Herb-drug interactions: Quantitative analysis of levofloxacin absorption and transporter expression in the rat intestine following combined treatment with Persicaria capitata (Buch.-Ham. ex D. Don) H. Gross.

Persicaria capitata (Buch.-Ham. ex D. Don) H. Gross, a traditional Chinese medicinal plant, is often used to treat various urologic disorders in China. P. capitata extracts (PCE) have been used in combination with levofloxacin (LVFX) to treat urinary tract infections (UTIs) for a long time. However, little is known about the absorption of LVFX and transporter expression in the intestine after combined treatment with PCE, restricting the development and utilization of PCE. In view of this, a UPLC-MS/MS method was established for the determination of LVFX in intestinal sac fluid samples and in situ intestinal circulation perfusate samples to explore the effect of PCE on the intestinal absorption characteristics of LVFX ex vivo and in vivo. To further evaluate the interaction between LVFX and PCE, western blotting, immunohistochemistry, and RT-qPCR were utilized to determine the expression levels of drug transporters (OATP1A2, P-gp, BCRP, and MRP2) involved in the intestinal absorption of LVFX after combined treatment with PCE. Using the everted intestinal sac model, the absorption rate constant (Ka) and cumulative drug absorption (Q) of LVFX in each intestinal segment were significantly lower in groups treated with PCE than in the control group. Ka at 2 h decreased most in the colon segment (from 0.088 to 0.016 µg/h·cm2), and Q at 2 h decreased most in the duodenum (from 213.29 to 33.92 µg). Using the intestinal circulation perfusion model, the Ka value and percentage absorption rate (A) of LVFX in the small intestine decreased significantly when PCE and LVFX were used in combination. These results showed that PCE had a strong inhibitory effect on the absorption of LVFX in the rat small intestine (ex vivo and in vivo intestinal segments). In addition, PCE increased the protein and mRNA expression levels of efflux transporters (P-gp, BCRP, and MRP2) and decreased the expression of the uptake transporter OATP1A2 significantly. The effects increased as the PCE concentration increased. These findings indicated that PCE changed the absorption characteristics of levofloxacin, possibly by affecting the expression of transporters in the small intestine. In addition to revealing a herb-drug interaction (HDI) between PCE and LVFX, these results provide a basis for further studies of their clinical efficacy and mechanism of action.

[Comparative study on excretion of Shuganning Injection and Scutellariae Radix extract in bile, urine, and feces of rats].

Scutellariae Radix extract is one of the important components in Shuganning Injection. In this study, an ultra-performance liquid chromatography-tandem mass spectrometry(UPLC-MS/MS) method was established for simultaneously determining five components in Shuganning Injection and Scutellariae Radix extract in bile, urine, and feces of rats, so as to reveal the difference in the excretion process of Shuganning Injection and Scutellariae Radix extract in rats and explore the law of the excretion process of the five components in vivo before and after the compatibility of Scutellariae Radix. Rats were injected with Shuganning Injection and Scutellariae Radix extract(4.2 mL·kg~(-1)), respectively, and the excretion of baicalin, baicalein, oroxylin A, oroxylin A-7-O-ß-D-glucuronide, and scutellarin in bile, urine, and feces of rats in 24 h was observed. The results showed that except for baicalin, the other four index components were excreted as prototype components in a high proportion after intravenous injection of Shuganning Injection and Scutellariae Radix extract in rats, respectively. The excretion of each component was relatively high in urine and less in feces and bile. After the compatibility of Scutellariae Radix extract, the accumulative excretion of five index components in rats all decreased. Among them, the cumulative excretion of baicalein in bile, urine, and feces significantly decreased by 26.67%, 48.11%, and 31.01%. The cumulative excretion of baicalin in bile, urine, and feces decreased significantly by 70.69%, 19.43%, and 31.22%. The result showed that the five index components in Scutellariae Radix extract were mainly excreted by the kidneys, and other components in Shuganning Injection delayed the excretion process and prolonged the residence time. This study is of great significance for elucidating the compatibility rationality of Shuganning Injection.

Danhongqing formula alleviates cholestatic liver fibrosis by downregulating long non-coding RNA H19 derived from cholangiocytes and inhibiting hepatic stellate cell activation.

