How renal toxins respond to renal function deterioration and oral toxic adsorbent in pH-controlled releasing capsule.

The number of patients with chronic kidney disease (CKD) is increasing. Oral toxin adsorbents may provide some value. Several uremic toxins, including indoxyl sulfate (IS), p-cresol (PCS), acrolein, per- and poly-fluoroalkyl substances (PFAS), and inflammation markers (interleukin 6 [IL-6] and tumor necrosis factor [TNF]-alpha) have been shown to be related to CKD progression. A total of 81 patients taking oral activated charcoal toxin adsorbents (AC-134), which were embedded in capsules that dissolved in the terminal ileum, three times a day for 1 month, were recruited. The renal function, hemoglobulin (Hb), inflammation markers, three PFAS (PFOA, PFOS, and PFNA), and acrolein were quantified. Compared with the baseline, an improved glomerular filtration rate (GFR) and significantly lower acrolein were noted. Furthermore, the CKD stage 4 and 5 group had significantly higher concentrations of IS, PCS, IL-6, and TNF but lower levels of Hb and PFAS compared with the CKD Stage 3 group at baseline and after the intervention. Hb was increased only in the CKD Stage 3 group after the trial (p = .032). Acrolein did not differ between the different CKD stage groups. Patients with improved GFR (responders) (about 77%) and nonresponders had similar baseline GFR. Responders had higher acrolein and PFOA levels throughout the study and a more significant reduction in acrolein, indicating a better digestion function. Both the higher PFOA and lower acrolein may be related to improved eGFR (and possibly to improvements in proteinuria, which we did not measure. Proteinuria is associated with PFAS loss in the urine), AC-134 showed the potential to improve the GFR and decrease acrolein, which might better indicate renal function change. Future studies are needed with longer follow-ups.

Association Between Leg Muscle Thickness and Walking Test with the Haemophilia-Specific Functional Parameters.

OBJECTIVE: To evaluate the muscle thickness and walking test in people with haemophilia A (PWH) and their correlation to joint health and functional impairments. DESIGN: Cross-sectional study. RESULTS: 29 severe/moderate PWH were enrolled. Muscle thickness of quadriceps and medial gastrocnemius were measured using ultrasound. Joint health and functional capacity were assessed using Haemophilia Joint Health Score (HJHS), Haemophilia Early Arthropathy Detection with Ultrasound (HEAD-US), 6-Minute Walking test (6MWT), Haemophilia Quality of Life Questionnaire for Adults (Haem-A-QoL), and Haemophilia Activities List (HAL). Quadriceps muscle thickness significantly correlated with HJHS knee, HEAD-US knee, and HAL. Calf muscle thickness significantly correlated with the HJHS ankle. After adjusted age and BMI, calf muscle thickness was inversely associated with the HJHS ankle. 6MWT was found to significantly correlate with HJHS total, HEAD-US total, Haem-A-QoL, and HAL. CONCLUSION: Muscle thickness and the distance of 6MWT were linked to assessment of joint health, quality of life and activity participation in PWH. Ultrasound measurement of muscle thickness and walking test appear to be useful tools for the assessment of joint health and functional status in PWH.

Cytotoxic Epipolythiodioxopiperazines from the Deep-Sea-Derived Fungus Exophiala mesophila MCCC 3A00939.

Four new aranotin-type epipolythiodioxopiperazines, graphiumins K-N (1-4), along with four known analogues (5-8), were isolated from the deep-sea-derived fungus Exophiala mesophila MCCC 3A00939. Their structures were elucidated by detailed interpretation of NMR and mass spectrometric data. The absolute configuration of the isolates was deduced by a single-crystal X-ray diffraction analysis and the comparisons of experimental electronic circular dichroism (ECD) data with calculated ECD spectra. Graphiumins K (1) and L (2) exhibited cytotoxic activities against the K562, H69AR, and MDA-MB-231 cancer cells with IC50 values ranging from 2.3 to 5.9 µM.

Intramural Hematoma of Gastrointestinal Tract in People with Hemophilia A and B.

