Rebalancing of the gut flora and microbial metabolism is responsible for the anti-arthritis effect of kaempferol

Kaempferol is a natural flavonol that possesses various pharmacological activities,including anti-arthritis effects,yet the underlying mechanisms remain controversial.To evaluate the anti-arthritis efficacy and the underlying mechanisms of kaempferol,collagen-induced arthritis(CIA)mice were treated with kaempferol intragastrically(200 mg·kg^−1·d^−1)and intraperitoneally(20 mg·kg^−1·d^−1).Pharmacodynamic and pharmacokinetic studies showed that the oral administration of kaempferol produced distinct anti-arthritis effects in model mice with arthritis in terms of the spleen index,arthritis index,paw thickness,and inflammatory factors;the bioavailability(1.5%,relative to that of the intraperitoneal injection)and circulatory exposure of kaempferol(Cmax=0.23±0.06 ng/mL)and its primary metabolite kaempferol-3-O-glucuronide(Cmax=233.29±89.64 ng/mL)were rather low.In contrast,the intraperitoneal injection of kaempferol caused marginal anti-arthritis effects,although it achieved a much higher in vivo exposure.The much higher kaempferol content in the gut implicated a potential mechanism involved in the gut.Analysis of 16S ribosomal RNA revealed that CIA caused imbalance of 14 types of bacteria at the family level,whereas kaempferol largely rebalanced the intestinal microbiota in CIA mice.A metabolomics study showed that kaempferol treatment significantly reversed the perturbation of metabolites involved in energy production and the tryptophan,fatty acid and secondary bile acid metabolisms in the gut contents of the CIA mice.In conclusion,we demonstrate for the first time that the high level of kaempferol in the gut regulates the intestinal flora and microbiotic metabolism,which are potentially responsible for the anti-arthritis activities of kaempferol.     

Annual advances of integrative pharmacology in 2019

Representative studies concerning the pharmacology of traditional medicine and active herbal products have been summarized over the past 12 months.This annual integrative pharmacology review encompasses research articles published during 2019 on the bioactive compounds and extracts used in traditional medicine.Reports highlighting the pharmacology progress of traditional medicine were specifically introduced,including artemisinin for cancer cell sensibility and induction to ferroptosis,rutin for neuroinflammation suppression,Ginseng Radix et Rhizoma for gut microbiota regulation against obesity,green tea and Pu-erh tea for metabolic syndrome,and marine-derived oligosaccharide(GV-971)from brown algae for anti-dementia.Moreover,novel TCM molecular targets and pharmacological mechanisms were trialed against different human diseases,including cancers,cardiovascular,cerebrovascular diseases,diabetes,and metabolic diseases.Notably,herb-derived bioactive products have become important treatment alternatives for cancer research in 2019.Cardiovascular and cerebrovascular diseases,together with diabetes and metabolic diseases,are ongoing research areas for traditional medicine.Moreover,inflammation and infectious disease are also attracting more attention by researchers,which might have been influenced by seasonal influenza or HIV/Ebola viral infections.Further traditional medicine investigations are required in neurodegenerative diseases,depression,and mental diseases.Taken together,the findings of the integrative pharmacology review in 2019 provide a vast number of novel lead compounds or drug candidates for future clinical agent development and also details a novel series of attractive therapeutic targets and molecular mechanisms for human diseases.     

The cancer-testis gene,MEIOB,sensitizes triple-negative breast cancer to PARP1 inhibitors by inducing homologous recombination deficiency

Objective:The newly defined cancer-testis(CT)gene,MEIOB,was previously found to play key roles in DNA double-strand break(DSB)repair.In this study,we aimed to investigate the effects and mechanisms of MEIOB in the carcinogenesis of triple-negative breast cancers(TNBCs).Methods:The Cancer Genome Atlas database was used to quantify the expression of MEIOB.Cox regression analysis was used to evaluate the association between MEIOB expression and the prognosis of human TNBC.The effects of MEIOB on cell proliferation and migration in TNBCs were also assessed in vitro.Patient-derived xenograft(PDX)models were used to assess the sensitivity of breast cancers with active MEIOB to PARP1 inhibitors.Results:We confirmed MEIOB as a CT gene whose expression was restricted to the testes and breast tumors,especially TNBCs.Its activation was significantly associated with poor survival in breast cancer patients[overall,hazard ratio(HR)=1.90(1.16–2.06);TNBCs:HR=7.05(1.16–41.80)].In addition,we found that MEIOB was oncogenic and significantly promoted the proliferation of TNBC cells.Further analysis showed that MEIOB participated in DSB repair in TNBCs.However,in contrast to its function in meiosis,it mediated homologous recombination deficiency(HRD)through the activation of poly ADP-ribose polymerase(PARP)1 by interacting with YBX1.Furthermore,activated MEIOB was shown to confer sensitivity to PARP inhibitors,which was confirmed in PDX models.Conclusions:MEIOB played an oncogenic role in TNBC through its involvement in HRD.In addition,dysregulation of MEIOB sensitized TNBC cells to PARP inhibitors,so MEIOB may be a therapeutic target of PARP1 inhibitors in TNBC.     

