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BioRxiv : the Preprint Server For... Jun 2024The extent to which live orally-administered rotavirus (RV) vaccines elicit protective immunity is highly heterogeneous. We hypothesized microbiota composition might...
BACKGROUND & AIMS
The extent to which live orally-administered rotavirus (RV) vaccines elicit protective immunity is highly heterogeneous. We hypothesized microbiota composition might influence vaccine efficacy.
METHODS
We tested this concept by examining extent to which colonizing mice with segmented filamentous bacteria (SFB) influenced RV vaccine efficacy.Influence of human microbiomes on RV vaccination was studied via administering germ-free mice fecal microbial transplants (FMT) from children with robust or minimal RV vaccine responsiveness. Post-FMT, mice were subjected to vaccination and challenge doses of RV.
RESULTS
SFB administration resulted in a phenotype reminiscent of RV vaccine failure, i.e. minimal generation of RV antigens and, consequently, lack of anti-RV antibodies resulting in proneness to RV challenge once SFB levels diminished. Transplant of microbiomes from children to mice recapitulated donor vaccination phenotype. Specifically, mice receiving FMT from high-responding children exhibited high levels of fecal RV antigen shedding and RV antibodies in response to RV vaccination and, concomitantly, were impervious to RV challenge. In contrast, mice receiving FMT from children who had not responded to RV vaccination exhibited only modest responses to RV challenge and, accordingly, remained prone to RV challenge. Microbiome analysis ruled out a role for SFB but suggested that RV vaccine failure might involve . Oral administration of cultured to gnotobiotic mice partially recapitulated the RV vaccine non-responder phenotype. Analysis of previously-reported microbiome data found C. perfringens abundance in children associated with RV vaccine failure.
CONCLUSION
Microbiota composition influences RV vaccine virus infection and, consequently, protective immunity. may be one, perhaps of many, bacterial species harbored in the intestine of RV-vaccine non-responders that influences RV vaccine outcomes.
PubMed: 38948828
DOI: 10.1101/2024.06.17.599343 -
Frontiers in Pharmacology 2024Amdizalisib, also named HMPL-689, a novel selective and potent PI3Kδ inhibitor, is currently under Phase II clinical development in China for treating hematological...
Amdizalisib, also named HMPL-689, a novel selective and potent PI3Kδ inhibitor, is currently under Phase II clinical development in China for treating hematological malignancies. The preclinical pharmacokinetics (PK) of amdizalisib were extensively characterized and to support the further development of amdizalisib. We characterized the plasma protein binding, blood-to-plasma partition ratio, cell permeability, hepatic microsomal metabolic stability, and drug-drug interaction potential of amdizalisib using experiments. PK assessment was undertaken in mice, rats, dogs, and monkeys following a single intravenous or oral administration of amdizalisib. The tissue distribution and excretion of amdizalisib were evaluated in rats. The PK parameters (CL and V) of amdizalisib in preclinical species (mice, rats, dogs, and monkeys) were utilized for the human PK projection using the allometric scaling (AS) approach. Amdizalisib was well absorbed and showed low-to-moderate clearance in mice, rats, dogs, and monkeys. It had high cell permeability without P-glycoprotein (P-gp) or breast cancer resistance protein (BCRP) substrate liability. Plasma protein binding of amdizalisib was high (approximately 90%). It was extensively distributed but with a low brain-to-plasma exposure ratio in rats. Amdizalisib was extensively metabolized , and the recovery rate of the prototype drug was low in the excreta. Amdizalisib and/or its metabolites were primarily excreted via the bile and urine in rats. Amdizalisib showed inhibition potential on P-gp but not on BCRP and was observed to inhibit CYP2C8 and CYP2C9 with IC values of 30.4 and 10.7 μM, respectively. It exhibited induction potential on CYP1A2, CYP2B6, CYP3A4, and CYP2C9. The preclinical data from these ADME studies demonstrate a favorable pharmacokinetic profile for amdizalisib, which is expected to support the future clinical development of amdizalisib as a promising anti-cancer agent.
