Retroelement decay by the exonuclease XRN1 is a viral mimicry dependency in cancer.

Viral mimicry describes the immune response induced by endogenous stimuli such as double-stranded RNA (dsRNA) from endogenous retroelements. Activation of viral mimicry has the potential to kill cancer cells or augment anti-tumor immune responses. Here, we systematically identify mechanisms of viral mimicry adaptation associated with cancer cell dependencies. Among the top hits is the RNA decay protein XRN1 as an essential gene for the survival of a subset of cancer cell lines. XRN1 dependency is mediated by mitochondrial antiviral signaling protein and protein kinase R activation and is associated with higher levels of cytosolic dsRNA, higher levels of a subset of Alus capable of forming dsRNA, and higher interferon-stimulated gene expression, indicating that cells die due to induction of viral mimicry. Furthermore, dsRNA-inducing drugs such as 5-aza-2'-deoxycytidine and palbociclib can generate a synthetic dependency on XRN1 in cells initially resistant to XRN1 knockout. These results indicate that XRN1 is a promising target for future cancer therapeutics.

Vitamin D deficiency in patients with cystic fibrosis: a systematic review and meta-analysis.

AIM: Vitamin D is a prominent modulator of immunity and respiratory function. It plays a vital role in respiratory diseases such as cystic fibrosis (CF). S. However, there is a dearth of information on patients with CF. The purpose of the meta-analysis is to highlight the importance of following the existing guidelines regarding maintenance of Vitamin D serum levels in patients with CF. METHODS: The systematic search was conducted without utilizing any time or language limitations in original database from the beginning until March 2022. The meta-analysis was performed using a random-effects model. Heterogeneity was determined by I2 statistics and Cochrane Q test. RESULTS: Pooled analysis using the random-effects model of the 8 case-control studies with 13 effect sizes revealed that the serum 25-OH-vitamin D in participants with cystic fibrosis was significantly lower than controls in pediatrics and adolescences (WMD: - 3.41 ng/ml, 95% CI - 5.02, - 1.80, p = < 0.001) and adults (WMD: - 2.60 ng/ml, 95% CI - 4.32, - 0.89, p = 0.003). Based on data from 12 studies (21 effect sizes) with a total of 1622 participants, the prevalence of vitamin D levels of 20-30 ng/ml in CF patients was 36% among pediatrics/adolescents and 63% among adults. In addition, 27% of pediatric/adolescent CF patients and 35% of adult CF patients had vitamin D levels of below 20 ng/ml. CONCLUSIONS: As a result, according to the existing guidelines, our results proved the need to pay attention to the level of vitamin D in these patients.

Lipid droplets and peroxisomes are co-regulated to drive lifespan extension in response to mono-unsaturated fatty acids.

Dietary mono-unsaturated fatty acids (MUFAs) are linked to longevity in several species. But the mechanisms by which MUFAs extend lifespan remain unclear. Here we show that an organelle network involving lipid droplets and peroxisomes is critical for MUFA-induced longevity in Caenorhabditis elegans. MUFAs upregulate the number of lipid droplets in fat storage tissues. Increased lipid droplet number is necessary for MUFA-induced longevity and predicts remaining lifespan. Lipidomics datasets reveal that MUFAs also modify the ratio of membrane lipids and ether lipids-a signature associated with decreased lipid oxidation. In agreement with this, MUFAs decrease lipid oxidation in middle-aged individuals. Intriguingly, MUFAs upregulate not only lipid droplet number but also peroxisome number. A targeted screen identifies genes involved in the co-regulation of lipid droplets and peroxisomes, and reveals that induction of both organelles is optimal for longevity. Our study uncovers an organelle network involved in lipid homeostasis and lifespan regulation, opening new avenues for interventions to delay aging.

The effects of saffron supplementation on cardiovascular risk factors in adults: A systematic review and dose-response meta-analysis.