OBJECTIVE: This study explores the mechanism of action of Danhongqing formula (DHQ), a compound-based Chinese medicine formula, in the treatment of cholestatic liver fibrosis. METHODS: In vivo experiments were conducted using 8-week-old multidrug resistance protein 2 knockout (Mdr2-/-) mice as an animal model of cholestatic liver fibrosis. DHQ was administered orally for 8 weeks, and its impact on cholestatic liver fibrosis was evaluated by assessing liver function, liver histopathology, and the expression of liver fibrosis-related proteins. Real-time polymerase chain reaction, Western blot, immunohistochemistry and other methods were used to observe the effects of DHQ on long non-coding RNA H19 (H19) and signal transducer and activator of transcription 3 (STAT3) phosphorylation in the liver tissue of Mdr2-/- mice. In addition, cholangiocytes and hepatic stellate cells (HSCs) were cultured in vitro to measure the effects of bile acids on cholangiocyte injury and H19 expression. Cholangiocytes overexpressing H19 were constructed, and a conditioned medium containing H19 was collected to measure its effects on STAT3 protein expression and cell activation. The intervention effect of DHQ on these processes was also investigated. HSCs overexpressing H19 were constructed to measure the impact of H19 on cell activation and assess the intervention effect of DHQ. RESULTS: DHQ alleviated liver injury, ductular reaction, and fibrosis in Mdr2-/- mice, and inhibited H19 expression, STAT3 expression and STAT3 phosphorylation. This formula also reduced hydrophobic bile acid-induced cholangiocyte injury and the upregulation of H19, inhibited the activation of HSCs induced by cholangiocyte-derived conditioned medium, and decreased the expression of activation markers in HSCs. The overexpression of H19 in a human HSC line confirmed that H19 promoted STAT3 phosphorylation and HSC activation, and DHQ was able to successfully inhibit these effects. CONCLUSION: DHQ effectively alleviated spontaneous cholestatic liver fibrosis in Mdr2-/- mice by inhibiting H19 upregulation in cholangiocytes and preventing the inhibition of STAT3 phosphorylation in HSC, thereby suppressing cell activation. Please cite this article as: Li M, Zhou Y, Zhu H, Xu LM, Ping J. Danhongqing formula alleviates cholestatic liver fibrosis by downregulating long non-coding RNA H19 derived from cholangiocytes and inhibiting hepatic stellate cell activation. J Integr Med. 2024; 22(2): 188-198.

Taohe Chengqi decoction alleviated metabolic-associated fatty liver disease by boosting branched chain amino acids catabolism in the skeletal muscles of type 2 diabetes mellitus.

OBJECTIVE: Metabolic-associated fatty liver disease (MAFLD) is the most prevalent liver disease, whereas type 2 diabetes mellitus (T2DM) is considered an independent risk factor for MAFLD incidence. Taohe Chengqi decoction (THCQ) is clinically prescribed for T2DM treatment; however, the hepatoprotective effect of THCQ against MAFLD is still unknown. This study intended to elucidate the therapeutic effect of THCQ on T2DM-associated MAFLD and to investigate the underlying mechanisms. METHODS: THCQ lyophilized powder was prepared and analyzed by UHPLC-MS/MS. A stable T2DM mouse model was established by high-fat diet (HFD) feeding combined with streptozotocin (STZ) injection. The T2DM mice were administered THCQ (2.5 g/kg or 5 g/kg) to explore the pharmacological effects of THCQ on T2DM-associated MAFLD. Liver tissue transcriptome was analyzed and the participatory roles of PPARα/γ pathways were verified both in vivo and in vitro. Serum metabolome analysis was used to explore the metabolome changes and skeletal muscle branched chain amino acid (BCAA) catabolic enzymes were further detected. Moreover, an AAV carrying BCKDHA shRNA was intramuscularly injected to verify the impact of THCQ on skeletal muscle BCAA catabolism and the potential therapeutic outcome on hepatic steatosis. RESULTS: THCQ improved hepatic steatosis in MAFLD. RNA-sequencing analysis showed dysregulation in the hepatic PPARγ-related fatty acid synthesis, while PPARα-dependent fatty acid oxidation was elevated following THCQ treatment. Interestingly, in vitro analyses of these findings showed that THCQ had minor effects on fatty acid oxidation and/or synthesis. The metabolomic study revealed that THCQ accelerated BCAA catabolism in the skeletal muscles, in which knockdown of the BCAA catabolic enzyme BCKDHA diminished the THCQ therapeutic effect on hepatic steatosis. CONCLUSION: This study highlighted the potential therapeutic effect of THCQ on hepatic steatosis in MALFD. THCQ upregulated fatty acid oxidation and reduced its synthesis via restoration of PPARα/γ pathways in HFD/STZ-induced T2DM mice, which is mediated through augmenting BCKDH activity and accelerating BCAA catabolism in the skeletal muscles. Overall, this study provided in-depth clues for "skeletal muscles-liver communication" in the therapeutic effect of THCQ against hepatic steatosis. These findings suggested THCQ might be a potential candidate against T2DM-associated MAFLD.

