The TLR2/TLR6 ligand FSL-1 mitigates radiation-induced hematopoietic injury in mice and nonhuman primates.

Thrombocytopenia, hemorrhage, anemia, and infection are life-threatening issues following accidental or intentional radiation exposure. Since few therapeutics are available, safe and efficacious small molecules to mitigate radiation-induced injury need to be developed. Our previous study showed the synthetic TLR2/TLR6 ligand fibroblast stimulating lipopeptide (FSL-1) prolonged survival and provided MyD88-dependent mitigation of hematopoietic acute radiation syndrome (H-ARS) in mice. Although mice and humans differ in TLR number, expression, and function, nonhuman primate (NHP) TLRs are like those of humans; therefore, studying both animal models is critical for drug development. The objectives of this study were to determine the efficacy of FSL-1 on hematopoietic recovery in small and large animal models subjected to sublethal total body irradiation and investigate its mechanism of action. In mice, we demonstrate a lack of adverse effects, an easy route of delivery (subcutaneous) and efficacy in promoting hematopoietic progenitor cell proliferation by FSL-1. NHP given radiation, followed a day later with a single subcutaneous administration of FSL-1, displayed no adversity but showed elevated hematopoietic cells. Our analyses revealed that FSL-1 promoted red blood cell development and induced soluble effectors following radiation exposure. Cytologic analysis of bone marrow aspirates revealed a striking enhancement of mononuclear progenitor cells in FSL-1-treated NHP. Combining the efficacy of FSL-1 in promoting hematopoietic cell recovery with the lack of adverse effects induced by a single administration supports the application of FSL-1 as a viable countermeasure against H-ARS.

Killing tumor-associated bacteria with a liposomal antibiotic generates neoantigens that induce anti-tumor immune responses.

Increasing evidence implicates the tumor microbiota as a factor that can influence cancer progression. In patients with colorectal cancer (CRC), we found that pre-resection antibiotics targeting anaerobic bacteria substantially improved disease-free survival by 25.5%. For mouse studies, we designed an antibiotic silver-tinidazole complex encapsulated in liposomes (LipoAgTNZ) to eliminate tumor-associated bacteria in the primary tumor and liver metastases without causing gut microbiome dysbiosis. Mouse CRC models colonized by tumor-promoting bacteria (Fusobacterium nucleatum spp.) or probiotics (Escherichia coli Nissle spp.) responded to LipoAgTNZ therapy, which enabled more than 70% long-term survival in two F. nucleatum-infected CRC models. The antibiotic treatment generated microbial neoantigens that elicited anti-tumor CD8+ T cells. Heterologous and homologous bacterial epitopes contributed to the immunogenicity, priming T cells to recognize both infected and uninfected tumors. Our strategy targets tumor-associated bacteria to elicit anti-tumoral immunity, paving the way for microbiome-immunotherapy interventions.

Knockdown of METTL16 disrupts learning and memory by reducing the stability of MAT2A mRNA.

N6-methyladenosine (m6A) is abundant in the mammalian brain and is considered to have a wide range of effects on learning and memory. Here, we found that the upregulated methyltransferase-like protein 16 (METTL16) in the hippocampal tissues of Morris water maze (MWM)-trained mice contributed to improved memory formation and hippocampal synaptic plasticity. Mechanismly, METTL16 promoted the expression of methionine adenosyltransferase 2A (MAT2A) by the m6A methylation of the MAT2A mRNA-3'UTR-end to increase its stability, and this involved in improving hippocampal global m6A levels, plasticity of dendritic spine, learning and memory. This study provides a new perspective to explore the regulatory mechanisms of m6A for learning and memory.

Comparison of Hysteroscopic Morcellation Versus Resectoscopy in Treatment of Patients with Endometrial Lesions: A Meta-Analysis.

BACKGROUND Hysteroscopic surgery has been widely used in clinical practice for more than 30 years due to its advantages of less trauma, less bleeding, and direct vision. The aim of this study was to compare hysteroscopic morcellation versus conventional resectoscopy for removal of endometrial lesions. MATERIAL AND METHODS For the database search, we used the keywords "morcellator," "morcellators," "morcellate," "morcellation," and "morcellated" combined with "hysteroscopy," "hysteroscopy," "uteroscope," and "transcervical". The last search was conducted on February 1, 2022. Randomized controlled trials (RCTs) were included in the meta-analysis. RESULTS According to our retrieval scheme and the inclusion and exclusion criteria, we found 6 studies including 565 patients. For enumeration data, we calculated the effect size as relative risk (RR) and 95% confidence interval (95% CI), while for quantitative data we used the weighted mean difference (WMD) and 95% confidence interval (95% CI). There was no significant difference between success rate of hysteroscopic morcellation and conventional resectoscopy (relative risk and 95% confidence interval 1.05(0.97,1.13); P=0.232). Procedure time was also shorter with hysteroscopic morcellation, the procedure time of the hysteroscopic morcellation group was 3.43 min shorter compared with the conventional resectoscopy group, and the operating time in the hysteroscopic morcellation group was 2.81 min shorter. In terms of fluid deficit, there was no statistically significant difference in fluid loss between the 2 groups (P=0.209). CONCLUSIONS Hysteroscopic morcellation is associated with a shorter procedure time and operative time among patients with endometrial lesions compared with resectoscopy.