Introduction: Cardiovascular disease (CVD) is one of the leading causes of death and disability in the world and is estimated to involve more people in the next years. It is said that alternative remedies such as herbs can be used to manage the complications of this disease. For this reason, we aimed to conduct this meta-analysis to systematically assess and summarize the effects of saffron supplementation as an important herb on cardiovascular risk factors in adults. Methods: A systematic search was done in PubMed, Scopus, and Web of Science to find eligible articles up to September 2022. Randomized controlled trials (RCTs) that evaluated the effects of saffron on lipid profiles, glycemic control, blood pressure, anthropometric measures, and inflammatory markers were included. In the meta-analysis, 32 studies were taken into account (n = 1674). Results: Consumption of saffron significantly decreased triglyceride (TG) (WMD = -8.81 mg/dl, 95%CI: -14.33, -3.28; P = 0.002), total cholesterol (TC) (WMD = -6.87 mg/dl, 95%CI: -11.19, -2.56; P = 0.002), low density lipoprotein (LDL) (WMD = -6.71 mg/dl, 95%CI: -10.51, -2.91; P = 0.001), (P = 0.660), fasting blood glucose (FBG) level (WMD = -7.59 mg/dl, 95%CI: -11.88, -3.30; P = 0.001), HbA1c (WMD = -0.18%, 95%CI: -0.21, -0.07; P < 0.001), homeostasis model assessment-insulin resistance (HOMA-IR) (WMD = -0.49, 95%CI: -0.89, -0.09; P = 0.016), systolic blood pressure (SBP) (WMD = -3.42 mmHg, 95%CI: -5.80, -1.04; P = 0.005), tumor necrosis factor α (TNF-α) (WMD = -2.54 pg/ml, 95%CI: -4.43, -0.65; P = 0.008), waist circumference (WC) (WMD = -1.50 cm; 95%CI: -2.83, -0.18; P = 0.026), malondialdehyde (MDA) (WMD = -1.50 uM/L, 95%CI: -2.42, -0.57; P = 0.001), and alanine transferase (ALT) (WMD = -2.16 U/L, 95%CI: -4.10, -0.23; P = 0.028). Also, we observed that saffron had an increasing effect on total antioxidant capacity (TAC) (WMD = 0.07 mM/L, 95%CI: 0.01, 0.13; P = 0.032). There was linear regression between FBG and the duration of saffron intake. Additionally, the non-linear dose-response analysis has shown a significant association of saffron intervention with HDL (P = 0.049), HOMA-IR (P = 0.002), weight (P = 0.036), ALP (P = 0.016), FBG (P = 0.011), HbA1c (P = 0.002), and TNF-α (P = 0.042). A non-linear association between the length of the intervention and the level of HDL and DBP was also found. Discussion: That seems saffron could effectively improve TG, TC, LDL, FBG, HbA1c, HOMA-IR, SBP, CRP, TNF-α, WC, MDA, TAC, and ALT.

The association between vitamin D status and inflammatory bowel disease among children and adolescents: A systematic review and meta-analysis.

Aim: Vitamin D deficiency is very common among children with IBD. Since there are conflicting results regarding the association of vitamin D with IBD, we conducted this systematic review to confirm the association of vitamin D with IBD. Methods: We conducted a systematic search in Scopus, Cochrane Library, Web of Science, PubMed, and Google Scholar to find relevant studies. Articles with cross-sectional and case-control designs that reported the association between vitamin D and IBD among children were included. Results: Eventually, 9 studies (with 16 effect sizes) reported the mean and SD or the median and the interquartile range of serum vitamin D levels in both subjects with IBD and control subjects. The random effects meta-analysis revealed that subjects with IBD had -1.159 ng/ml (95% CI: -2.783, 0.464) lower serum vitamin D concentrations compared with their healthy counterparts, but this difference was not significant. A total of 14 studies (with 18 effect sizes) with 2,602 participants provided information for the prevalence of vitamin D deficiency or insufficiency in patients with IBD as 44% (95% CI: 0.34-0.54) with significant heterogeneity noted among studies (p < 0.001; I2 = 97.31%). Conclusion: This systematic and meta-analysis study revealed that vitamin D deficiency was associated with IBD. Longitudinal studies should be conducted in the future to confirm our findings. Large randomized controlled trials assessing the doses of supplementation of vitamin D would provide a better understanding of the association between vitamin D and IBD.

Flexural strength of polymethyl methacrylate reinforced with high-performance polymer and metal mesh.

