Xiang Li

Colorectal cancer (CRC) is a globally prevalent malignancy that poses a substantial threat to human health. Despite advancements in prevention, diagnosis, and treatment, CRC remains a formidable clinical challenge due to the incomplete elucidation of its pathological mechanisms. Glutamine, an abundant amino acid, exerts pivotal roles in energy production, redox homeostasis, macromolecular biosynthesis, and signal transduction within cancer cells. Elucidating the role of glutamine in CRC pathogenesis is therefore of profound significance. In this study, we investigated the regulatory role of Cyclin-dependent kinase 5 (Cdk5) in glutamine metabolism in CRC, employing both human CRC cell models and murine models. Our findings demonstrated that Cdk5 knockdown accelerated glutamine uptake while suppressing the proliferation of CRC cells. Further exploration of the underlying molecular mechanisms revealed that Cdk5 physically interacts with EZH2. Besides, Cdk5 phosphorylates EZH2 at specific sites, and then the PRC2 complex (centered around EZH2) catalyzes the production of H3K27me3, an inhibitory marker, to regulate the expression of genes involved in glutamine metabolism. At the same time, we also found that modulation of the Cdk5-EZH2 axis alters the epigenetic landscape of genes associated with glutamine transporters and tricarboxylic acid cycle (TCA) enzymes, resulting in reduced mitochondrial activity, impaired glutamine utilization in the TCA cycle, and decreased ATP production—collectively impacting the global glutamine metabolic processes in CRC cells. In in vivo experiments utilizing a murine CRC model, we established five experimental groups. Results showed that Dinaciclib treatment suppressed tumor growth in the CRC model, with this inhibitory effect being further potentiated upon combination with glutamine deprivation. These findings not only uncover the intricate interplay between Cdk5, EZH2, and glutamine metabolism in CRC but also offer novel insights into the pathogenic mechanisms of CRC and identify potential therapeutic targets.

BACKGROUND Deoxycholic acid (DCA), a secondary bile acid, is associated with colorectal carcinogenesis, but its mechanisms remain unclear. AIM To investigate how DCA regulates apoptosis in colorectal cancer (CRC) cells. METHODS SW480 and DLD-1 CRC cell lines were used to investigate the mechanism of apoptosis by western blotting, flow cytometry, confocal microscopy, and other methods. RESULTS DCA significantly induced apoptosis, with rates increasing to 7.2% ± 1.5% in SW480 cells and 14.3% ± 0.6% in DLD-1 cells after treatment, compared to 4.7% ± 1.0% and 11.6% ± 0.8% in controls (P < 0.05). Western blot analysis showed upregulation of pro-apoptotic proteins Bax and Cleaved-PARP, with a significant increase in the Cleaved-PARP/PARP ratio (P < 0.001). DCA treatment also increased the intracellular reactive oxygen species (ROS) levels of SW480 and DLD-1 cells to 1.2-fold and 1.3-fold, respectively (P < 0.01), while the increase of mitochondrial ROS levels in these cells was statistically significant under confocal microscopy. Additionally, cytosolic and mitochondrial Ca2+ levels increased 1.3-fold and 1.2-fold, respectively, in SW480 cells (P < 0.01), and 1.1-fold and 1.1-fold, respectively, in DLD-1 cells compared with controls (P < 0.05). p-CaMKII protein levels were also elevated (P < 0.01), indicating activation of the Ca2+-CaMKII signaling pathway. Pharmacological inhibition with BAPTA-AM (1 μM) reduced mitochondrial Ca2+ accumulation and ROS levels in SW480 cells (P < 0.05), and suppressed apoptosis. CONCLUSION DCA activates the Ca2+-CaMKII pathway, leading to ROS-mediated apoptosis in CRC cells, providing insights for potential therapeutic targets.