People with hemophilia (PWH), especially severe hemophilia, often experience bleeding episodes, which occur mostly at major joints. Intramural hematoma of the gastrointestinal (GI) tract is a rare, potentially life-threatening clinical bleeding manifestation in PWH. Prompt identification and timely administration of clotting factor concentrates are of utmost importance for effective management and optimal patient outcomes. In this report, we present the case of a 48-year-old male with severe hemophilia A. The patient developed a spontaneous intramural hematoma of the jejunum, leading to signs of acute abdomen, bloody stool, and paralytic ileus. Conservative management with factor VIII (FVIII) infusion was successfully administered. However, within a span of three months, the patient suffered from a recurrent episode of intramural hematoma, which was again effectively treated with conservative therapy. Subsequently, prophylactic FVIII therapy was administered to the patient, resulting in the absence of recurrence for over three years. Inspired by this case, we conducted a comprehensive review of the relevant literature and gathered data from 79 reported cases of intramural hematoma that were documented between the years 1956 and 2022. We classified these cases based on the site affected within the gastrointestinal (GI) tract (spread across five different locations) and proceeded to conduct a simple pooling analysis on the data collected, which subsequently revealed that the overall mortality rate of intramural hematoma in people with hemophilia (PWH) was found to be 12.2%, while children have a higher mortality rate (23.3%) than adults (4.9%). We hope this case report and literature review increase awareness of this rare bleeding manifestation in PWH, the effectiveness of conservative treatment, and the possibility of prophylaxis against recurrence.

Real-world bleeding outcomes and product utilization in people with severe-type hemophilia A before and after switching to extended half-life rFVIIIFc prophylaxis therapy.

BACKGROUND: Recombinant factor VIII-Fc (rFVIIIFc) became available in Taiwan in 2018. Before this date, no people with hemophilia A (PwHA) were enrolled in a clinical trial of rFVIIIFc. We investigated changes in bleeding outcomes and product utilization in PwHA switching from rFVIII to rFVIIIFc. METHODS: Data were collected for Taiwanese PwHA (severe-type) who switched from rFVIII to rFVIIIFc, including annualized bleeding rate (ABR) and weekly dose consumption 12 months pre-switch and > 6 months post-switch. RESULTS: The 51 patients were divided into 3 groups according to their pre-switch treatment: on-demand treatment, intermittent periodic prophylaxis, and regular prophylaxis. In every group, the post-switch median ABR was significantly reduced, with no significant differences between groups. Meanwhile, the post-switch median weekly dose of each group was significantly increased. In 32 patients on pre-switch prophylaxis, switching brought a further reduction in median ABR, associated with a significant increase in median weekly dose. No adverse effects or novel inhibitor development were seen. CONCLUSION: This is the first report from Asia on real-world experience of rFVIIIFc, showing that switching to rFVIIIFc prophylaxis led to further reduction in ABR and increase in weekly dose for all patient groups, even those on pre-switch rFVIII prophylaxis.

Total Synthesis of Leptochartamides A and B: Two Enantiomeric Pairs of Hydroxybenzyl Dimers from a Deep-Sea Fungus Leptosphaerulina chartarum.

Leptochartamides A and B (±1 and ±2), two pairs of enantiomeric hybrids with the same cyclo-bridged skeleton containing an unusual dioxa-azabicyclo[3.2.1]octane core system, were isolated from the deep-sea-derived fungus Leptosphaerulina chartarum. Their structures were determined by detailed spectroscopic analysis, single-crystal X-ray diffraction, electronic circular dichroism calculations, and the total synthesis. Compounds 2a and 2b showed selective cytotoxicity against Ewings sarcoma cells A673, with IC50 values of 8.98 ± 0.23 and 4.18 ± 0.27 µM, respectively. The colony formation assay of compounds 2a and 2b against A673 cells was completed.

Liver and urine metabolomics reveal the protective effect of Gandou decoction in copper-laden Hepatolenticular degeneration model rats.