PubMed: 38948472
DOI: 10.3389/fphar.2024.1392209 -
Journal of Pharmacopuncture Jun 2024Warts caused by the human papillomavirus (HPV) are generally treated with cryotherapy, CO laser ablation, interferon injections, and bleomycin injections. However, it is...
Warts caused by the human papillomavirus (HPV) are generally treated with cryotherapy, CO laser ablation, interferon injections, and bleomycin injections. However, it is sometimes difficult to treat children because the treatment can be painful. In addition, recurrence may occur after treatment. In this study, warts completely disappeared following the administration of herbal medicine in two children, with warts in multiple parts of the hands and around the nails. Two pediatric patients visited the hospital for treatment of warts around their fingers and nails. Both patients received Taeeumjowi-tang (TJT) as a decoction for 60 days. TJT was performed twice per day for the 11-year-old patient and once per day for the 7-year-old patient. Patient progress was observed monthly, and the visual condition of the warts was photographed during the visits. After approximately two months of treatment, the warts disappeared from the fingers and nails of both patients. This case study suggests that the oral administration of TJT may be effective for pediatric patients with warts. Further studies are required to determine the efficacy and safety of these therapies.
PubMed: 38948305
DOI: 10.3831/KPI.2024.27.2.172 -
Sichuan Da Xue Xue Bao. Yi Xue Ban =... May 2024This study aims to analyze the relationship between reproductive tract microecological changes, metabolic differences, and pregnancy outcomes at different time points in...
OBJECTIVE
This study aims to analyze the relationship between reproductive tract microecological changes, metabolic differences, and pregnancy outcomes at different time points in the frozen-thawed embryo transfer cycle while patients are undergoing hormone replacement therapy, which will be a breakthrough point for improving outcomes.
METHODS
A total of 20 women undergoing frozen-thawed single blastocyst transfer for the first time at the Reproductive Medicine Center of Fujian Maternal and Child Health Hospital between July 2022 and January 2023 were recruited for this study. Their vaginal and cervical secretions were collected for 16S rRNA sequencing and non-targeted metabolomics analysis on days 2-5 of menstruation, day 7 after estrogen replacement therapy started, the day when progesterone was added, and the day of transplantation. The subjects were divided into different groups according to their clinical pregnancy status and the sequencing results were analyzed using bioinformatics methods.
RESULTS
1) The alpha-diversity index of the vaginal and cervical microbiota was higher on days 2-5 of menstruation (<0.01), but did not differ significantly on day 7 after oral estrogen replacement therapy started, the day of progesterone administration, and the day of transplantation (≥0.1). 2) Both the pregnant group and the non-pregnant group showed a variety of microorganisms and metabolites with significant differences in the lower reproductive tract at different time points. 3) Microbial analysis at different time points showed that there were significant differences in vaginal flora, including , , , , , , , , , and in the pregnant group (<0.05). 4) Metabolite analysis at different time points showed that there were significant differences in 3-hydroxybenzoic acid, linatine, (R)-amphetamine, hydroxychloroquine, and L-altarate in the vaginal secretions of the pregnant group (<0.05), and that there were significant differences in isocitric acid, quassin, citrinin, and 12(R)-HETE in the cervical secretions (<0.05). 5) Metabolite analysis at different time points showed that, in the non-pregnant group, there were significant differences in linatine, decanoyl-L-carnitine, aspartame, sphingosine, and hydroxychloroquine in the vaginal secretions (<0.05), and the isocitric acid, quassin, ctrinin, and 12(R)-HETE in the cervical secretions (<0.05). 6) Combined microbiome and metabolomics analysis showed that certain metabolites were significantly associated with microbial communities, especially .
CONCLUSIONS
Significant differences in the microbiota genera and metabolites at different time points were found during the frozen-embryo transfer cycle of hormone replacement therapy, which may be used as potential biomarkers to predict pregnancy outcomes of embryo transfer.
