A Real-World Study on Safety and Efficacy of TAF Treatment in HBV Patients with High Risk of Osteoporosis or Osteopenia in China.

Objective: Long-term antiviral treatment is necessary for chronic hepatitis B (CHB) patients, and treatment safety is imperative for these patients. Previous studies showed tenofovir alafenamide (TAF) has shown efficacy non-inferior to that of tenofovir disoproxil fumarate (TDF) with improved renal and bone safety. However, there is still a lack of a rapid and convenient method to identify CHB patients at high risk of osteoporosis before initiating antiviral treatment. The International Osteoporosis Foundation (IOF) recommended a one-minute osteoporosis risk test to identify early high-risk patients. Our aim was to evaluate the feasibility of the one-minute osteoporosis risk test, along with evaluating the effectiveness and safety for virologically suppressed CHB patients switching to TAF. Methods: In this multicenter, prospective study, patients with chronic HBV infection who had been receiving TDF or Entecavir (ETV) for 48 weeks or more with HBV DNA less than 20 IU/mL for longer than 6 months were screened by one-minute osteoporosis risk test. Patients with a high risk of osteoporosis and then diagnosed with osteopenia or osteoporosis by dual-energy X-ray absorptiometry (DEXA) were enrolled. Safety in bone and bone turnover markers and antiviral efficacy of TAF were assessed respectively at 24 and 48 weeks. Results: 84.95% (175/206) CHB patients screened by one-minute osteoporosis risk test were at risk of osteoporosis.85.71% (150/175) were diagnosed with osteopenia by DEXA. The analysis included a total of 138 patients, of whom 92(62.3%) were male and 46 (37.7%) were female, with a mean age of 45 years old. HBV DNA was suppressed at 48 weeks at 88% (35/40) in the prior ETV group and 90% (88/98) at 48 weeks group in the prior TDF group. Bone mineral density (BMD) of the lumbar spine (L1-L4) from TDF switching to TAF was improved at 24 weeks (1.03±0.11 vs. 0.97±0.12, P = .001) than baseline. Propeptides of type I procollagen (PINP) and beta-C-terminal telopeptides of type 1 collagen (CTX) in serum at 24 weeks after switching from TDF to TAF declined compared with baseline (50.35±18.90 vs. 63.65±19.17, P = .016 and 0.21±0.13 vs. 0.32±0.10, P = .017). BMD, PINP, and CTX in ETV to TAF group remained stable during treatment. Conclusion: Attention should be paid to osteoporosis risk during lone-term nucleot(s)ide analogue treatment. One minute test of osteoporosis risk could rapidly identify most CHB patients at risk of osteoporosis. Given its convenience, we recommend using this test for early screening in CHB patients prior to initiating antiviral treatment. Our results further demonstrated that an improvement in bone safety after switching to TAF in virologically suppressed CHB patients with osteoporosis.

Modified Gexia-Zhuyu Tang inhibits gastric cancer progression by restoring gut microbiota and regulating pyroptosis.

BACKGROUND: Gexia-Zhuyu Tang (GZT), a traditional Chinese medicine formula, is used to treat a variety of diseases. However, its roles in gastric cancer (GC) remain unclear. OBJECTIVE: The aim of this study was to explore the roles and underlying molecular mechanisms of modified GZT in GC. METHODS: The effects of modified GZT on GC were investigated by constructing mouse xenograft models with MFC cell line. The fecal samples from low-dose, high-dose, and without modified GZT treatment groups were collected for the 16S rRNA gene sequencing and fecal microbiota transplantation (FMT). Histopathological alterations of mice were evaluated using the hematoxylin-eosin (HE). Immunohistochemical (IHC) analysis with Ki67 and GSDMD was performed to measure tissue cell proliferation and pyroptosis, respectively. Proteins associated with pyroptosis, invasion, and metastasis were detected by Western blotting. Enzyme-linked immunosorbent assay (ELISA) was used to assess inflammation-related factors levels. RESULTS: Modified GZT inhibited GC tumor growth and reduced metastasis and invasion-related proteins expression levels, including CD147, VEGF, and MMP-9. Furthermore, it notably promoted caspase-1-dependent pyroptosis, as evidenced by a dose-dependent increase in TNF-α, IL-1ß, IL-18, and LDH levels, along with elevated protein expression of NLRP3, ASC, and caspase-1. Additionally, modified GZT increased species abundance and diversity of the intestinal flora. FMT assay identified that modified GZT inhibited GC tumor progression through regulation of intestinal flora. CONCLUSIONS: Modified GZT treatment may promote pyroptosis by modulating gut microbiota in GC. This study identifies a new potential approach for the GC clinical treatment.