BACKGROUND: The flexural strength (FS) of a denture base material is of great concern, and many approaches have been used to strengthen the denture acrylic resins. The present study aimed to evaluate the effect of high-performance polymer (BioHPP) and metal mesh reinforcement on the FS of a heat-cured poly methyl methacrylate (PMMA) acrylic resin. MATERIALS AND METHODS: This experimental study was done on 30 rectangular specimens (64 mm × 13 mm × 3 mm) of a heat-cured PMMA resin. The specimens were divided into three groups (n = 10) to be reinforced with either metal mesh or BioHPP mesh; one group was left nonreinforced, serving as the control group. The FS of specimens was assessed through a 3-point bending test by using a universal testing machine at a crosshead speed of 2 mm/min. Kruskal-Wallis H and Dunn's post hoc tests were used to compare the FS among the groups (alpha = 0.05). RESULTS: The FS in the metal-reinforced group was statistically significantly higher than the two other groups (P < 0.001). However, the FS of the BioHPP-reinforced samples was not statistically significantly higher than the nonreinforced ones (P = 0.614). CONCLUSION: Reinforcing the PMMA with metal mesh significantly enhances its FS while BioHPP has no significant effect on the PMMA FS.

Sex and Age Determination by Measurement of Foramen Magnum Dimensions on Computer Tomography Scanning Study in the Iranian Population.

BACKGROUND: Individual distinguishing evidence may be an imperative field of measurable investigation which demonstrates higher correct expectation rates. This process of recognizable Evidence is facilitated by the assurance of sex and age. In circumstances where there are fragmented and mangled skeletal remains, sex assurance is moderately troublesome, and it becomes important to set up the precision of cadaver bones. Therefore, this study aims to evaluate sexual dimorphism and age determination by measuring foramen magnum (FM) dimensions in the Iranian population using digital computed tomography scan. METHODS: The study sample consisted of a modern adult Iranian population of 120 males and 109 females (age range: 15-50 years). Length, width, and area of FM, also FM index were measured on base skull computed tomography scan. RESULT: All of the parameters of FM (length, width, area, and FM index), were larger in men than women. The accuracy of sex determination was up to 50.2. The highest accuracy for sex determination was FM width (67.9). This study also helps craniofacial surgeon for exact reference value of FM, which are authorize neurosurgeons' accessibility to the brain stem approach and FM region with minimum retraction. CONCLUSIONS: It can be concluded from the result, that morphometric analyze of FM is useful for sex determination but cannot be suitable for age determination.

The effects of Chlorella supplementation on glycemic control, lipid profile and anthropometric measures on patients with type 2 diabetes mellitus.

BACKGROUND: Diabetes is a chronic disease and the prevalence of it is rapidly increasing. Recently, the use of natural products in chronic diseases such as diabetes has gained more attention. Chlorella, a single-celled green alga, is one of them. There have been some studies on the effects of chlorella supplementation in chronic diseases such as NAFLD, prediabetes, and diabetic mice, but none of them examined the effects of chlorella in patients with T2DM. The present study was designed to evaluate the effects of chlorella supplementation on glycemic control, lipid profile, and anthropometric indices in type 2 diabetic patients. METHODS: This study is a double-blind, randomized controlled trial. 84 patients with T2DM assigned into two groups, receiving 1500 mg/day C. vulgaris or placebo for 8 weeks. Anthropometric information, blood pressure, 24-h food intake recall, and blood samples were collected at the beginning and end of the study to determine the changes of FBS, HbA1c, insulin concentration, insulin resistance, and lipid profile. RESULTS: None of the variables investigated in this study showed a significant change after 8 weeks of intervention with C. vulgaris. CONCLUSION: According to the findings of this study, supplementation with C. vulgaris with a dosage of 1500 mg/day for 8 weeks, does not improve the anthropometric measurements, glycemic status, and lipid profile as well. Thus, it cannot be considered as a complementary therapeutic approach to common medications at this dosage and duration. However, future studies with a higher dosage of C. vulgaris and more prolonged than 8 weeks are needed to be done.

Epigenetic therapy induces transcription of inverted SINEs and ADAR1 dependency.