Topics: Humans; Female; Pregnancy; Embryo Transfer; Pregnancy Outcome; Microbiota; Vagina; Progesterone; Adult; Cryopreservation; RNA, Ribosomal, 16S; Cervix Uteri
PubMed: 38948288
DOI: 10.12182/20240560509 -
Avicenna Journal of Phytomedicine 2024Lead (Pb) poisoning affects multiple organs including the reproductive system. The experiment was performed to explore the protective effect of naringin on testicular...
OBJECTIVE
Lead (Pb) poisoning affects multiple organs including the reproductive system. The experiment was performed to explore the protective effect of naringin on testicular apoptosis, neuronal dysfunction and markers of stress in cockerel chicks.
MATERIALS AND METHODS
Thirty-six cockerel chicks were used for this study, and randomly grouped into six chicks per group viz. control, Pb only (600 ppm), Pb and naringin (80 mg/kg), Pb and Naringin (160 mg/kg), naringin only (80 mg/kg) and naringin only (160 mg/kg), respectively, for eight weeks. Pb was administered via drinking water while naringin was administered via oral gavage. Oxidative stress indices in the brain and testes were assessed, and immunohistochemistry of TNF-α and caspase 3 was done in the brain and testes, respectively.
RESULTS
Lead administration induced inflammatory and testicular apoptosis cascade accompanied with increased oxidative stress and upregulation of brain and testicular antioxidant enzymes in comparison to the control and Pb-only-treated cockerels. Immunohistochemistry showed significant immunoreactivity of testicular caspase 3 and TNF-α in the brain.
CONCLUSION
Treatment of Pb-exposed chickens with naringin offered protection to Pb acetate-induced testicular oxidative stress, apoptosis, and neuroinflammation in cockerel chicks.
PubMed: 38948173
DOI: 10.22038/AJP.2023.22946 -
Theranostics 2024Cancer therapy has moved from single agents to more mechanism-based targeted approaches. In recent years, the combination of HDAC inhibitors and other anticancer...
Cancer therapy has moved from single agents to more mechanism-based targeted approaches. In recent years, the combination of HDAC inhibitors and other anticancer chemicals has produced exciting progress in cancer treatment. Herein, we developed a novel prodrug via the ligation of dichloroacetate to selenium-containing potent HDAC inhibitors. The effect and mechanism of this compound in the treatment of prostate cancer were also studied. The concerned prodrug SeSA-DCA was designed and synthesized under mild conditions. This compound's preclinical studies, including the pharmacokinetics, cell toxicity, and anti-tumor effect on prostate cancer cell lines, were thoroughly investigated, and its possible synergistic mechanism was also explored and discussed. SeSA-DCA showed good stability in physiological conditions and could be rapidly decomposed into DCA and selenium analog of SAHA (SeSAHA) in the tumor microenvironment. CCK-8 experiments identified that SeSA-DCA could effectively inhibit the proliferation of a variety of tumor cell lines, especially in prostate cancer. In further studies, we found that SeSA-DCA could also inhibit the metastasis of prostate cancer cell lines and promote cell apoptosis. At the animal level, oral administration of SeSA-DCA led to significant tumor regression without obvious toxicity. Moreover, as a bimolecular coupling compound, SeSA-DCA exhibited vastly superior efficacy than the mixture with equimolar SeSAHA and DCA both and . Our findings provide an important theoretical basis for clinical prostate cancer treatment. Our and results showed that SeSA-DCA is a highly effective anti-tumor compound for PCa. It can effectively induce cell cycle arrest and growth suppression and inhibit the migration and metastasis of PCa cell lines compared with monotherapy. SeSA-DCA's ability to decrease the growth of xenografts is a little better than that of docetaxel without any apparent signs of toxicity. Our findings provide an important theoretical basis for clinical prostate cancer treatment.
