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.     

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.     

Leukoaraiosis is associated with clinical symptom severity,poor neurological function prognosis and stroke recurrence in mild intracerebral hemorrhage:a prospective multi-center cohort study

Leukoaraiosis(LA)results from ischemic injury in small cerebral vessels,which may be attributable to decreased vascular density,reduced cerebrovascular angiogenesis,decreased cerebral blood flow,or microcirculatory dysfunction in the brain.In this study,we enrolled 357 patients with mild intracerebral hemorrhage(ICH)from five hospitals in China and analyzed the relationships between LA and clinical symptom severity at admission,neurological function prognosis at 3 months,and 1-year stroke recurrence.Patients were divided into groups based on Fazekas scale scores:no LA(n=83),mild LA(n=64),moderate LA(n=98)and severe LA(n=112).More severe LA,larger hematoma volume,and higher blood glucose level at admission were associated with more severe neurological deficit.More severe LA,older age and larger hematoma volume were associated with worse neurological function prognosis at 3 months.In addition,moderate-to-severe LA,admission glucose and symptom-free cerebral infarction were associated with 1-year stroke recurrence.These findings suggest that LA severity may be a potential marker of individual ICH vulnerability,which can be characterized by poor tolerance to intracerebral attack or poor recovery ability after ICH.Evaluating LA severity in patients with mild ICH may help neurologists to optimize treatment protocols.This study was approved by the Ethics Committee of Ruijin Hospital Affiliated to Shanghai Jiao Tong University(approval No.12)on March 10,2011.     

Nogo-A expression dynamically varies after spinal cord injury

The mechanism involved in neural regeneration after spinal cord injury is unclear. The myelin-derived protein Nogo-A, which is specific to the central nervous system, has been identified to negatively affect the cytoskeleton and growth program of axotomized neurons. Studies have shown that Nogo-A exerts immediate and chronic inhibitory effects on neurite outgrowth. In vivo, inhibitors of Nogo-A have been shown to lead to a marked enhancement of regenerative axon extension. We established a spinal cord injury model in rats using a free-falling weight drop device to subsequently investigate Nogo-A expression. Nogo-A mR NA and protein expression and immunoreactivity were detected in spinal cord tissue using real-time quantitative PCR, immunohistochemistry and western blot analysis. At 24 hours after spinal cord injury, Nogo-A protein and mR NA expression was low in the injured group compared with control and sham-operated groups. The levels then continued to drop further and were at their lowest at 3 days, rapidly rose to a peak after 7 days, and then gradually declined again after 14 days. These changes were observed at both the mR NA and protein level. The transient decrease observed early after injury followed by high levels for a few days indicates Nogo-A expression is time dependent. This may contribute to the lack of regeneration in the central nervous system after spinal cord injury. The dynamic variation of Nogo-A should be taken into account in the treatment of spinal cord injury.     

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.     

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.     

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.