Scope
Obesity has reached epidemic proportions worldwide. Obesity is a complex metabolic disorder that is linked to numerous serious health complications with high morbidity. The present study ...evaluated the effects of kefir peptides on high fat diet (HFD)‐induced obesity in rats.
Methods and results
Kefir peptides markedly improved obesity, including body weight gain, inflammatory reactions and the formation of adipose tissue fat deposits around the epididymis and kidney, and adipocyte size. Treating high fat diet (HFD)‐induced obese rats with kefir peptides significantly reduced the fatty acid synthase protein and increased the p‐acetyl‐CoA carboxylase protein to block lipogenesis in the livers. Kefir peptides also increased fatty acid oxidation by increasing the protein expressions of phosphorylated AMP‐activated protein kinase, peroxisome proliferator‐activated receptor‐α, and hepatic carnitine palmitoyltransferase‐1 in the livers. In addition, administration of kefir peptides significantly decreased the inflammatory response (TNF‐α, IL‐1β, and TGF‐β) to modulate oxidative damage.
Conclusion
These results demonstrate that kefir peptides treatment improves obesity via inhibition of lipogenesis, modulation of oxidative damage, and stimulation of lipid oxidation. Therefore, kefir peptides may act as an anti‐obesity agent to prevent body fat accumulation and obesity‐related metabolic diseases.
The effects of kefir peptides on obese rats may occur through the inhibition of lipogenesis pathway by reduced the FAS enzyme and increased the p‐ACC protein and stimulation of the lipid oxidation pathway via increased expression of p‐AMPK, PPAR‐α, and CPT1. Administration of kefir peptides also significantly decreased the inflammatory response (TNF‐α, IL‐1β, and TGF‐β) to modulate oxidative damage.
Osteoporosis is a major skeletal disease associated with estrogen deficiency in postmenopausal women. Kefir-fermented peptides (KPs) are bioactive peptides with health-promoting benefits that are ...produced from the degradation of dairy milk proteins by the probiotic microflora in kefir grains. This study aimed to evaluate the effects of KPs on osteoporosis prevention and the modulation of the composition of the gut microbiota in ovariectomized (OVX) mice. OVX mice receiving an 8-week oral gavage of 100 mg of KPs and 100 mg of KPs + 10 mg Ca exhibited lower trabecular separation (Tb. Sp), and higher bone mineral density (BMD), trabecular number (Tb. N) and bone volume (BV/TV), than OVX groups receiving Ca alone and untreated mice, and these effects were also reflected in bones with better mechanical properties of strength and fracture toughness. The gut microbiota of the cecal contents was examined by 16S rDNA amplicon sequencing. α-Diversity analysis indicated that the gut microbiota of OVX mice was enriched more than that of sham mice, but the diversity was not changed significantly. Treatment with KPs caused increased microbiota richness and diversity in OVX mice compared with those in sham mice. The microbiota composition changed markedly in OVX mice compared with that in sham mice. Following the oral administration of KPs for 8 weeks, the abundances of
,
,
,
,
and
genera were restored to levels close to those in the sham group. However, the correlation of these bacterial populations with bone metabolism needs further investigation. Taken together, KPs prevent menopausal osteoporosis and mildly modulate the structure of the gut microbiota in OVX mice.
Milk products are good sources of calcium that may reduce bone resorption and help prevent bone loss as well as promote bone remodeling and increase bone formation. Kefir is a product made by kefir ...grains that degrade milk proteins into various peptides with health-promoting effects, including antithrombotic, antimicrobial and calcium-absorption enhancing bioactivities. In a controlled, parallel, double-blind intervention study over 6 months, we investigated the effects of kefir-fermented milk (1,600 mg) supplemented with calcium bicarbonate (CaCO3, 1,500 mg) and bone metabolism in 40 osteoporosis patients, and compared them with CaCO3 alone without kefir supplements. Bone turnover markers were measured in fasting blood samples collected before therapy and at 1, 3, and 6 months. Bone mineral density (BMD) values at the spine, total hip, and hip femoral neck were assessed by dual-energy x-ray absorptiometry (DXA) at baseline and at 6 months. Among patients treated with kefir-fermented milk, the relationships between baseline turnover and 6 months changes in DXA-determined BMD were significantly improved. The serum β C-terminal telopeptide of type I collagen (β-CTX) in those with T-scores > -1 patients significantly decreased after three months treatment. The formation marker serum osteocalcin (OC) turned from negative to positive after 6 months, representing the effect of kefir treatment. Serum parathyroid hormone (PTH) increased significantly after treatment with kefir, but decreased significantly in the control group. PTH may promote bone remodeling after treatment with kefir for 6 months. In this pilot study, we concluded that kefir-fermented milk therapy was associated with short-term changes in turnover and greater 6-month increases in hip BMD among osteoporotic patients.