Manganese and IL-12 treatment alters the ovarian tumor microenvironment.

Metal immunotherapy is a novel adjuvant immunotherapy. Mn2+ can activate STING-a type I IFN response protein-that promotes innate immunity and increases anti-tumor activity by promoting macrophage phagocytosis. IL-12, a cytokine that increases the antigen-presenting ability to promote effector T-cell activation, has potent antitumor activity, albeit with severe adverse effects. In this study, we observed that the combination of Mn2+ and IL-12 has a better antitumor effect and possibly reflects a better safety profile, providing a novel approach and theoretical basis for safe and rapid cancer treatment.

Evaluating the adverse effects and mechanisms of nanomaterial exposure on longevity of C. elegans: A literature meta-analysis and bioinformatics analysis of multi-transcriptome data.

Exposure to large-size particulate air pollution (PM2.5 or PM10) has been reported to increase risks of aging-related diseases and human death, indicating the potential pro-aging effects of airborne nanomaterials with ultra-fine particle size (which have been widely applied in various fields). However, this hypothesis remains inconclusive. Here, a meta-analysis of 99 published literatures collected from electronic databases (PubMed, EMBASE and Cochrane Library; from inception to June 2023) was performed to confirm the effects of nanomaterial exposure on aging-related indicators and molecular mechanisms in model animal C. elegans. The pooled analysis by Stata software showed that compared with the control, nanomaterial exposure significantly shortened the mean lifespan [standardized mean difference (SMD) = -2.30], reduced the survival rate (SMD = -4.57) and increased the death risk (hazard ratio = 1.36) accompanied by upregulation of ced-3, ced-4 and cep-1, while downregulation of ctl-2, ape-1, aak-2 and pmk-1. Furthermore, multi-transcriptome data associated with nanomaterial exposure were retrieved from Gene Expression Omnibus (GSE32521, GSE41486, GSE24847, GSE59470, GSE70509, GSE14932, GSE93187, GSE114881, and GSE122728) and bioinformatics analyses showed that pseudogene prg-2, mRNAs of abu, car-1, gipc-1, gsp-3, kat-1, pod-2, acdh-8, hsp-60 and egrh-2 were downregulated, while R04A9.7 was upregulated after exposure to at least two types of nanomaterials. Resveratrol (abu, hsp-60, pod-2, egrh-2, acdh-8, gsp-3, car-1, kat-1, gipc-1), naringenin (kat-1, egrh-2), coumestrol (egrh-2) or swainsonine/niacin/ferulic acid (R04A9.7) exerted therapeutic effects by reversing the expression levels of target genes. In conclusion, our study demonstrates the necessity to use phytomedicines that target hub genes to delay aging for populations with nanomaterial exposure.

Advances in drug structure-activity-relationships for the development of selenium-based compounds against HIV.

INTRODUCTION: Selenium possesses numerous advantageous properties in the field of medicine, and a variety of selenium-containing compounds have been documented to exhibit anti-HIV activity. This paper aims to categorize these compounds and conduct SAR analysis to offer guidance for drug design and optimization. AREAS COVERED: The authors present a comprehensive review of the reported SAR analysis conducted on selenium-based compounds against HIV, accompanied by a concise discussion regarding the pivotal role of selenium in drug development. EXPERT OPINION: In addition to the conventional bioisosterism strategy, advanced strategies such as covalent inhibition, fragment-based growth and drug repositioning can also be incorporated into research on selenium-containing anti-HIV drugs. Ebselen, which acts as an HIV capsid inhibitor, serves as a valuable probe compound for the discovery of novel HIV integrase inhibitors. Furthermore, it is crucial not to underestimate the potential toxicity associated with organic selenium compounds despite no reported instances of severe toxicity.

New insights into HgSe antagonism: Minor impact on inorganic Hg mobility while potential impacts on microorganisms.