Topics: Male; Prostatic Neoplasms; Humans; Animals; Apoptosis; Histone Deacetylase Inhibitors; Cell Line, Tumor; Cell Cycle Checkpoints; cdc25 Phosphatases; Mice; Antineoplastic Agents; Cell Proliferation; Mice, Nude; Selenium; Xenograft Model Antitumor Assays; Prodrugs; Mice, Inbred BALB C
PubMed: 38948069
DOI: 10.7150/thno.92119 -
Drug Design, Development and Therapy 2024To quantitatively assess all dosage forms of three active vitamin D and its analogs, namely, calcitriol, alfacalcidol, and eldecalcitol, to provide a basis for the...
OBJECTIVE
To quantitatively assess all dosage forms of three active vitamin D and its analogs, namely, calcitriol, alfacalcidol, and eldecalcitol, to provide a basis for the selection of active vitamin D and its analogs in hospitals.
METHODS
In this study, three active vitamin D and its analogs were evaluated by quantitative scoring in five dimensions, including pharmaceutical properties (28 points), efficacy (27 points), safety (25 points), economy (10 points), and other attributes (10 points).
RESULTS
The final scores of quantitative assessment for the selection of alfacalcidol soft capsules, calcitriol soft capsules I, calcitriol soft capsules II, alfacalcidol tablets, alfacalcidol capsules, alfacalcidol oral drops, calcitriol injection, and eldecalcitol soft capsules were 73.17, 72.06, 71.52, 71.29, 69.62, 68.86, 65.60, 64.05 points.
CONCLUSION
Based on the scoring results, alfacalcidol soft capsules, calcitriol soft capsules I, calcitriol soft capsules II, alfacalcidol tablets can be entered into the medication list of medical institutions as strongly recommended drugs. This study offers guidance on selecting and using active vitamin D and its analogs in hospitals, with consideration for the patient's needs.
Topics: Humans; Osteoporosis; Vitamin D; Hydroxycholecalciferols; Technology Assessment, Biomedical; Bone Density Conservation Agents; China; Calcitriol; Capsules
PubMed: 38947224
DOI: 10.2147/DDDT.S465960 -
Journal of Veterinary Research Jun 2024Chicken bones, a by-product of the poultry industry, can directly or indirectly enter the food chain. Bone meal and bone products could be sources of many contaminants....
INTRODUCTION
Chicken bones, a by-product of the poultry industry, can directly or indirectly enter the food chain. Bone meal and bone products could be sources of many contaminants. Considering the wide range of uses made of bones in the culinary and food industries, this material needs to be safe and antibiotic residue-free. To determine if such is the case, the concentration of doxycycline in chicken bones was investigated, this antimicrobial being one of the most commonly used in poultry production.
MATERIAL AND METHODS
Ross 308 broilers were grouped into three experimental and one control group. Doxycycline was administered in drinking water at therapeutic and sub-therapeutic doses, as well as spray treatment. The concentration of doxycycline in bones was determined post slaughter by ultra-high performance liquid chromatography-tandem mass spectrometry.
RESULTS
Doxycycline was quantified at 135 μg/kg 22 days after the last day of antibiotic administration at therapeutic doses; 2,285 μg/kg after sub-therapeutic treatment for 27 days and 9.62 μg/kg 22 days after the end of spray application.
CONCLUSION
High concentrations and long persistence of doxycycline in bones were found in this study. Doxycycline can contaminate all bone-derived products in the food and fertiliser industries.
PubMed: 38947148
DOI: 10.2478/jvetres-2024-0030 -
International Journal of Nanomedicine 2024It is well-established that osteoclast activity is significantly influenced by fluctuations in intracellular pH. Consequently, a pH-sensitive gated nano-drug delivery...