Hepatolenticular degeneration (HLD) is an inherited disorder associated with human copper metabolism. Gandou decoction (GDD), a traditional Chinese medicinal formula, has been used as a therapeutic agent for the treatment of HLD in China for decades. Recent pharmacological evaluation in our laboratory has demonstrated that GDD exerts positive and beneficial effects on HLD model rats. However, its underlying therapeutic mechanisms are not yet well understood. To explore the potential therapeutic effects of GDD against HLD, liver and urine metabolomics approach combined with histopathological examination were performed to reveal the underlying mechanisms. Changes in metabolic profiles were estimated by ultra-performance liquid chromatography quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF-MS) coupled with multivariate statistical analyses. The results indicated that GDD could significantly improve liver pathological variations. Moreover, 19 and 11 significantly altered metabolites were found in the liver and urine between the normal and model groups, respectively. After GDD treatment, the levels of all these disordered metabolites showed different degrees of improvement compared with the model group, including lysoPC(18:2), lysoPE(20:2/0:0), PC(18:1/14:1), alpha-linolenic acid, sphinganine, taurochenodesoxycholic acid, tetracosahexaenoic acid, 13-OxoODE, and 13-L-hydroperoxyl inoleic acid. Metabolic pathway enrichment suggested that lipid and oxidative stress metabolism were the two main pathways that participated in copper-laden rat models with GDD administration. This work indicates that GDD could achieve a therapeutic effect on HLD by ameliorating the associated metabolic disturbances.

Fabrication of self-healing pectin/chitosan hybrid hydrogel via Diels-Alder reactions for drug delivery with high swelling property, pH-responsiveness, and cytocompatibility.

Self-healing hydrogels with pH-responsiveness could protect loaded drugs from being destroyed till it arrives to the target. The pectin-based hydrogel is a candidate due to the health benefit, anti-inflammation, antineoplastic activity, nontoxicity, and biospecific degradation, et al. However, the abundant existence of water-soluble branched heteropolysaccharide chains influenced its performance resulting in limitation of the potential. In the present study, we prepared a series of self-healing pectin/chitosan hydrogels via the Diels-Alder reaction. Moreover, pectin/chitosan composite hydrogel was prepared as a contrast. By comparison, it can be seen that the Diels-Alder reaction greatly improved the cross-linking density of hydrogels. The self-healing experiments showed excellent self-healing performance. In different swelling mediums, significant transformation in the swelling ratio was shown, indicating well-swelling property, pH- and thermo-responsiveness. The drug loading and release studies presented high loading efficiency and sustained release performance. The cytotoxicity assay that showed a high cell proliferation ratio manifested great cytocompatibility.

Penitol A and Penicitols E-I: Citrinin Derivatives from Penicillium citrinum and the Structure Revision of Previously Proposed Analogues.

Penitol A (1), a new citrinin derivative with a rare tricyclic spiro skeleton, was isolated from a coral-derived strain of the fungus Penicillium citrinum. In addition, penicitols E-I (2-6), five new citrinin analogues, were coisolated. Their structures were determined by an analysis of 1D/2D NMR and HRESIMS data, statistical DP4+ analyses based on DFT-GIAO NMR calculations, quantum chemistry ECD calculations, and a single-crystal X-ray diffraction study. The structures of penicitol A (7) and two related synthetic intermediates were revised. Biological evaluation results revealed that penitol A (1) exhibited cytotoxic activity against K562 tumor cells, with an IC50 value of 8.8 µM. A proposed route of formation of compounds 1-7 was reported.

Design and preparation of quaternized pectin-Montmorillonite hybrid film for sustained drug release.

Montmorillonite (MMT) presents nonocclusive lamellar structure which restricts the potential use for sustained drug release. To solve the limitation, the quaternized pectin (QP) was synthesized and firstly introduced to form QP-MMT hybrid film containing 5-FU. The Fourier transform infrared spectroscopy (FT-IR) and X-Ray diffraction (XRD) were employed to determine the variation of the functional group and crystallinity between pectin and QP. The resultant composite film was characterized by FT-IR, XRD and Field Emission Scanning Electron Microscope. The results of the characterization indicated that intercalation reaction happened in the blending process. The optimum film showed high value of drug encapsulation efficiency (36.50%) and loading efficiency (80.30%). The in vitro drug release studies revealed that the MMT significantly improved the sustained-release performance in all simulated mediums. The cumulative release rate of sample QP10-MMT0.1 was all around 20% in the first half-hour in all simulated mediums and sustained increased for more than 8 h. The cytotoxicity assay was performed to prove the great biocompatibility of QP-MMT hybrid film. The present study introduced a facile route to prepare the composite film which presented sustained drug release performance.

