The link between the gut microbiome, inflammation, and Parkinson's disease.

As our society ages, the growing number of people with Parkinson's disease (PD) puts tremendous pressure on our society. Currently, there is no effective treatment for PD, so there is an urgent need to find new treatment options. In recent years, increasing studies have shown a strong link between gut microbes and PD. In this review, recent advances in research on gut microbes in PD patients were summarized. Increased potential pro-inflammatory microbes and decreased potential anti-inflammatory microbes are prominent features of gut microbiota in PD patients. These changes may lead to an increase in pro-inflammatory substances (such as lipopolysaccharide and H2S) and a decrease in anti-inflammatory substances (such as short-chain fatty acids) to promote inflammation in the gut. This gut microbiota-mediated inflammation will lead to pathological α-synuclein accumulation in the gut, and the inflammation and α-synuclein can spread to the brain via the microbiota-gut-brain axis, thereby promoting neuroinflammation, apoptosis of dopaminergic neurons, and ultimately the development of PD. This review also showed that therapies based on gut microbiota may have a bright future for PD. However, more research and new approaches are still needed to clarify the causal relationship between gut microbes and PD and to determine whether therapies based on gut microbiota are effective in PD patients. KEY POINTS: • There is a strong association between gut microbes and PD. • Inflammation mediated by gut microbes may promote the development of PD. • Therapies based on the gut microbiome provide a promising strategy for PD prevention.

Selenium speciation-dependent cancer radiosensitization by induction of G2/M cell cycle arrest and apoptosis.

Introduction: Radiation therapy has Q6long been a routine and effective treatment for non-small cell lung cancer (NSCLC), but the radioresistance and side effects have limited its application. In recent years, the superiority showed by trace element selenium in tumor radiotherapy sensitization has received wide attention. However, different forms of selenium compounds exhibit different chemical properties and their mechanisms of action on tumors may be different. Methods: Human non-small cell lung cancer SPC-A1 cells were studied. Drug toxicity was detected by MTT assay. The selenium content absorbed in vitro at different time points was detected by ICP-MS. Colony formation were conducted to observe the radiosensitization effect of different selenium compounds on SPC-A1 cells, and to compare the proliferation ability of SPC-A1 cells treated by radiation alone and radiation combined with different selenium compounds. Cell migration was detected by cell scratch assay. The changes of cell cycle and apoptosis were detected by flow cytometry. DCFH-DA fluorescent probe was used to detect the effects of different selenium compounds combined with X-ray on ROS production. Results: In this study, these four representative selenium compounds all have a certain ability to enhance the ability of radiotherapy to inhibit tumor cell proliferation and migration, and the mechanism may be related to blocking cell cycle in G2/M phase, activating the caspase cascade and reducing intracellular ROS levels to induce tumor cell apoptosis. Among them, -2-valent organic selenium has the most obvious effect, mainly inhibits cell migration, and induces early apoptosis by activating a large number of caspase-3, and arrest the cell cycle in S phase and G2/M phase. 0-valent selenium nanoparticles mainly arrest the cell cycle in G2/M phase. +4-valent inorganic selenium exerts its antitumor effects primarily by inhibiting tumor cell migration and inducing early apoptosis of tumor cells. Discussion: In this paper, the antitumor effects of four different forms of selenium compounds combined with X-rays on SPC-A1 cells were investigated, and their inhibitory effects on the proliferation and migration of cancer cells and their mechanisms were examined. We found that the radiosensitizing effect of selenium on NSCLC was closely related to its selenium form through the study of the sensitizing effect of different kinds of selenium compounds on radiotherapy.

The link between increased Desulfovibrio and disease severity in Parkinson's disease.