Cancer therapies that target epigenetic repressors can mediate their effects by activating retroelements within the human genome. Retroelement transcripts can form double-stranded RNA (dsRNA) that activates the MDA5 pattern recognition receptor1-6. This state of viral mimicry leads to loss of cancer cell fitness and stimulates innate and adaptive immune responses7,8. However, the clinical efficacy of epigenetic therapies has been limited. To find targets that would synergize with the viral mimicry response, we sought to identify the immunogenic retroelements that are activated by epigenetic therapies. Here we show that intronic and intergenic SINE elements, specifically inverted-repeat Alus, are the major source of drug-induced immunogenic dsRNA. These inverted-repeat Alus are frequently located downstream of 'orphan' CpG islands9. In mammals, the ADAR1 enzyme targets and destabilizes inverted-repeat Alu dsRNA10, which prevents activation of the MDA5 receptor11. We found that ADAR1 establishes a negative-feedback loop, restricting the viral mimicry response to epigenetic therapy. Depletion of ADAR1 in patient-derived cancer cells potentiates the efficacy of epigenetic therapy, restraining tumour growth and reducing cancer initiation. Therefore, epigenetic therapies trigger viral mimicry by inducing a subset of inverted-repeats Alus, leading to an ADAR1 dependency. Our findings suggest that combining epigenetic therapies with ADAR1 inhibitors represents a promising strategy for cancer treatment.

Targeting the scaffolding role of LSD1 (KDM1A) poises acute myeloid leukemia cells for retinoic acid-induced differentiation.

The histone demethylase LSD1 is deregulated in several tumors, including leukemias, providing the rationale for the clinical use of LSD1 inhibitors. In acute promyelocytic leukemia (APL), pharmacological doses of retinoic acid (RA) induce differentiation of APL cells, triggering degradation of the PML-RAR oncogene. APL cells are resistant to LSD1 inhibition or knockout, but targeting LSD1 sensitizes them to physiological doses of RA without altering of PML-RAR levels, and extends survival of leukemic mice upon RA treatment. The combination of RA with LSD1 inhibition (or knockout) is also effective in other non-APL, acute myeloid leukemia (AML) cells. Nonenzymatic activities of LSD1 are essential to block differentiation, while RA with targeting of LSD1 releases a differentiation gene expression program, not strictly dependent on changes in histone H3K4 methylation. Integration of proteomic/epigenomic/mutational studies showed that LSD1 inhibitors alter the recruitment of LSD1-containing complexes to chromatin, inhibiting the interaction between LSD1 and the transcription factor GFI1.

Combination of Hypoglycemia and Metformin Impairs Tumor Metabolic Plasticity and Growth by Modulating the PP2A-GSK3ß-MCL-1 Axis.

Tumor cells may adapt to metabolic challenges by alternating between glycolysis and oxidative phosphorylation (OXPHOS). To target this metabolic plasticity, we combined intermittent fasting, a clinically feasible approach to reduce glucose availability, with the OXPHOS inhibitor metformin. In mice exposed to 24-h feeding/fasting cycles, metformin impaired tumor growth only when administered during fasting-induced hypoglycemia. Synergistic anti-neoplastic effects of the metformin/hypoglycemia combination were mediated by glycogen synthase kinase 3ß (GSK3ß) activation downstream of PP2A, leading to a decline in the pro-survival protein MCL-1, and cell death. Mechanistically, specific activation of the PP2A-GSK3ß axis was the sum of metformin-induced inhibition of CIP2A, a PP2A suppressor, and of upregulation of the PP2A regulatory subunit B56δ by low glucose, leading to an active PP2A-B56δ complex with high affinity toward GSK3ß.

Targeting axonal degeneration and demyelination using combination administration of 17ß-estradiol and Schwann cells in the rat model of spinal cord injury.

Schwann cells (SCs) are known to be responsible for axonal ensheathing and myelination, and their transplantation is used commonly for treatment of spinal cord injury (SCI). 17ß-estradiol (E2) has also reported for its protective roles in neurons in the transplanted SCs to the SCI model. In the current study, we evaluated the roles of E2 administration before SCs transplantation in targeting SCI-induced axonal degeneration and demyelination. E2 (25 µg/kg, IP) was administered to the male Wistar rats underwent contusive SCI at T10 segment. At 7 days after injury, 1 × 106 SCs were transplanted to the injury epicenter of the spinal cord. The groups were laminectomy, SCI, SCI+E2, and SCI+E2+SCs. Functional recovery was evaluated using the Basso-Bresnahan-Beattie locomotor test. Sections from spinal cord were also assessed for histoloical staining, including Luxol fast blue, Bielschowsky's silver and immunofluorescence evaluation of myelin basic protein (MBP). The SCI group showed impaired locomotion in the hind limb, increased number of cavities within spinal cord, low observable numbers of regenerating fibers, and a significant decrease in the rate of expression for MBP. These changes were counteracted in the treatment groups ( P < 0.05 vs SCI) with no significant changes among them. From the results, it may be concluded that application of E2 and SCs could be effective when axons undergo demyelination and degenerative processes, and their combination could partly provide cumulative outcomes.