Analysis of factors associated with vision after cataract surgery in chronic renal failure patients on dialysis.

BACKGROUND: To analyze the related factors of visual acuity after phacoemulsification and intraocular lens implantation in chronic renal failure (CRF) patients. METHODS: We retrospectively analyzed 42 patients (51 eyes) with CRF (failure, uremia) on hemodialysis or peritoneal dialysis and 40 patients (50 eyes) without CRF as a control group. Each individual underwent physical and laboratory examinations including best corrected visual acuity (BCVA), slit lamp examination, intraocular pressure, corneal endothelial cell count, fundus examination and optical coherence tomography (OCT) for macular examination. The patients with abnormal platelet, liver and kidney function, coagulation function received treatment accordingly to reduce the perioperative risk. All patients underwent phacoemulsification with IOL implantation. Follow-up examinations were performed at 1 week, 1 month and 3 months after surgery and included BCVA, slit lamp examination, noncontact IOP, dilated fundus examination and OCT of the macula. RESULTS: In control group the preoperative RBC, HB, Cr, and urea values were not associated with the pre- or postoperative BCVA. The RBC, HB, Cr, urea, SBP, DBP, preoperative BCVA and postoperative BCVA values were all significantly different between CRF and control group(P < 0.05). CONCLUSION: In CRF patients, the RBC, HB, Cr and Urea indexes should be monitored before the cataract operation for guarded visual outcome. The pre-existing ocular comorbidities could significantly compromise the vision. The CRF patients could achieve relatively good visual outcome after cataract surgery when the underlaying diseases are effectively managed.

Isoflavone daidzein regulates immune responses in the B6C3F1 and non-obese diabetic (NOD) mice.

Daidzein (DAZ), a dominant isoflavone in various natural products such as soybeans, has been gaining attention due to the beneficial health effects (e.g., protection against cancer and diabetes) of its metabolites. Our major hypothesis was that dietary exposure to the soy phytoestrogen DAZ could modulate the immune responses toward a protective effect and lead to improved metabolic functions (such as glucose metabolism). In this study, we applied complementary mouse models, the hybrid B6C3F1 and inbred type 1 diabetes prone non-obese diabetic (NOD) mice, to investigate if DAZ exposure modulated the immune responses. The animals were orally administered DAZ at various physiological doses (2-20 mg/kg body weight) during adulthood. DAZ significantly altered the relative organ weights in female B6C3F1 mice and decreased the B cell population (represented by CD3-IgM+), while the T cell populations (represented by CD3+IgM-, CD4+CD8- and CD4-CD8+) were increased. In addition, DAZ dosing produced a decrease in the percentage of late apoptotic thymocytes. However, the activities cytotoxic T cells and natural killer cells were not altered in the B6C3F1 mice. In NOD mice, the blood glucose level and glucose tolerance were not affected by DAZ exposure, but DAZ modulated the antibody production, as shown by increased levels of IgG2b in NOD females and IgG1 in NOD males. Further, DAZ increased CD8+CD25+ splenocytes in NOD females. Taken together, DAZ induced an immunomodulatory effect in both NOD and B6C3F1 mouse strains; however, minimal effects on glucose homeostasis were observed.

A clinical analysis of vitrectomy for severe vitreoretinopathy in patients with chronic renal.

BACKGROUND: The recent advancement in the management of chronic renal failure (CRF) has significantly increased the longevity of the patients, which increase the incidence of severe vitreoretinopathy. The vitrectomy is highly risky in this particular group of patients due to their systemic comorbidity. The timing surgical intervention is usually delayed because of the systemic conditions. This study is to evaluate the safety and effectiveness of 25-guage vitrectomy for severe vitreoretinopathy in the CRF patients. METHODS: In this retrospective study, 16 eyes of 16 CRF patients with severe vitreoretinopathy were undergone 25-guage vitrectomy in the department of Ophthalmology of the Second Hospital of Tianjin Medical University from February 2015 to April 2017. The visual outcome, complications and perioperative medical management were documented and analyzed. RESULTS: The best-corrected visual acuity(BCVA)of fourteen eyes were lower than 20/200 preoperatively. Surgery duration ranged from 28 to 72 min, with a mean of 48.4 ± 13.6 min. During the surgery, 12 eyes were diagnosed with DR, while two them were complicated with tractional retinal detachment and one with branch retinal vein occlusion. Three eyes were diagnosed with branch retinal vein occlusion, and one eye was diagnosed with hypertensive retinopathy. Postoperative BCVA of six eyes ≥20/40, seven eyes ≥20/200, and three eyes < 20/200. BCVA of eight eyes improved more than three lines, three eyes improved two lines, and four eyes improved one line. BCVA decreased from hand movement to light perception in one patient who developed neovascular glaucoma two weeks after surgery. CONCLUSION: In chronic renal failure patients with severe vitreoretinopathy, the well-planned minimally invasive vitrectomy is effective and safe. Additionally, careful management of the perioperative systemic conditions is important to improve the visual acuity and quality of life as well.