Selenium (Se) is a crucial antagonistic factor of mercury (Hg) methylation in soil, with the transformation of inorganic Hg (IHg) to inert mercury selenide (HgSe) being the key mechanism. However, little evidence has been provided of the reduced Hg mobility at environmentally relevant doses of Hg and Se, and the potential impacts of Se on the activities of microbial methylators have been largely ignored. This knowledge gap hinders effective mitigation for methylmercury (MeHg) risks, considering that Hg supply and microbial methylators serve as materials and workers for MeHg production in soils. By monitoring the mobility of IHg and microbial activities after Se spike, we reported that 1) active methylation might be the premise of HgSe antagonism, as higher decreases in MeHg net production were found in soils with higher constants of Hg methylation rate; 2) IHg mobility did not significantly change upon Se addition in soils with high DOC concentrations, challenging the long-held view of Hg immobilization by Se; and 3) the activities of iron-reducing bacteria (FeRB), an important group of microbial methylators, might be potentially regulated by Se addition at a dose of 4 mg/kg. These findings provide empirical evidence that IHg mobility may not be the limiting factor under Se amendment and suggest the potential impacts of Se on microbial activities.

[Screening and promoting effect of grow-promoting fungi in rhizosphere of Angelica dahurica var. formosana].

Excessive application of chemical fertilizer has caused many problems in Angelica dahurica var. formosana planting, such as yield decline and quality degradation. In order to promote the green cultivation mode of A. dahurica var. formosana and explore rhizosphere fungus resources, the rhizosphere fungi with nitrogen fixation, phosphorus solubilization, potassium solubilization, iron-producing carrier, and IAA-producing properties were isolated and screened in the rhizosphere of A. dahurica var. formosana from the genuine and non-genuine areas, respectively. The strains were identified comprehensively in light of the morphological characteristics and ITS rDNA sequences, and the growth-promoting effect of the screened strains was verified by pot experiment. The results showed that 37 strains of growth-promoting fungi were isolated and screened from the rhizosphere of A. dahurica var. formosana, mostly belonging to Fusarium. The cultured rhizosphere growth-promoting fungi of A. dahurica var. formosana were more abundant and diverse in the genuine producing areas than in the non-genuine producing areas. Among all strains, Aspergillus niger ZJ-17 had the strongest growth promotion potential. Under the condition of no fertilization outdoors, ZJ-17 inoculation significantly promoted the growth, yield, and accumulation of effective components of A. dahurica var. formosana planted in the soil of genuine and non-genuine producing areas, with yield increases of 73.59% and 37.84%, respectively. To a certain extent, it alleviated the restriction without additional fertilization on the growth of A. dahurica var. formosana. Therefore, A. niger ZJ-17 has great application prospects in increasing yield and quality of A. dahurica var. formosana and reducing fertilizer application and can be actually applied in promoting the growth of A. dahurica var. formosana and producing biofertilizer.

Maternal vitamin B1 is a determinant for the fate of primordial follicle formation in offspring.

The mediation of maternal-embryonic cross-talk via nutrition and metabolism impacts greatly on offspring health. However, the underlying key interfaces remain elusive. Here, we determined that maternal high-fat diet during pregnancy in mice impaired preservation of the ovarian primordial follicle pool in female offspring, which was concomitant with mitochondrial dysfunction of germ cells. Furthermore, this occurred through a reduction in maternal gut microbiota-related vitamin B1 while the defects were restored via vitamin B1 supplementation. Intriguingly, vitamin B1 promoted acetyl-CoA metabolism in offspring ovaries, contributing to histone acetylation and chromatin accessibility at the promoters of cell cycle-related genes, enhancement of mitochondrial function, and improvement of granulosa cell proliferation. In humans, vitamin B1 is downregulated in the serum of women with gestational diabetes mellitus. In this work, these findings uncover the role of the non-gamete transmission of maternal high-fat diet in influencing offspring oogenic fate. Vitamin B1 could be a promising therapeutic approach for protecting offspring health.

[Discussion on the location of Dazhui (GV 14) and Yaoyangguan (GV 3)].