Combined effects of rat Schwann cells and 17ß-estradiol in a spinal cord injury model.

Spinal cord injury (SCI) is a devastating traumatic event which burdens the affected individuals and the health system. Schwann cell (SC) transplantation is a promising repair strategy after SCI. However, a large number of SCs do not survive following transplantation. Previous studies demonstrated that 17ß-estradiol (E2) protects different cell types and reduces tissue damage in SCI experimental animal model. In the current study, we evaluated the protective potential of E2 on SCs in vitro and investigated whether the combination of hormonal and SC therapeutic strategy has a better effect on the outcome after SCI. Primary SC cultures were incubated with E2 for 72 h. In a subsequent experiment, thoracic contusion SCI was induced in male rats followed by sustained administration of E2 or vehicle. Eight days after SCI, DiI-labeled SCs were transplanted into the injury epicenter in vehicle and E2-treated animals. The combinatory regimen decreased neurological and behavioral deficits and protected neurons and oligodendrocytes in comparison to vehicle rats. Moreover, E2 and SC significantly decreased the number of Iba-1+ (microglia) and GFAP+ cells (astrocyte) in the SCI group. In addition, we found a significant reduction of mitochondrial fission-markers (Fis1) and an increase of fusion-markers (Mfn1 and Mfn2) in the injured spinal cord after E2 and SC treatment. These data demonstrated that E2 protects SCs against hypoxia-induced SCI and improves the survival of transplanted SCs.

Comparative efficacy of Er,Cr:YSGG and Er:YAG lasers for etching of composite for orthodontic bracket bonding.

Several techniques have been proposed to obtain a durable bond, and the efficacy of these techniques is assessed by measuring parameters such as bond strength. Laser has provided a bond strength as high as that of acid etching in vitro and has simpler use with shorter clinical time compared to acid etching. This study aimed to compare the efficacy of Er:YAG and Er,Cr:YSGG lasers for etching and bonding of composite to orthodontic brackets. No previous study has evaluated the effect of these particular types of laser. A total of 70 composite blocks were randomly divided into five groups (n = 14): group 1, etching with phosphoric acid for 20 s; group 2, Er:YAG laser irradiation with 2 W power for 10 s; group 3, Er:YAG laser with 3 W power for 10 s; group 4, Er,Cr:YSGG laser with 2 W power for 10 s; group 5, Er,Cr:YSGG laser with 3 W power for 10 s. Metal brackets were then bonded to composites, and after 5000 thermal cycles, they were subjected to shear bond strength test in a universal testing machine after 24 h of water storage. One sample of each group was evaluated under a scanning electron microscope (SEM) to assess changes in composite surface after etching. The adhesive remnant index (ARI) was calculated under a stereomicroscope. Data were statistically analyzed. The mean and standard deviation of shear bond strength were 18.65 ± 3.36, 19.68 ± 5.34, 21.31 ± 4.03, 17.38 ± 6.94, and 16.45 ± 4.26 MPa in groups 1-5, respectively. The ARI scores showed that the bond failure mode in all groups was mainly mixed. The groups were not significantly different in terms of shear bond strength. Er:YAG and Er,Cr:YSGG lasers with the mentioned parameters yield optimal shear bond strength and can be used as an alternative to acid etching for bracket bond to composite.

Association of miR-146a rs2910164 and miR-222 rs2858060 polymorphisms with the risk of polycystic ovary syndrome in Iranian women: A case-control study.