BACKGROUND
It is well-established that osteoclast activity is significantly influenced by fluctuations in intracellular pH. Consequently, a pH-sensitive gated nano-drug delivery system represents a promising therapeutic approach to mitigate osteoclast overactivity. Our prior research indicated that naringin, a natural flavonoid, effectively mitigates osteoclast activity. However, naringin showed low oral availability and short half-life, which hinders its clinical application. We developed a drug delivery system wherein chitosan, as gatekeepers, coats mesoporous silica nanoparticles loaded with naringin (CS@MSNs-Naringin). However, the inhibitory effects of CS@MSNs-Naringin on osteoclasts and the underlying mechanisms remain unclear, warranting further research.
METHODS
First, we synthesized CS@MSNs-Naringin and conducted a comprehensive characterization. We also measured drug release rates in a pH gradient solution and verified its biosafety. Subsequently, we investigated the impact of CS@MSNs-Naringin on osteoclasts induced by bone marrow-derived macrophages, focusing on differentiation and bone resorption activity while exploring potential mechanisms. Finally, we established a rat model of bilateral critical-sized calvarial bone defects, in which CS@MSNs-Naringin was dispersed in GelMA hydrogel to achieve in situ drug delivery. We observed the ability of CS@MSNs-Naringin to promote bone regeneration and inhibit osteoclast activity in vivo.
RESULTS
CS@MSNs-Naringin exhibited high uniformity and dispersity, low cytotoxicity (concentration≤120 μg/mL), and significant pH sensitivity. In vitro, compared to Naringin and MSNs-Naringin, CS@MSNs-Naringin more effectively inhibited the formation and bone resorption activity of osteoclasts. This effect was accompanied by decreased phosphorylation of key factors in the NF-κB and MAPK signaling pathways, increased apoptosis levels, and a subsequent reduction in the production of osteoclast-specific genes and proteins. In vivo, CS@MSNs-Naringin outperformed Naringin and MSNs-Naringin, promoting new bone formation while inhibiting osteoclast activity to a greater extent.
CONCLUSION
Our research suggested that CS@MSNs-Naringin exhibited the strikingly ability to anti-osteoclasts in vitro and in vivo, moreover promoted bone regeneration in the calvarial bone defect.
Topics: Flavanones; Animals; Osteoclasts; Bone Regeneration; Silicon Dioxide; Hydrogen-Ion Concentration; Nanoparticles; Rats; Mice; Rats, Sprague-Dawley; Chitosan; Male; Drug Liberation; Porosity; Drug Carriers; Bone Resorption; RAW 264.7 Cells; Drug Delivery Systems; Cell Differentiation
PubMed: 38946884
DOI: 10.2147/IJN.S456545 -
Frontiers in Cell and Developmental... 2024Duchenne muscular dystrophy (DMD) is a genetic disorder caused by mutations in the dystrophin-encoding gene that leads to muscle necrosis and degeneration with chronic...
INTRODUCTION
Duchenne muscular dystrophy (DMD) is a genetic disorder caused by mutations in the dystrophin-encoding gene that leads to muscle necrosis and degeneration with chronic inflammation during growth, resulting in progressive generalized weakness of the skeletal and cardiac muscles. We previously demonstrated the therapeutic effects of systemic administration of dental pulp mesenchymal stromal cells (DPSCs) in a DMD animal model. We showed preservation of long-term muscle function and slowing of disease progression. However, little is known regarding the effects of cell therapy on the metabolic abnormalities in DMD. Therefore, here, we aimed to investigate the mechanisms underlying the immunosuppressive effects of DPSCs and their influence on DMD metabolism.
METHODS
A comprehensive metabolomics-based approach was employed, and an ingenuity pathway analysis was performed to identify dystrophy-specific metabolomic impairments in the mice to assess the therapeutic response to our established systemic DPSC-mediated cell therapy approach.
RESULTS AND DISCUSSION
We identified DMD-specific impairments in metabolites and their responses to systemic DPSC treatment. Our results demonstrate the feasibility of the metabolomics-based approach and provide insights into the therapeutic effects of DPSCs in DMD. Our findings could help to identify molecular marker targets for therapeutic intervention and predict long-term therapeutic efficacy.
PubMed: 38946797
DOI: 10.3389/fcell.2024.1363541