Parkinson's disease (PD), a progressive and incurable neurodegenerative disease, has taken a huge economic toll and medical burden on our society. Increasing evidence has shown a strong link between PD and the gut microbiome, but studies on the relationship between the gut microbiome and the severity of PD are limited. In this study, 90 fecal samples were collected from newly diagnosed and untreated patients with PD (n = 47) and matched healthy control subjects (n = 43). The 16S rRNA amplicon and shotgun metagenomic sequencing was performed, aiming to uncover the connection between the gut microbiome and disease severity in PD. The results showed that Desulfovibrio was significantly increased in PD compared to healthy controls and positively correlated with disease severity. The increase in Desulfovibrio was mainly driven by enhanced homogeneous selection and weakened drift. Moreover, through metagenome-assembled genomes (MAGs) analysis, a Desulfovibrio MAG (MAG58) was obtained which was also positively correlated with disease severity. MAG58 possesses a complete assimilatory sulfate reduction pathway and a near-complete dissimilatory sulfate reduction pathway to produce hydrogen sulfide which may influence the development of PD. Based on these results, a potential pathogenic mechanism was presented to illustrate how the increased Desulfovibrio accelerates the development of PD by producing excessive hydrogen sulfide. The present study highlighted the vital role of Desulfovibrio in the development of PD, which may provide a new target for the diagnosis and treatment of PD. KEY POINTS: • The evidence for the link between increased Desulfovibrio and disease severity in PD • A Desulfovibrio MAG was obtained which was correlated with PD • A model was presented to illustrate how increased Desulfovibrio causes PD.

Coupling effects of nitrate reduction and sulfur oxidation in a subtropical marine mangrove ecosystem with Spartina alterniflora invasion.

The mangrove ecosystem has a high nitrate reduction capacity, which significantly alleviates severe nitrogen pollution. However, current research on nitrate reduction mechanisms in the mangrove ecosystem is limited. Furthermore, Spartina alterniflora invasion has disrupted the balance of the mangrove ecosystem and the effect of S. alterniflora on nitrate reduction has not yet been fully elucidated. Nitrate reduction was comprehensively investigated in a subtropical mangrove ecosystem in this study, which has been invaded by S. alterniflora for 40 years. Results showed that S. alterniflora significantly increased the relative and absolute abundance of nitrate reduction genes, especially nirS (nitrite reductase), in the mangrove ecosystem. Dissimilatory nitrate reduction to ammonium was the main pathway of nitrate reduction in the mangrove ecosystem. Nitrate reduction was mainly performed by Desulfobacterales and occurred in the shallow layers (0-10 cm) of mangrove sediments. A strong positive correlation was found between nitrate reduction and sulfur oxidation (especially sulfide oxidation), and the sulfide content was significantly positively correlated with the relative abundance of nitrate reduction genes. Moreover, 207 metagenomic assembled genomes (MAGs) were constructed, including 50 MAGs with high numbers (≥ 10) of nitrate reduction genes. This finding indicates that the dominant microbes had strong nitrate reduction potential in mangrove sediments. Our findings highlight the impact of S. alterniflora invasion on nitrate reduction in a subtropical marine mangrove ecosystem. This study provides new insights into our understanding of nitrogen pollution control and contributes to the exploration of new nitrogen-degrading microbes in mangrove ecosystems.

Inflammatory microbes and genes as potential biomarkers of Parkinson's disease.

