mucositis and alters fecal microbiota in mice.

Chemotherapy-induced intestinal mucositis (CIM) is a principal reason for reduced living quality of patients undergoing chemotherapy. Growing evidence showed gut microbiota played an important role in the development of intestinal mucositis. Dihydrotanshinone I (DHTS) is a liposoluble extract of Salvia miltiorrhiza Bunge with many bioactivities. Here we investigated the effect of DHTS on intestinal mucositis induced by 5-fluorouracil and irinotecan in mice. We detected the degree of intestinal mucosal damage and inflammatory response in CIM mice with or without DHTS administration. The body weight and disease activity index (DAI) of mice were monitored each day. H&E staining was used to evaluate pathological damage. The contents of interleukin 6 (IL-6), tumor necrosis factor (TNFα), diacylglycerol (DAO) and triglyceride (TG) in serum were determined by commercial kits. We also investigated the changes of fecal microbiota by 16S rRNA high-throughput sequencing. Spearman correlation analysis was used to evaluate the correlation between fecal microbiota and inflammatory factors. Tax4Funwas performed to infer the potential function of the microbial community. Results showed DHTS significantly reduced DAI, intestinal mucosal damage and inflammatory response in CIM mice by decreasing serum IL-6 and TNFα. In addition, there is an intense correlation between fecal microbiota and inflammatory factors. DHTS efficiently reversed disordered fecal microflora close to normal and increased the abundance of g__Akkermansia. DHTS also enriched bacterial species which promote butyric acid metabolism or negatively correlated with inflammatory factors. Besides, species enriched by DHTS in fecal microbiota were probably involved in glutamine production and ammonia oxidation. In conclusion, our study provides evidence that DHTS effectively attenuates CIM induced by 5-fluorouracil and irinotecan in mice. Regulation of the composition and function of fecal microbiota probably plays a critical role in the therapeutic effect of DHTS in CIM mice.

[Gene analysis in a family of hereditary hemorrhagic telangiectasia].

OBJECTIVE: To investigate the clinical feature of a family with hereditary hemorrhagic telangiectasia (HHT), and to study the mutation of its related genes. METHODS: Medical histories of the family were analyzed to detect HHT patients according to the diagnostic criteria. ENG and ALK-1 genes of the proband and her two daughters were analyzed. DNA from the three patients' peripheral blood was extracted. The exons 2-10 and their intron-exon boundaries of ALK1 were amplified with PCR, and then the PCR products were sequenced and analyzed to identify the mutation. RESULTS: There were 11 people in 41 family members of 4 generations were diagnosed as HHT. The proband and her two daughters suffered from multiple organ damage, the younger daughter appeared only imaging features instead of corresponding clinical symptoms. A missense mutation at the 1321 bp of cDNA (c.1321G>A) was detected in the exon 9 of ALK1, which resulted in valine 441 to methionine replacement in ALK-1 protein (p.Val441Met). CONCLUSION: A Chinese family with HHT was studied and a missense mutation (c.1321G>A, p.Val441Met) of ALK-1 was discovered. This mutation is the genetic basis of the family with HHT and is reported for the first time in China. This research will not only help to further investigate molecular mechanism of pathogenesis of HTT, but also provide evidences and references for the following gene screening and genetic counseling on HTT family members.