The amyloid deposition-to-cognitive impairment pathway is crucial in Alzheimer’s disease (AD) pathogenesis, with gut microbes influencing its development. Our study evaluated Clostridium butyricum MIYAIRI 588 (CBM588) as a potential AD treatment. In APP/PS1 mice, CBM588 improved cognitive function and alleviated colonic tissue pathology by modulating tight junction proteins (upregulating Claudin 1, ZO-1, and Occludin) and reducing inflammatory cytokines (IL-6, IL-1β, and TNF-α mRNA). It also reduced Aβ plaque deposition in the brain, regulated the JNK/CDK5/GSK-3β pathway to inhibit Tau hyperphosphorylation, and maintained neuronal integrity by downregulating Bax/Bcl-2 and inflammatory cytokines, thereby inhibiting apoptosis. While not altering the overall gut flora structure, CBM588 increased acetate-producing bacteria and decreased pro-inflammatory genera, reducing lipopolysaccharide levels. It also elevated short-chain fatty acids, particularly acetate, in colonic feces and brain tissue. Sodium acetate further inhibited BV2 cell apoptosis by suppressing JAK/STAT signaling and reducing Aβ and p-Tau expressions. In conclusion, CBM588 holds great potential as a novel probiotic for AD control. IMPORTANCE: The current study underscores the pivotal role of gut microbiota modulation in the treatment of Alzheimer’s disease(AD). Our comprehensive evaluation of CBM588 demonstrates its remarkable potential to ameliorate cognitive impairment in APP/PS1 mice by modulating gut microbiota composition, upregulating short-chain fatty acids, particularly acetate, and mitigating neuroinflammation. These findings not only provide novel insights into the gut-brain axis in AD but also offer a promising therapeutic strategy, highlighting the importance of targeting gut microbiota in future AD research and interventions.

Alzheimer’s disease (AD) is a prevalent and progressive neurodegenerative disorder that is the leading cause of dementia. The underlying mechanisms of AD have not yet been completely explored. Neuroinflammation, an inflammatory response mediated by certain mediators, has been exhibited to play a crucial role in the pathogenesis of AD. Additionally, disruption of the gut microbiota has been found to be associated with AD, and fecal microbiota transplantation (FMT) has emerged as a potential therapeutic approach. However, the precise mechanism of FMT in the treatment of AD remains elusive. In this study, FMT was performed by transplanting fecal microbiota from healthy wild-type mice into APP/PS1 mice (APPswe, PSEN1dE9) to assess the effectiveness of FMT in mitigating AD-associated inflammation and to reveal its precise mechanism of action. The results demonstrated that FMT treatment improved cognitive function and reduced the expression levels of inflammatory factors by regulating the TLR4/MyD88/NF-κB signaling pathway in mice, which was accompanied by the restoration of gut microbial dysbiosis. These findings suggest that FMT has the potential to ameliorate AD symptoms and delay the disease progression in APP/PS1 mice.

BACKGROUND Colorectal cancer (CRC) ranks among the most prevalent malignant tumors globally. Recent reports suggest that Fusobacterium nucleatum (F. nucleatum ) contributes to the initiation, progression, and prognosis of CRC. Butyrate, a short-chain fatty acid derived from the bacterial fermentation of soluble dietary fiber, is known to inhibit various cancers. This study is designed to explore whether F. nucleatum influences the onset and progression of CRC by impacting the intestinal metabolite butyric acid. AIM To investigate the mechanism by which F. nucleatum affects CRC occurrence and development. METHODS Alterations in the gut microbiota of BALB/c mice were observed following the oral administration of F. nucleatum . Additionally, DLD-1 and HCT116 cell lines were exposed to sodium butyrate (NaB) and F. nucleatum in vitro to examine the effects on proliferative proteins and mitochondrial function. RESULTS Our research indicates that the prevalence of F. nucleatum in fecal samples from CRC patients is significantly greater than in healthy counterparts, while the prevalence of butyrate-producing bacteria is notably lower. In mice colonized with F. nucleatum , the population of butyrate-producing bacteria decreased, resulting in altered levels of butyric acid, a key intestinal metabolite of butyrate. Exposure to NaB can impair mitochondrial morphology and diminish mitochondrial membrane potential in DLD-1 and HCT116 CRC cells. Consequently, this leads to modulated production of adenosine triphosphate and reactive oxygen species, thereby inhibiting cancer cell proliferation. Additionally, NaB triggers the adenosine monophosphate-activated protein kinase (AMPK) signaling pathway, blocks the cell cycle in HCT116 and DLD-1 cells, and curtails the proliferation of CRC cells. The combined presence of F. nucleatum and NaB attenuated the effects of the latter. By employing small interfering RNA to suppress AMPK, it was demonstrated that AMPK is essential for NaB’s inhibition of CRC cell proliferation. CONCLUSION F. nucleatum can promote cancer progression through its inhibitory effect on butyric acid, via the AMPK signaling pathway.