Since the anatomical location of acupoints was recorded in The latest Practice of Western Acupuncture in 1915, and Lecture Notes on Advanced Acupuncture in 1931, the Japanese acupuncture works of Chinese translation version, the location of Dazhui (GV 14) (under the spinous process of the 7th cervical vertebra) and Yaoyangguan (GV 3) (under the spinous process of the 4th lumbar vertebra) had rarely been questioned for nearly a century. In order to confirm the above statement, the writers have reviewed ancient literature, combined with the modern anatomical knowledge and searched the evidences from the core arguments of the acupuncture Mingtang chart and the bronze acupuncture statue. It is believed that Dazhui （GV 14） should be positioned under the spinous process of the 1st thoracic vertebra, and Yaoyangguan（GV 3） be under the spinous process of the 5th lumbar vertebra. Accordingly, all of the other acupoints of these meridians should be moved down by 1 vertebra, i.e. those on the governor vessel from Dazhui (GV 14) to Yaoyangguan (GV 3), those on the 1st lateral line of the bladder meridian of foot-taiyang from Dazhu (BL 11) to Baihuanshu (BL 30) and those on the 2nd lateral line of the bladder meridian from Fufen (BL 41) to Zhibian (BL 54).

Increasing trends of overweight and obesity in treatment-naive people living with HIV in Shenzhen from 2014 to 2020: an emerging health concern.

Background: With the early initiation of antiretroviral therapy (ART) in China, the demographics of treatment-naïve people living with HIV (PLWH) are moving closer to those of the general population, which is characterized by a gradual increase in metabolic indicators. However, the epidemic trends of overweight and obesity over the past decade in treatment-naïve PLWH ready to initiate ART have not yet been investigated. Methods: A cross-sectional study was conducted, including 12,135 consecutive treatment-naïve PLWH ready to initiate ART in Shenzhen, using data retrieved from the China National Free Antiretroviral Treatment Program database from 2014 to 2020. The chi-square test was used to examine the trends of overweight and obesity between age groups, and multivariate logistic regression was used to identify the association of overweight and obesity with hyperglycemia and dyslipidemia. Results: During the 7-year study period, 12,135 treatment-naïve PLWH ready to initiate ART were included, among whom 1,837 (15.1%) were overweight and 388 (3.2%) were obese. The prevalence of overweight rose from 11.4 to 17.3% (Z = -4.58, P for trend <0.01) and that of obesity from 2.0% to 4.2% (Z = -6.45, P for trend <0.01) from 2014 to 2020. The annual prevalence of overweight was the highest in the age group of participants >35 years compared to prevalence in other age groups during the period 2014-2020. Compared with those who were not overweight or obese, PLWH who were overweight or obese were more likely to have hyperglycemia (aOR 1.84, 95% CI: 1.37-2.49 for overweight; aOR 2.68, 95% CI: 1.62-4.44 for obesity), higher ALT level (aOR 2.70, 95% CI: 2.33-3.13 for overweight; aOR 3.85, 95% CI: 2.93-5.05 for obesity), higher TG levels (aOR 1.89, 95% CI 1.63-2.19 for overweight; aOR 2.56, 95% CI 1.97-3.32 for obesity), and lower HDL levels (aOR 1.67, 95% CI 1.44-1.95 for overweight; aOR 2.06, 95% CI 1.54-2.77 for obesity). Conclusion: The prevalence of overweight and obesity in treatment-naive PLWH increased steadily from 2014 to 2020 in Shenzhen. Overweight and obese in treatment-naive PLWH ready to initiate ART were associated with dyslipidemia and hyperglycemia. Public health authorities should take proactive steps to address these issues by implementing targeted screening, intervention programs including lifestyle modifications, and integrated healthcare services.

Discovery and Optimization of Novel hDHODH Inhibitors for the Treatment of Inflammatory Bowel Disease.

As a key rate-limiting enzyme in the de novo synthesis of pyrimidine nucleotides, human dihydroorotate dehydrogenase (hDHODH) is considered a known target for the treatment of autoimmune diseases, including inflammatory bowel disease (IBD). Herein, BAY 41-2272 with a 1H-pyrazolo[3,4-b]pyridine scaffold was identified as an hDHODH inhibitor by screening an active compound library containing 5091 molecules. Further optimization led to 2-(1-(2-chloro-6-fluorobenzyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-cyclopropylpyrimidin-4-amine (w2), which was found to be the most promising and drug-like compound with potent inhibitory activity against hDHODH (IC50 = 173.4 nM). Compound w2 demonstrated acceptable pharmacokinetic characteristics and alleviated the severity of acute ulcerative colitis induced by dextran sulfate sodium in a dose-dependent manner. Notably, w2 exerted better therapeutic effects on ulcerative colitis than hDHODH inhibitor vidofludimus and Janus kinase (JAK) inhibitor tofacitinib. Taken together, w2 is a promising hDHODH inhibitor for the treatment of IBD and deserves to be developed as a preclinical candidate.