Cranioplasty of large cranial defect at an early stage after decompressive craniectomy performed for severe head trauma

Large cranial defects resulting from decompressive craniectomy performed for refractory intracranial hypertension after head trauma is one of the indications for cranioplasty, and this procedure is commonly performed 3 months after craniectomy. However, the large cranial defect would lead to the kinds of complications early during the phase of these patients' recovery, which would go against rehabilitation. This study retrospectively reviewed 23 patients undergoing early cranioplasty (5-8 weeks after craniectomy) in the last 4 years with a detailed choice of patients, outcome of complications after head trauma and large craniectomy, as well as assessment of prognosis. The early outcome (1 month later) revealed most of the patients who had conscious disturbance before the cranioplasty recovered their consciousness and presented an improved neurologic function. The long-dated prognosis (18 months later) revealed that 17 patients were good (independent patients) in this series (74%), whereas four patients survived with a severe disability (17%) and two remained in a vegetative state (9%). No dead patients or intracranial infection after the procedure were found in this study. Most patients' complications were relieved after the cranioplasty with improvements of symptoms or image of computed tomography scan. In conclusion, we consider that with the appropriate choice of patients and materials, early cranioplasty for large cranial defects after decompressive craniectomy would be safe and helpful for the improvement of patients' neurologic function and prognosis. To our knowledge, this series may be the first detailed report in English about early cranioplasty after decompressive craniectomy. We are going to perform prospective and retrospective contrastive studies to further confirm the effects of this procedure on the patients with large cranial defects after decompressive craniectomy.     

Cloning, characterization and immunolocalization of human ameloblastin

Amelogenesis imperfecta is a broad classification of hereditary enamel defects, exhibiting both genetic and clinical diversity. Most amelogenesis imperfecta cases are autosomal dominant disorders, yet only the local hypoplastic form has been mapped to human chromosome 4q between D4S242 1 and the albumin gene. An enamel protein cDNA, termed ameloblastin (also known as amelin and sheathlin), has been isolated from rat, mouse and pig. Its human homolog has been mapped to chromosome 4q21 between markers D4S409 and D4S400, flanking the local hypoplastic amelogenesis imperfecta critical region. Therefore, ameloblastin is a strong candidate gene for this form of amelogenesis imperfecta. To facilitate genetic studies related to this dental disease, we isolated and characterized a human ameloblastin cDNA. A human third molar cDNA library was screened and two ameloblastin clones identified. Nucleotide sequencing of these cDNAs indicated alternative splicing of the putative open reading frame, use of different polyadenylation signals, and a high degree of similarity to reported rat, mouse and porcine cDNAs. Immunohistochemistry studies on embryonic human teeth using an antibody to recombinant ameloblastin indicated ameloblastin expression by ameloblasts with localization in the enamel matrix associated with the sheath structures.     

Enamelin maps to human chromosome 4q21 within the autosomal dominant amelogenesis imperfecta locus