As the second-largest neurodegenerative disease in the world, Parkinson's disease (PD) has brought a severe economic and medical burden to our society. Growing evidence in recent years suggests that the gut microbiome may influence PD, but the exact pathogenesis of PD remains unclear. In addition, the current diagnosis of PD could be inaccurate and expensive. In this study, the largest meta-analysis currently of the gut microbiome in PD was analyzed, including 2269 samples by 16S rRNA gene and 236 samples by shotgun metagenomics, aiming to reveal the connection between PD and gut microbiome and establish a model to predict PD. The results showed that the relative abundances of potential pro-inflammatory bacteria, genes and pathways were significantly increased in PD, while potential anti-inflammatory bacteria, genes and pathways were significantly decreased. These changes may lead to a decrease in potential anti-inflammatory substances (short-chain fatty acids) and an increase in potential pro-inflammatory substances (lipopolysaccharides, hydrogen sulfide and glutamate). Notably, the results of 16S rRNA gene and shotgun metagenomic analysis have consistently identified five decreased genera (Roseburia, Faecalibacterium, Blautia, Lachnospira, and Prevotella) and five increased genera (Streptococcus, Bifidobacterium, Lactobacillus, Akkermansia, and Desulfovibrio) in PD. Furthermore, random forest models performed well for PD prediction based on 11 genera (accuracy > 80%) or 6 genes (accuracy > 90%) related to inflammation. Finally, a possible mechanism was presented to explain the pathogenesis of inflammation leading to PD. Our results provided further insights into the prediction and treatment of PD based on inflammation.

Effects of Spartina alterniflora Invasion on Nitrogen Fixation and Phosphorus Solubilization in a Subtropical Marine Mangrove Ecosystem.

Nitrogen fixation (NF) and phosphorus solubilization (PS) play a key role in maintaining the stability of mangrove ecosystems. In China, the invasion of Spartina alterniflora has brought a serious threat to the mangrove ecosystem. However, systematic research on NF and PS in mangrove sediments has not been conducted, and limited studies have focused on the response of NF and PS to S. alterniflora invasion, particularly at different sediment depths. In the present study, shotgun metagenomics and quantitative PCR were used to study the 0- to 100-cm sediment profile of the mangrove ecosystem in the Beibu Gulf of China. Results showed that the PS potential of mangrove sediments was primarily caused by enzymes encoded by phoA, phoD, ppx, ppa, and gcd genes. S. alterniflora changed environmental factors, such as total nitrogen, total phosphorus, and total organic carbon, and enhanced the potential of NF and PS in sediments. Moreover, most microorganisms involved in NF or PS (NFOPSMs) responded positively to the invasion of S. alterniflora. Cd, available iron, and salinity were the key environmental factors that affected the distribution of NF and PS genes (NFPSGs) and NFOPSMs. A strong coupling effect was observed between NF and PS in the mangrove ecosystem. S. alterniflora invasion enhanced the coupling of NF and PS and the interaction of microorganisms involved in NF and PS (NFAPSM), thereby promoting the turnover of NP and improving sediment quality. Finally, 108 metagenome-assembled genomes involved in NF or PS were reconstructed to further evaluate NFOPSMs. IMPORTANCE This study revealed the efficient nutrient cycling mechanism of mangroves. Positive coupling effects were observed in sediment quality, NF and PS processes, and NFOPSMs with the invasion of S. alterniflora. This research contributed to the understanding of the effects of S. alterniflora invasion on the subtropical mangrove ecosystem and provided theoretical guidance for mangrove protection, restoration, and soil management. Additionally, novel NFOPSMs provided a reference for the development of marine biological fertilizers.

Desulfobacterales stimulates nitrate reduction in the mangrove ecosystem of a subtropical gulf.