Geographical origin traceability of mulberry leaves using stable hydrogen, oxygen, and carbon isotope ratios.

Geographical discrimination of mulberry leaves is very important for their efficacy and quality as a traditional Chinese medicine. Stable hydrogen, oxygen, and carbon isotope ratios were measured in 292 mulberry leaves collected at 2 growth stages in 2 seasons from 8 regions of China. A stepwise linear discriminant analysis (LDA) approach were proposed to combine with stable isotope technology to tracing the origin of mulberry leaves. The results showed that leaves sampled in autumn were extremely depleted in 2H and 18O and slightly enriched in 13C compared with leaves sampled in summer, correlated with the effect of season, transpiration and photorespiration on stable isotopes. δ2H and δ18O of the leaves were enriched during the growth process. The overall discrimination accuracy of the autumn tender model was 81%, demonstrating that analysis of δ2H, δ18O, and δ13C is a promising technique for tracing the geographical origin of mulberry leaves, although season, growth stage and number of samples affect the accuracy of discrimination.

Targeted trace ingredients coupled with chemometric analysis for consistency evaluation of Panax notoginseng saponins injectable formulations.

Evaluating the consistency of herb injectable formulations could improve their product quality and clinical safety, particularly concerning the composition and content levels of trace ingredients. Panax notoginseng Saponins Injection (PNSI), widely used in China for treating acute cardiovascular diseases, contains low-abundance (10%-25%) and trace saponins in addition to its five main constituents (notoginsenoside R1, ginsenoside Rg1, ginsenoside Re, ginsenoside Rb1, and ginsenoside Rd). This study aimed to establish a robust analytical method and assess the variability in trace saponin levels within PNSI from different vendors and formulation types. To achieve this, a liquid chromatography-triple quadrupole mass spectrometry (LC-MS/MS) method employing multiple ions monitoring (MIM) was developed. A "post-column valve switching" strategy was implemented to eliminate highly abundant peaks (NR1, Rg1, and Re) at 26 min. A total of 51 saponins in PNSI were quantified or relatively quantified using 18 saponin standards, with digoxin as the internal standard. This study evaluated 119 batches of PNSI from seven vendors, revealing significant variability in trace saponin levels among different vendors and formulation types. These findings highlight the importance of consistent content in low-abundance and trace saponins to ensure product control and clinical safety. Standardization of these ingredients is crucial for maintaining the quality and effectiveness of PNSI in treating acute cardiovascular diseases.

Structural elucidation of hemicelluloses from oil-tea camellia fruit shell.

Oil-tea camellia fruit shell (CFS) is a very abundant waste lignocellulosic resource. The current treatments of CFS, i.e. composting and burning, pose a severe threat on environment. Up to 50 % of the dry mass of CFS is composed of hemicelluloses. However, chemical structures of the hemicelluloses in CFS have not been extensively studied, which limits their high-value utilization. In this study, different types of hemicelluloses were isolated from CFS through alkali fractionation with the assistance of Ba(OH)2 and H3BO3. Xylan, galacto-glucomannan and xyloglucan were found to be the major hemicelluloses in CFS. Through methylation, HSQC and HMBC analyses, we have found that the xylan in CFS is composed of →4)-ß-D-Xylp-(1→ and →3,4)-ß-D-Xylp-(1→ linked by (1→4)-ß glycosidic bond as the main chain; the side chains are α-L-Fucp-(1→, →5)-α-L-Araf-(1→, ß-D-Xylp-(1→, α-L-Rhap-(1→ and 4-O-Me-α-D-GlcpA-(1→, connected to the main chain through (1→3) glycosidic bond. The main chain of galacto-glucomannan in CFS consists of →6)-ß-D-Glcp-(1→, →4)-ß-D-Glcp-(1→, →4,6)-ß-D-Glcp-(1→ and →4)-ß-D-Manp-(1→; the side chains are ß-D-Glcp-(1→, →2)-ß-D-Galp-(1→, ß-D-Manp-(1→ and →6)-ß-D-Galp-(1→ connected to the main chain through (1→6) glycosidic bonds. Moreover, galactose residues are connected by α-L-Fucp-(1→. The main chain of xyloglucan is composed of →4)-ß-D-Glcp-(1→, →4,6)-ß-D-Glcp-(1→ and →6)-ß-D-Glcp-(1→; the side groups, i.e. ß-D-Xylp-(1→ and →4)-ß-D-Xylp-(1→, are connected to the main chain by (1→6) glycosidic bond; →2)-ß-D-Galp-(1→ and α-L-Fucp-(1→ can also connect to →4)-ß-D-Xylp-(1→ forming di- or trisaccharide side chains.