Introduction: Recent studies have provided insights into the important contribution of gut microbiota in the development of Pulmonary Tuberculosis (PTB). As a chronic consumptive infectious disease, PTB involves many pathological characteristics. At present, research on intestinal flora and clinical pathological Index of PTB is still rare.Methods: We performed a cross-sectional study in 63 healthy controls (HCs) and 69 patients with untreated active PTB to assess the differences in their microbiota in feces via 16S rRNA gene sequencing.Results: Significant alteration of microbial taxonomic and functional capacity was observed in PTB as compared to the HCs. The results showed that the alpha diversity indexes of the PTB patients were lower than the HCs (P<0.05). Beta diversity showed differences between the two groups (P<0.05). At the genus level, the relative abundance of Bacteroides, Parabacteroides and Veillonella increased, while Faecalibacterium, Bifidobacterium, Agathobacter and CAG-352 decreased significantly in the PTB group, when compared with the HCs. The six combined genera, including Lactobacillus, Faecalibacterium, Roseburia, Dorea, Monnoglobus and [Eubacterium]_ventriosum_group might be a set of diagnostic biomarkers for PTB (AUC=0.90). Besides, the predicted bacterial functional pathway had a significant difference between the two groups (P<0.05), which was mainly related to the nutrient metabolism pathway. Significant alterations in the biochemical index were associated with changes in the relative abundance of specific bacteria, the short chain fatty acid (SCFA)-producing bacteria enriched in HCs had a positively correlated with most of the biochemical indexes.Discussion: Our study indicated that the gut microbiota in PTB patients was significantly different from HCs as characterized by the composition and metabolic pathway, which related to the change of biochemical indexes in the PTB group. It was hypothesized that the abovementioned changes in the gut microbiota could exert an impact on the clinical characteristics of PTB through the regulation of the nutrient utilization pathway of the host by way of the gut-lung axis.

Fucoidan has many biological activities, including the inhibitory effect on the development of various cancer types. This study showed that lipopolysaccharide-induced inflammation in FHC cells (normal human colonic epithelial cells) could be reversed using fucoidan at different concentrations. The fucoidan-induced anti-inflammatory effect was also confirmed through in vivo experiments in mice. Compared to the mice of the model group, the ratio of Firmicutes/Bacteroidetes in feces increased and the diversity of gut microbial composition was restored in mice after fucoidan intervention. In colorectal cancer (CRC) cells DLD-1 and SW480, fucoidan inhibited cell proliferation and promoted cell apoptosis. It also blocked the cell cycle of DLD-1 and SW480 at the G0/G1 phase. The animal model of inflammation-related CRC showed that the incidence of tumors in mice was significantly reduced by fucoidan intervention. Furthermore, the administration of fucoidan decreased the expression levels of inflammatory factors such as TNF-α IL-6 and IL-1β in the colonic tissues. Therefore, fucoidan can effectively prevent the development of colitis-associated CRC.