Clinicopathological and biochemical findings of thyroid amyloid in hereditary transthyretin amyloidosis with and without liver transplantation.

Hereditary transthyretin (TTR) amyloidosis is a fatal disease causing systemic organ dysfunctions. Histopathological studies revealed that thyroid glands are major target tissues. However, details about thyroid functions remain to be fully elucidated in this disease. For patient treatment, liver transplantation (LT) reportedly prolongs patient survival, but thyroid gland function after LT still remains poorly understood. In this study, we investigated the thyroid functions in 101 patients with hereditary TTR amyloidosis and the effects of LT on thyroid functions in those patients. In addition, we investigated histopathological and biochemical findings of thyroid specimens obtained at autopsy. Disease duration and age at examination inversely correlated with serum levels of free triiodothyronine (fT3) in hereditary TTR amyloidosis. On the contrary, in patients who underwent transplantation, time from disease onset to transplantation and age at transplantation clearly correlated with serum fT3and thyroid stimulating hormone (TSH) levels. In autopsy studies, amounts of thyroid amyloid deposits in patients with transplantation were significantly lower than those in patients without transplantation. Mass spectrometric analyzes also revealed that proportions of wild-type (WT) TTR in thyroid amyloid deposits in patients with hereditary TTR amyloidosis who underwent transplantations were higher than those in patients without transplantation. Thyroid hormone functions may diminish according to the disease progression. LT could prevent thyroid dysfunction in hereditary TTR amyloidosis.

TCDD modulation of gut microbiome correlated with liver and immune toxicity in streptozotocin (STZ)-induced hyperglycemic mice.

An increasing body of evidence has shown the important role of the gut microbiome in mediating toxicity following environmental contaminant exposure. The goal of this study was to determine if the adverse metabolic effects of chronic 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) exposure would be sufficient to exacerbate hyperglycemia, and to further determine if these outcomes were attributable to the gut microbiota alteration. Adult male CD-1 mice were exposed to TCDD (6µg/kg body weight biweekly) by gavage and injected (i.p.) with STZ (4×50mg/kg body weight) to induced hyperglycemia. 16S rRNA sequencing was used to characterize the changes in the microbiome community composition. Glucose monitoring, flow cytometry, histopathology, and organ characterization were performed to determine the deleterious phenotypic changes of TCDD exposure. Chronic TCDD treatment did not appear to exacerbate STZ-induced hyperglycemia as blood glucose levels were slightly reduced in the TCDD treated mice; however, polydipsia and polyphagia were observed. Importantly, TCDD exposure caused a dramatic change in microbiota structure, as characterized at the phylum level by increasing Firmicutes and decreasing Bacteroidetes while at the family level most notably by increasing Lactobacillaceae and Desulfovibrionaceae, and decreasing Prevotellaceae and ACK M1. The changes in microbiota were further found to be broadly associated with phenotypic changes seen from chronic TCDD treatment. In particular, the phylum level Bacteroidetes to Firmicutes ratio negatively correlated with both liver weight and liver pathology, and positively associated with %CD3(+)NK(+) T cells, a key mediator of host-microbial interactions. Collectively, these findings suggest that the dysregulated gut microbiome may contribute to the deleterious effects (e.g., liver toxicity) seen with TCDD exposure.

Developmental Bisphenol A Exposure Modulates Immune-Related Diseases.

Bisphenol A (BPA), used in polycarbonate plastics and epoxy resins, has a widespread exposure to humans. BPA is of concern for developmental exposure resulting in immunomodulation and disease development due to its ability to cross the placental barrier and presence in breast milk. BPA can use various mechanisms to modulate the immune system and affect diseases, including agonistic and antagonistic effects on many receptors (e.g., estrogen receptors), epigenetic modifications, acting on cell signaling pathways and, likely, the gut microbiome. Immune cell populations and function from the innate and adaptive immune system are altered by developmental BPA exposure, including decreased T regulatory (Treg) cells and upregulated pro- and anti-inflammatory cytokines and chemokines. Developmental BPA exposure can also contribute to the development of type 2 diabetes mellitus, allergy, asthma and mammary cancer disease by altering immune function. Multiple sclerosis and type 1 diabetes mellitus may also be exacerbated by BPA, although more research is needed. Additionally, BPA analogs, such as bisphenol S (BPS), have been increasing in use, and currently, little is known about their immune effects. Therefore, more studies should be conducted to determine if developmental exposure BPA and its analogs modulate immune responses and lead to immune-related diseases.