Metabolomics and Transcriptomics Reveal that Diarylheptanoids Vary in Amomum tsao-ko Fruit Development.

Amomum tsao-ko is an important spice and medicinal plant that has received extensive attention in recent years for its high content of bioactive constituents with the potential for food additives and drug development. Diarylheptanoids are major and characteristic compounds in A. tsao-ko; however, the biochemical and molecular foundation of diarylheptanoids in fruit is unknown. We performed comparative metabolomics and transcriptomics studies in the ripening stages of A. tsao-ko fruit. The chemical constituents of fruit vary in different harvest periods, and the diarylheptanoids have a trend to decrease or increase with fruit development. GO enrichment analysis revealed that plant hormone signaling pathways including the ethylene-activated signaling pathway, salicylic acid, jasmonic acid, abscisic acid, and response to hydrogen peroxide were associated with fruit ripening. The biosynthetic pathways including phenylpropanoid, flavonoids, and diarylheptanoids biosynthesis were displayed in high enrichment levels in ripening fruit. The molecular networking and phytochemistry investigation of A. tsao-ko fruit has isolated and identified 10 diarylheptanoids including three new compounds. The candidate genes related to diarylheptanoids were obtained by coexpression network analysis and phylogenetic analysis. Two key genes have been verified to biosynthesize linear diarylheptanoids. This integrative approach provides gene regulation and networking associated with the biosynthesis of characteristic diarylheptanoids, which can be used to improve the quality of A. tsao-ko as food and medicine.

20S-ginsenoside Rg3 inhibits the biofilm formation and haemolytic activity of Staphylococcus aureus by inhibiting the SaeR/SaeS two-component system.

Introduction. Staphylococcus aureus is a major cause of chronic diseases and biofilm formation is a contributing factor. 20S-ginsenoside Rg3 (Rg3) is a natural product extracted from the traditional Chinese medicine red ginseng.Gap statement. The effects of Rg3 on biofilm formation and haemolytic activity as well as its antibacterial mechanism against S. aureus have not been reported.Aim. This study aimed to investigate the effects of Rg3 on biofilm formation and haemolytic activity as well as its antibacterial action against clinical S. aureus isolates.Methodology. The effect of Rg3 on biofilm formation of clinical S. aureus isolates was studied by crystal violet staining. Haemolytic activity analysis was carried out. Furthermore, the influence of Rg3 on the proteome profile of S. aureus was studied by quantitative proteomics to clarify the mechanism underlying its antibacterial action and further verified by reverse transcription quantitative real-time polymerase chain reaction (RT-qPCR).Results. Rg3 significantly inhibited biofilm formation and haemolytic activity in clinical S. aureus isolates. A total of 63 with >1.5-fold changes in expression were identified, including 34 upregulated proteins and 29 downregulated proteins. Based on bioinformatics analysis, the expression of several virulence factors and biofilm-related proteins, containing CopZ, CspA, SasG, SaeR/SaeS two-component system and SaeR/SaeS-regulated proteins, including leukocidin-like protein 2, immunoglobulin-binding protein G (Sbi) and fibrinogen-binding protein, in the S. aureus of the Rg3-treated group was downregulated. RT-qPCR confirmed that Rg3 inhibited the regulation of SaeR/SaeS and decreased the transcriptional levels of the biofilm-related genes CopZ, CspA and SasG.Conclusions. Rg3 reduces the formation of biofilm by reducing cell adhesion and aggregation. Further, Rg3 can inhibit the SaeR/SaeS two-component system, which acts as a crucial signal transduction system for the anti-virulence activity of Rg3 against clinical S. aureus isolates.

The Mechanism of Action of Ginkgolic Acid (15:1) against Gram-Positive Bacteria Involves Cross Talk with Iron Homeostasis.