Urinary Tract Infections Caused by Uropathogenic Escherichia coli: Mechanisms of Infection and Treatment Options.

Urinary tract infections (UTIs) are common bacterial infections that represent a severe public health problem. They are often caused by Escherichia coli (E. coli), Klebsiella pneumoniae (K. pneumonia), Proteus mirabilis (P. mirabilis), Enterococcus faecalis (E. faecalis), and Staphylococcus saprophyticus (S. saprophyticus). Among these, uropathogenic E. coli (UPEC) are the most common causative agent in both uncomplicated and complicated UTIs. The adaptive evolution of UPEC has been observed in several ways, including changes in colonization, attachment, invasion, and intracellular replication to invade the urothelium and survive intracellularly. While antibiotic therapy has historically been very successful in controlling UTIs, high recurrence rates and increasing antimicrobial resistance among uropathogens threaten to greatly reduce the efficacy of these treatments. Furthermore, the gradual global emergence of multidrug-resistant UPEC has highlighted the need to further explore its pathogenesis and seek alternative therapeutic and preventative strategies. Therefore, a thorough understanding of the clinical status and pathogenesis of UTIs and the advantages and disadvantages of antibiotics as a conventional treatment option could spark a surge in the search for alternative treatment options, especially vaccines and medicinal plants. Such options targeting multiple pathogenic mechanisms of UPEC are expected to be a focus of UTI management in the future to help combat antibiotic resistance.

Geniposide alleviated bile acid-associated NLRP3 inflammasome activation by regulating SIRT1/FXR signaling in bile duct ligation-induced liver fibrosis.

BACKGROUND: Geniposide (GE), the active compound derived from Gardeniae Fructus, possesses valuable bioactivity for liver diseases, but GE effects on bile duct ligation (BDL)-induced cholestasis remain unclear. This study aimed to elucidate the influence of GE on BDL-induced liver fibrosis and to investigate the underlying mechanisms. METHODS: GE (25 or 50 mg/kg) were intragastrical administered to C57BL/6 J mice for two weeks to characterize the hepatoprotective effect of GE on BDL-induced liver fibrosis. NLRP3 inflammasome activation was detected in vivo, and BMDMs were isolated to explore whether GE directly inhibited NLRP3 inflammasome activation. Serum bile acid (BA) profiles were assessed utilizing UPLC-MS/MS, and the involvement of SIRT1/FXR pathways was identified to elucidate the role of SIRT1/FXR in the hepaprotective effect of GE. The veritable impact of SIRT1/FXR signaling was further confirmed by administering the SIRT1 inhibitor EX527 (10 mg/kg) to BDL mice treated with GE. RESULTS: GE treatment protected mice from BDL-induced liver fibrosis, with NLRP3 inflammasome inhibition. However, development in vitro experiments revealed that GE could not directly inhibit NLRP3 activation under ATP, monosodium urate, and nigericin stimulation. Further mechanistic data showed that GE activated SIRT1, which subsequently deacetylated FXR and restored CDCA, TUDCA, and TCDCA levels, thereby contributing to the observed hepaprotective effect of GE. Notably, EX527 treatment diminished the hepaprotective effect of GE on BDL-induced liver fibrosis. CONCLUSION: This study first proved the hepaprotective effect of GE on liver fibrosis in BDL mice, which was closely associated with the restoration of BA homeostasis and NLRP3 inflammasome inhibition. The activation of SIRT1 and the subsequent FXR deacetylation restored the BA profiles, especially CDCA, TUDCA, and TCDCA contents, which was the main contributor to NLRP3 inhibition and the hepaprotective effect of GE. Overall, our work provides novel insights that GE as well as Gardeniae Fructus might be the potential attractive candidate for ameliorating BDL-induced liver fibrosis.