Amelogenesis imperfecta is a group of hereditary enamel defects. Of the autosomal dominant forms, only the local hypoplastic type has been mapped to human chromosome 4q 13-4q21. Enamelin is a large enamel matrix protein secreted by ameloblasts. The purpose of this study was to determine the human chromosomal localization of enamelin to establish an association with various forms of amelogenesis imperfecta. Chromosomal mapping was performed by polymerase chain reaction (PCR) amplification using somatic hybrid and deletion/derivation cell line panels with an enamelin primer set based on 100% conserved regions between pig and mouse cDNAs. Sequence-tagged site content mapping using eight markers within the critical local hypoplastic amelogenesis imperfecta region was then performed using an isolated human enamelin genomic BAC clone. The human enamelin amplicon was confirmed by DNA sequence analysis, revealing 81% and 73% identity to pig and mouse cDNAs, respectively. PCR amplification using a somatic cell hybrid panel placed enamelin on chromosome 4 with analysis of a regional chromosome 4 mapping panel refining the localization to 4q 13.1-q21.23. An identified human enamelin BAC genomic clone was shown to contain markers D4S2604 and D4S2670, as well as the first exon of the human ameloblastin gene, placing enamelin in the critical amelogenesis imperfecta locus between markers HIS1 and D4S2604 at 4q21. Our results suggest that enamelin is a strong candidate gene for this disease. Furthermore, human 4q21 may contain a second cluster of enamel matrix genes located proximally to the identified cluster of dentin and bone genes.     

Type II collagen and aggrecan mRNA expressions in rabbit condyle following disc displacement

The aim of this investigation was to study the remodelling of cartilage in the mandibular condyle following disc displacement (DD) of the temporomandibular joint (TMJ). Forty adult Japanese white rabbits were used in this study. The right joints of 28 of the 40 rabbits had their discs surgically displaced. Four of the 28 were killed at 4 days or 1, 2, 4, 6, 8 and 12 weeks after surgery. The messenger RNA (mRNA) expression levels of aggrecan and type II collagen in cartilages were measured using in situ hybridization techniques. Results showed that aggrecan mRNA expression reduced in the first week after DD. The expression began to recover after 4 weeks and reached a normal level after 6 weeks. Type II collagen mRNA expression reduced from 4 weeks and the expression recovered after 8 weeks. This suggests that the chondrocyte reacting to the displacement of the TMJ disc, alters its matrix gene expression patterns and it is may be the cause of the shape changes of TMJ after DD.     

The effect of xylitol on Streptococcus mutans in children

A study was performed on 91 second-grade students from the Los Angeles Unified School District to test the effects of xylitol chewing gum on Streptococcus mutans in the saliva. Saliva was collected from students and tested for the first time using the new University of California, Los Angeles, monoclonal antibody testing method. Students found to have moderate or high levels of salivary S. mutans were administered four tablets/day of xylitol gum for three weeks. The levels of S. mutans in the saliva of children in the high caries index subgroup decreased by 61.7 percent. Xylitol can be dispensed in a public school setting by school nurses and can be a very safe, efficient and inexpensive preventative measure for children at high risk for dental caries.     

Respiratory outcome of mid-face advancement with distraction: a comparison between Le Fort III and frontofacial monobloc

Upper airway stenosis in patients with faciocraniosynostosis is very common and often severe. Mid-face advancement, either with a Le Fort III or concomitantly to a monobloc frontofacial advancement, may prevent a tracheotomy or result in its ablation. The amelioration of respiratory function appears to be much better if the mid-face advancement is combined with distraction osteogenesis, although large studies with long-term follow-up are rare. In this study we reviewed the respiratory outcome between Le Fort III with distraction and monobloc advancement with distraction in 55 faciocraniosynostotic patients. Early respiratory results of both procedures were very good and stable at long-term follow-up. The choice between a Le Fort III and a monobloc procedure is made based on presenting morphology, previous surgery, and age. Both can be expected to give a long-lasting improvement of upper airway obstruction.     

Intermittent force in orthodontic tooth movement

A single orthodontic activation lasting one hour can initiate tooth movement. The purpose of this study is to examine tooth movement, osteoclasts, and root resorption in rats following several one-hour activations. Rats (n = 144) were randomly assigned to intermittent (multiple activations of 1 hr/day), continuous, and sham appliances. Twelve rats were killed at 3, 5, 7, and 14 days. Tooth movement, osteoclasts, osteoclast %, and root resorption % were quantified. Continuous force moved molars mesially at days 3 and 14 (p < 0.05), but intermittent and sham did not. Intermittent and continuous force increased osteoclast numbers at days 3, 5, and 7 (p < 0.05). Continuous force increased osteoclast surface on days 3 and 14 (p < 0.05). Continuous force increased root resorption at days 5, 7, and 14 (p < 0.05). These results demonstrate that orthodontic force for one hour in 24 stimulates osteoclasts at compression sites but does not stimulate tooth movement or root resorption.