Biological and Chemical Diversity of Marine Sponge-Derived Microorganisms over the Last Two Decades from 1998 to 2017.

Marine sponges are well known as rich sources of biologically natural products. Growing evidence indicates that sponges harbor a wealth of microorganisms in their bodies, which are likely to be the true producers of bioactive secondary metabolites. In order to promote the study of natural product chemistry and explore the relationship between microorganisms and their sponge hosts, in this review, we give a comprehensive overview of the structures, sources, and activities of the 774 new marine natural products from sponge-derived microorganisms described over the last two decades from 1998 to 2017.

Gandou Decoction Decreases Copper Levels and Alleviates Hepatic Injury in Copper-Laden Hepatolenticular Degeneration Model Rats.

Objective: This study was designed to investigate the therapeutic efficacy and underlying mechanisms of Gandou Decoction (GDD) in copper-laden hepatolenticular degeneration (HLD) model rats. Methods: In this study, high-performance liquid chromatography (HPLC) fingerprint analysis and eight representative active components were simultaneously measured for quality control of GDD. The therapeutic effect of GDD in HLD was studied by constructing a rat model of copper-laden HLD. The copper levels in the liver, serum, urine, and feces were quantified by atomic absorption spectrophotometry (AAS). Subsequently, UV-Vis spectrophotometry was used to study the coordination ability of copper ion (Cu2+) with six representative active components in GDD to explore its potential copper expulsion mechanism. Serological indexes including alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (AKP) were evaluated. Hepatic indicators including superoxide dismutase (SOD), glutathione (GSH), and the total antioxidant capacity (T-AOC) were determined. Moreover, the liver tissue was stained with hematoxylin-eosin to observe the histological changes. Results: Thirty characteristic fingerprint peaks were used to assess the similarities among 10 samples and showed the similarity was >0.98, indicating a good correlation among the common peaks. Simultaneous quantification of eight markers in GDD was then performed to determine the consistency of quality. GDD could decrease the serum and hepatic copper levels by increasing the urinary and fecal copper content in copper-laden rats. Meanwhile, the results of UV-Vis absorption studies show that six representative active ingredients in GDD can coordinate with Cu2+, indicating that complexing copper removal may be a potential mechanism for GDD to play a role in copper removal. Serum hepatic enzyme markers AST, ALT, and AKP activities and antioxidant enzyme SOD, T-AOC activities, and GSH level in hepatic tissue showed the protection of GDD against liver injury induced by excessive copper. Additionally, the hepatoprotective effect of GDD was also evidenced by the results of the liver histological evaluation. Conclusions: This study suggested that GDD could reduce the serum and hepatic copper levels through promoting urinary and fecal copper excretion in copper-laden rats. At the same time, GDD could alleviate hepatic injury by inhibition of oxidative stress.

Metabolic profiling of copper-laden hepatolenticular degeneration model rats and the interventional effects of Gandou decoction using UPLC-Q-TOF/MS.