The amount of nitrogen compounds discharged into the natural environment has increased drastically due to frequent human activities and led to worsening pollution. The mangrove ecosystem can remove nitrogen pollution, in this regard, few studies had focused on the relationship among nitrogen cycling genes, environmental factors, and taxonomic composition. In this study, shotgun metagenomic sequencing and quantitative polymerase chain reaction were used to understand the nitrogen cycle in the subtropical mangrove ecosystem in the Beibu Gulf of China. Eight nitrogen cycling pathways were annotated. Nitrogen metabolism activities were significantly higher in the wet season than those in the dry season. The most abundant genes were those related to the synthesis and degradation of organic nitrogen, followed by the genes involved in nitrate reduction (denitrification, dissimilation/assimilation nitrate reduction). Furthermore, dissimilation nitrate reduction was the main nitrate reduction pathway. Desulfobacterales plays an important role in nitrogen cycling and contributes 12% of the genes of nitrogen pathways on average; as such, a strong coupling relationship exists among nitrogen cycling, sulfur cycling, and carbon cycling in the mangrove ecosystem. Nitrogen pollution in the mangrove wetland can be efficiently alleviated by nitrate reduction of Desulfobacterales. Nevertheless, only 50% of genes can be matched among the known species, suggesting that many unknown microorganisms in the mangrove ecosystem can perform nitrogen cycling. Total phosphorus, available iron, and total organic carbon are the key environmental factors that influence the distribution of nitrogen cycling genes, related pathways, and the taxonomic composition. Our study clearly illustrates how the mangrove ecosystem mitigates nitrogen pollution through Desulfobacterales. This finding could provide a research reference for the whole nitrogen cycling in the mangrove ecosystem.

Parthenolide Augments the Chemosensitivity of Non-small-Cell Lung Cancer to Cisplatin via the PI3K/AKT Signaling Pathway.

The mortality rate of non-small-cell lung cancer (NSCLC) remains high worldwide. Although cisplatin-based chemotherapy may greatly enhance patient prognosis, chemotherapy resistance remains an obstacle to curing patients with NSCLC. Therefore, overcoming drug resistance is the main route to successful treatment, and combinatorial strategies may have considerable clinical value in this effort. In this study, we observed that both parthenolide (PTL) and cisplatin (DDP) inhibited the growth of NSCLC cells in a dose- and time-dependent manner. The combination of PTL and DDP presented a synergistic inhibitory effect on NSCLC at a ratio of 50:1. The combination of PTL and DDP synergistically inhibited cell migration and invasion, inhibited cell cycle progression, and induced apoptosis of A549 and PC9 cells. Bioinformatics and network pharmacology analysis indicated that PTL may primarily affect the phosphatidylinositol 3-kinase (PI3K)-AKT signaling pathway. After treatment with PTL and DDP either alone or in combination, Western blot analysis revealed that the proteins levels of Bax and cleaved Caspase-3 were upregulated, while p-PI3K, p-Akt, Caspase-3, and Bcl-2 proteins were downregulated. Among these alterations, the combination of PTL and DDP was found to exhibit the most significant effects. PTL might therefore be considered as a new option for combination therapy of NSCLC.

Carbohydrate metabolism genes dominant in a subtropical marine mangrove ecosystem revealed by metagenomics analysis.

Mangrove sediment microorganisms play a vital role in the energy transformation and element cycling in marine wetland ecosystems. Using metagenomics analysis strategy, we compared the taxonomic structure and gene profile of the mangrove and non-mangrove sediment samples at the subtropical estuary in Beibu Gulf, South China Sea. Proteobacteria, Bacteroidetes, and Firmicutes were the most abundant bacterial phyla. Archaeal family Methanosarcinaceae and bacterial genera Vibrio and Dehalococcoides were significantly higher in the mangrove sediments than in the nonmangrove sediments. Functional analysis showed that "Carbohydrate metabolism" was the most abundant metabolic category. The feature of carbohydrate-active enzymes (CZs) was analyzed using the Carbohydrate-Active EnZymes Database. The significant differences of CZs between mangrove and non-mangrove sediments, were attributed to the amounts of polyphenol oxidase (EC 1.10.3.-), hexosyltransferase (EC 2.4.1.-), and ß-N-acetylhexosaminidase (EC 3.2.1.52), which were higher in the mangrove sediment samples. Principal component analysis indicated that the microbial community and gene profile between mangrove and non-mangrove sediments were distinct. Redundancy analysis showed that total organic carbon is a significant factor that affects the microbial community and gene distribution. The results indicated that the mangrove ecosystem with massive amounts of organic carbon may promote the richness of carbohydrate metabolism genes and enhance the degradation and utilization of carbohydrates in the mangrove sediments.