OBJECTIVE: Today, many single nucleotide polymorphisms in microRNA genes are known to alter the microRNA expression levels or processing causing susceptibility of several human diseases. The present study aimed to investigate the association of microRNA-146a (rs2910164) and microRNA-222 (rs2858060) polymorphisms with susceptibility to polycystic ovary syndrome (PCOS) in an Iranian population. MATERIALS AND METHODS: This case-control study was performed on 205 patients with PCOS and 205 normal women as the control group. After DNA extraction, Tetra-amplification refractory mutation system polymerase chain reaction (T-ARMS-PCR) was used to detect the polymorphisms. The association between genotypes and the risk of PCOS was examined by odds ratios (OR) and 95% of confidence intervals (CIs). RESULTS: Our results showed that there are significant differences in CG genotype frequencies between case and control groups regarding miR-146a rs2910164 polymorphism (OR = 2.03, CI = 1.3-3, P = 0.001). In a dominant model for the C allele, CC + CG genotypes were associated with PCOS risk (OR = 2, 95% CI = 1.3-2.9, P = 0.001) and the C allele increased the risk of PCOS (OR = 1.6, 95% CI = 1.1-2.1, P = 0.004). Furthermore, a positive association was observed between miR-222 CG genotype and the risk of PCOS (OR = 2.2, 95% CI = 1.1-4.1, P = 0.02). These results were evident after adjustment for age and body mass index. CONCLUSION: The present results suggest that the miR-146a rs2910164 and miR-222 rs2858060 polymorphisms are associated with an increased risk of PCOS. Therefore, both polymorphisms could play an important role as a genetic risk factor for development of PCOS in the Iranian population.

A comprehensive review of lysine-specific demethylase 1 and its roles in cancer.

Histone methylation plays a key role in the regulation of chromatin structure, and its dynamics regulates important cellular processes. The investigation of the role of alterations in histone methylation in cancer has led to the identification of histone methyltransferases and demethylases as promising novel targets for therapy. Lysine-specific demethylase 1(LSD1, also known as KDM1A) is the first discovered histone lysine demethylase, with the ability to demethylase H3K4me1/2 and H3K9me1/2 at target loci in a context-dependent manner. LSD1 regulates the balance between self-renewal and differentiation of stem cells, and is highly expressed in various cancers, playing an important role in differentiation and self-renewal of tumor cells. In this review, we summarize recent studies about the LSD1, its role in normal and tumor cells, and the potential use of small molecule LSD1 inhibitors in therapy.

Preconditioning with melatonin improves therapeutic outcomes of bone marrow-derived mesenchymal stem cells in targeting liver fibrosis induced by CCl4.

Preconditioning of mesenchymal stem cells (MSCs) with melatonin (MT) has shown promising results in animal models of myocardial infarction, renal ischemia and cerebral ischemia. Here, we use this strategy in the liver fibrosis induced by CCl4. There were five groups: normal, CCl4, CCl4 + vehicle, CCl4 + BMMSCs and CCl4 + MT-bone marrow (BM)-derived MSCs (MT-BMMSCs). CCl4 was injected twice weekly for 8 weeks and treatment either with cells or vehicle was performed at the beginning of week 5 with a single dose. BMMSCs were preconditioned with MT for 24 h before injection. MT-BMMSCs had a high ability of homing into the injured liver (P ≤ 0.05 vs. BMMSCs). The CCl4 + MT-BMMSCs group showed higher percentage of glycogen storage but lower percentage of collagen and lipid accumulation (P ≤ 0.05 vs. CCl4 + BMMSCs). The CCl4 + MT-BMMSCs group showed lower expressions of transforming growth factor-ß1 (TGF-ß1) and Bax and lower content of sera alanine aminotransferase (ALT) but higher expressions of matrix metalloproteinases (MMPs) and Bcl2 compared with the BMMSCs group (P ≤ 0.05). The results showed the better therapeutic outcomes of MT preconditioning by probably improving cell homing and also better maintenance of the balance between matrix degrading and accumulating factors.

Integrated line-by-line optical pulse shaper for high-fidelity and rapidly reconfigurable RF-filtering.

We present a 32 channel indium phosphide integrated pulse shaper with 25 GHz channel spacing, where each channel is equipped with a semiconductor optical amplifier allowing for programmable line-by-line gain control with submicrosecond reconfigurability. We critically test the integrated pulse shaper by using it in comb-based RF-photonic filtering experiments where the precise gain control is leveraged to synthesize high-fidelity RF filters which we reconfigure on a microsecond time scale. Our on-chip pulse shaping demonstration is unmatched in its combination of speed, fidelity, and flexibility, and will likely open new avenues in the field of advanced broadband signal generation and processing.