With the increasing reports of community-acquired and nosocomial infection caused by multidrug-resistant Gram-positive pathogens, there is an urgent need to develop new antimicrobial agents with novel antibacterial mechanisms. Here, we investigated the antibacterial activity of the natural product ginkgolic acid (GA) (15:1), derived from Ginkgo biloba, and its potential mode of action against the Gram-positive bacteria Enterococcus faecalis and Staphylococcus aureus. The MIC values of GA (15:1) against clinical E. faecalis and S. aureus isolates from China were ≤4 and ≤8 µg/mL, respectively, from our test results. Moreover, GA (15:1) displayed high efficiency in biofilm formation inhibition and bactericidal activity against E. faecalis and S. aureus. During its inhibition of the planktonic bacteria, the antibacterial activity of GA (15:1) was significantly improved under the condition of abolishing iron homeostasis. When iron homeostasis was abolished, inhibition of planktonic bacteria by GA (15:1) was significantly improved. This phenomenon can be interpreted as showing that iron homeostasis disruption facilitated the disruption of the functions of ribosome and protein synthesis by GA (15:1), resulting in inhibition of bacterial growth and cell death. Genetic mutation of ferric uptake regulator (Fur) led to GA (15:1) tolerance in in vitro-induced resistant derivatives, while overexpression of Fur led to increased GA (15:1) susceptibility. Additionally, GA (15:1) significantly decreased the bacterial loads of S. aureus strain USA300 in the lung tissues of mice in a pneumonic murine model. Conclusively, this study revealed an antimicrobial mechanism of GA (15:1) involving cross talk with iron homeostasis against Gram-positive pathogens. In the future, the natural product GA (15:1) might be applied to combat infections caused by Gram-positive pathogens. IMPORTANCE The increasing emergence of infectious diseases associated with multidrug-resistant Gram-positive pathogens has raised the urgent need to develop novel antibiotics. GA (15:1) is a natural product derived from Ginkgo biloba and possesses a wide range of bioactivities, including antimicrobial activity. However, its antibacterial mechanisms remain unclear. Our current study found that the function of ferric uptake regulator (Fur) was highly correlated with the antimicrobial activity of GA (15:1) against E. faecalis and that the antibacterial activity of GA (15:1) could be strengthened by the disruption of iron homeostasis. This study provided important insight into the mode of action of GA (15:1) against Gram-positive bacteria and suggested that GA (15:1) holds the potential to be an antimicrobial treatment option for infection caused by multidrug-resistant Gram-positive pathogens.

Linezolid Consumption Facilitates the Development of Linezolid Resistance in Enterococcus faecalis in a Tertiary-Care Hospital: A 5-Year Surveillance Study.

Although case reports and clinical studies of linezolid (LZD)-resistant Enterococcus faecalis (LREF) have gradually increased in recent years, the relationship between LZD resistance and antibiotic consumption in hospital settings still remains unclear. In this study, we aimed to investigate the dynamic relationship between the yearly detection frequency of LREF clinical isolates and yearly consumption of LZD and vancomycin (VCM) over a 5-year period in a Chinese hospital setting. Antibiotic consumption data (LZD and VCM) from 2011 to 2015 were obtained from a computerized database and recalculated as the defined daily doses (DDDs) per 100 bed-days (DBD). All 268 E. faecalis clinical isolates were retrospectively collected from 2011 to 2015 in this hospital. LZD resistance mechanism and multilocus sequence typing of E. faecalis were determined by PCR. The annual detection frequency of LREF clinical isolates tested in this hospital was shown with 1.89% (1/53), 2% (1/50), 2.04% (1/49), 0% (0/45), and 7.04% (5/71), respectively, and the detection frequency of LZD-nonsusceptible E. faecalis (LNSEF; n = 59, including LZD-resistant and intermediate isolates) was determined with 26.42% (14/53), 34% (17/50), 16.33% (8/49), 22.22% (10/45), and 14.08% (10/71), respectively. Spearman correlation analysis revealed that LZD DBD significantly correlated positively with the detection frequency of LREF (r = 0.886, p = 0.019). Moreover, VCM DBD significantly correlated positively with the frequency of LNSEF (r = 0.943, p = 0.005). Furthermore, the detection frequency of optrA-positive E. faecalis also correlated positively with high LZD consumption load in this hospital setting. Conclusively, high LZD consumption load facilitates the development of LZD resistance and promotes the selection of optrA-positive E. faecalis clinical isolates under antibiotic pressure in a hospital setting.