Background/Aims: Intestinal flora, especially Fusobacterium nucleatum (Fn), can affect the development of colorectal cancer (CRC). In this study, we examined the composition of intestinal flora and metabolites in the tissues, serum and feces of CRC patients. Materials and Methods CRC tissues, adjacent normal colonic tissues, and fecal and serum samples were collected from CRC patients who received surgical treatment between January 2018 and January 2020. Fecal and serum samples were collected from healthy individuals for comparison. In addition, fecal samples were collected from BALB/c female mice. SW480, a human CRC cell line, was utilized for in vitro studies. Results The abundance of Bacteroides and propionic acid concentration were decreased. The abundance of Lactobacillus and lactic acid concentration were increased in CRC tissues. KEGG pathway analysis showed that Bacteroides and Lactobacillus were related to the apoptotic pathway. Additionally, lactic acid inhibited and propionic acid promoted apoptosis among SW480 CRC cells. Similar findings were noted in the feces of Fn gavage mice. In addition, the abundances of Ruminococcus, Prevotella, and Sutterell were decreased in CRC patients. The levels of leucine and isoleucine were decreased in the serum and tumor tissues of CRC patients. Aspartate, glutamate and glutathione levels were elevated in the tissues of CRC patients only. The serum glutamine, tyrosine, valine, alanine, and histidine levels were decreased significantly. Conclusions Fn affected the apoptosis of CRC cells and promoted the progression of CRC by affecting the distribution of intestinal flora, which altered the concentrations of metabolites such as lactic acid, propionic acid, and amino acids.

To investigate the target-specificity and biological activity of Streptococcus serum antibody and sulfate amikacin conjugates. The recent used polyethylene glycol 6000 (PEG6000) as the coupling agent to produce Coupled complexes of Streptococcus serum antibody and sulfate amikacin. Then, analyzed the antibody being in conjugates specificity which against Streptococcus, and the antibody being in conjugates immunogenicity. Besides, we also detected the acute toxicity, antimicrobial activity and bioavailability of sulfate amikacin being in conjugates. As a result, the antibody specific binding to Streptococcus, instead of Escherichia coil, Pasteurella and Staphylococcus aureus. Biological activity results showed that coupling decreased Streptococcus serum antibody immunogenicity, increased Streptococcus serum antibody response sensitivity. Simultaneously, the results indicated that coupling reduced the acute toxicity of sulfate amikacin, improved sulfate amikacin bioavailability and antimicrobial activity of sulfate amikacin. The combination effect on the antibacterial activity of drug and the biological activity of serum antibody is helpful for the practical application of targeted drugs.

Talin is a key component molecule of the extracellular matrix‑integrin‑cytoskeleton. It serves an important role in the activation of integrin, which, in turn, is known to mediate physiological and pathological processes, including cell adhesion, growth, tumorigenesis, and metastasis. In vertebrates, there are two Talin genes, Talin1 and Talin2. Talin1 is known to regulate focal adhesion dynamics, cell migration and cell invasion; however, the precise role of Talin2 in cancer remains unclear. In the present study, the functional role of Talin2 was examined in the MDA‑MB‑231 breast cancer cell line. Talin2 knockdown significantly inhibited growth, migratory capacity and invasiveness of MDA‑MB‑231 cells, and promoted apoptosis. The expression levels of Talin2 in breast cancer cells and in the peritumoral normal breast tissues were also determined by immunohistochemistry. Talin2 was identified to be overexpressed in breast cancer tissues compared with that in the peritumoral breast tissues. In addition, the knockdown of Talin2 by specific RNA interference markedly inhibited cell growth, and caused the downregulation of the apoptotic markers, cleaved Caspase‑3 and phosphorylation of poly ADP‑ribose polymerase. These findings demonstrate that Talin2 expression is upregulated in human breast cancer and that downregulation of Talin2 may serve as a useful therapeutic target in patients with breast cancer.