The direct cause of hepatolenticular degeneration (HLD) is copper metabolic disorder caused by autosomal recessive inheritance. Gandou decoction (GDD), a classical traditional Chinese medicine formula, exhibits unambiguous therapeutic effect on HLD in China for decades. However, the mechanism of effect on HLD is not clear. With this purpose, the effects of copper content and histopathology inspection on the HLD rat model were investigated. Then, metabolomics study based on ultra-performance liquid chromatography quadrupole-time-of-flight mass spectrometry (UPLC-Q-TOF/MSE) analysis and multivariate statistical analysis was adopted to further reveal the mechanism of action of GDD against HLD. The results showed that the characteristics of liver tissues after GDD treatment were significantly reversed, close to the control group, suggesting that GDD has a therapeutic effect on HLD. Furthermore, HLD interferes with 2 metabolites of the metabolic pathway in rats. Among them, up-regulation of Lactic acid, Tryptophan, Phenylalanine, Triacylglycerol and down-regulation of Linoleic acid, Alpha Linolenic acid, Phosphatidylcholine, Taurine is particularly significant. Analysis of metabolic pathways by a unique pathway analysis revealed significant changes in several pathways including lipid metabolism, amino metabolism and glucose metabolism in HLD. This study showed that GDD could provide satisfactory therapeutic effects on HLD and metabolomics study can be utilized to further understand the molecular mechanisms.

[Intestinal absorptive characteristics of ingredients from ethanol extracts of Gandou decoction by rat everted intestinal sac models].

To study the intestinal absorptive characteristics of the ethanol extracts from Gandou decoction(GDD), everted intestinal sac models were used. The six representative ingredients (berberine hydrochloride, quercetin, kaempferide, rhein, chrysophanol, and aloe emodin) of GDD, were selected as the experimental targets to investigate the absorptive characteristics of various ingredients in different intestinal sections. The results showed that all six ingredients from GDD were detected in the intestinal sac, three active ingredients (berberine hydrochloride, quercetin, kaempferide) in high, medium and low doses had linear absorption properties in the small intestine segment, consistent with zero-order absorption rate; in addition, the absorption rate constant (Ka) of three components in jejunum and ileum were increased with the increase of the concentration of GDD (P<0.05), consistent with passive absorption. However, the Ka of rhein in jejunum and ileum showed little difference with the increase of dosage, suggesting a possibility of active transport mechanism. Chrysophanol and aloe-emodin were poorly absorbed in the two segments, which had not been detected in the previous time. The results suggested that the components of GDD were selectively absorbed in the intestinal sac, and the absorption characteristic of the ingredients were not exactly similar.

Spontaneous bilateral perirenal hemorrhage following prolonged fever: an uncommon presentation of polyarteritis nodosa.

A 68-year-old man presented with a spontaneous bilateral perirenal hemorrhage following a 2-month fever of unknown origin. A renal biopsy for a pathologic diagnosis seemed very risky because of the patient's bilateral perirenal hemorrhage. Therefore, we diagnosed polyarteritis nodosa using an abdominal computed tomography scan, a renal angiogram, and American College of Rheumatology criteria. The patient's multiple symptoms then responded well to the prescribed immunosuppressive regimen. This case is an uncommon presentation of polyarteritis nodosa with fever of unknown origin before a spontaneous bilateral perirenal hemorrhage.

Development of serum IgA and IgM levels in breast-fed and formula-fed infants during the first week of life.

BACKGROUND: IgA and IgM antibodies play important roles to protect infants in early life AIM: To study the effects of breast milk feeding versus formula feeding in early infancy on the development of serum IgA and IgM. METHODS: A group of 220 healthy infants born after uncomplicated pregnancies and deliveries were enrolled. The infants were divided into three groups according to feeding type: breast-fed (BF), formula-fed (FF), and mixed-fed (MF). Capillary blood was collected for serum IgA and IgM detection at the first week of life. RESULTS: The average concentrations of serum IgA and IgM in all infants were 1.171±1.079 and 256.2±165.8 µg/ml, respectively. There were significantly higher concentrations of serum IgA in the FF group than MF group at 3, 4 and 6 days of age and BF group at 5 and 6 days old. Paired serum IgA concentrations revealed that IgA significantly decreased in the BF group, but not in the FF and MF groups. Meanwhile, paired serum IgM concentrations revealed that IgM increased significantly during early infancy in all groups. However, the IgM levels had no difference among the 3 groups within 7 days of age. CONCLUSIONS: Our study demonstrated the development of serum IgA and IgM in early life. Formula feeding induced higher serum IgA concentrations than breast-feeding within 7 days of age. However, serum IgM concentration was significantly increased in early life in all groups but had no differences between the different feeding types. Breast-feeding may protect antigen loading in early life.