ClinicalTrials.gov NCT02361372.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Bisphenol A (BPA) is an estrogen‐like compound, and an environmental hormone, that is commonly used in daily life. Therefore, it may enter the human body through food or direct contact, causing BPA ...residues in blood and urine. Because most studies focused on the analysis of BPA in reproductive cells or tissues, regarding evidence the effect of BPA on human retinal pigment epithelium (ARPE‐19) cells unavailable. Accordingly, the present study explored the cytotoxicity of BPA on ARPE‐19 cells. After BPA treatment, the expression of Bcl‐XL an antiapoptotic protein, in the mitochondria decreased, and the expression of Bax, a proapoptotic protein increased. Then the mitochondrial membrane potential was affected. BPA changed in mitochondrial membrane potential led to the release of cytochrome C, which activated caspase‐9 to promote downstream caspase‐3 leading to cytotoxicity. The nuclear factor (erythroid‐derived 2)‐like 2 (Nrf2) and heme oxygenase 1 (HO‐1) pathway play a major role in age‐related macular degeneration. Our results showed that expression of HO‐1 and Nrf2 suppressed by BPA. Superoxide dismutase and catalase, which Nrf2 downstream antioxidants, were degraded by BPA. AMP‐activated kinase (AMPK), which can regulate the phosphorylation of Nrf2, and the phosphorylation of AMPK expression was reduced by BPA. Finally, BPA‐induced ROS generation and cytotoxicity were reduced by N‐acetyl‐l‐cysteine. Taken together, these results suggest that BPA induced ARPE‐19 cells via oxidative stress, which was associated with down regulated Nrf2/HO‐1 pathway, and the mitochondria dependent apoptotic signaling pathway.
Lactoferrin (LF) stands as one of the extensively investigated iron-binding glycoproteins within milk, exhibiting diverse biological functionalities. The global demand for LF has experienced ...consistent growth. Biotechnological strategies aimed at enhancing LF productivity through microbial expression systems offer substantial cost-effective advantages and exhibit fewer constraints compared to traditional animal bioreactor technologies. This study devised a novel recombinant plasmid, wherein the
promoter was replaced with a glucose-inducible
promoter (P
) to govern the expression of recombinant porcine LF (rpLF) in
GS115. High-copy-number P
-rpLF yeast clones were meticulously selected, and subsequent induction with 0.05 g/L glucose demonstrated robust secretion of rpLF. Scaling up production transpired in a 5 L fermenter, yielding an estimated rpLF productivity of approximately 2.8 g/L by the conclusion of glycerol-fed fermentation. A three-step purification process involving tangential-flow ultrafiltration yielded approximately 6.55 g of rpLF crude (approximately 85% purity). Notably, exceptional purity of rpLF was achieved through sequential heparin and size-exclusion column purification. Comparatively, the present glucose-inducible system outperformed our previous methanol-induced system, which yielded a level of 87 mg/L of extracellular rpLF secretion. Furthermore, yeast-produced rpLF demonstrated affinity for ferric ions (Fe
) and exhibited growth inhibition against various pathogenic microbes (
,
, and
) and human cancer cells (A549, MDA-MB-231, and Hep3B), similar to commercial bovine LF (bLF). Intriguingly, the hydrolysate of rpLF (rpLFH) manifested heightened antimicrobial and anticancer effects compared to its intact form. In conclusion, this study presents an efficient glucose-inducible yeast expression system for large-scale production and purification of active rpLF protein with the potential for veterinary or medical applications.
The immunohistochemical analysis was used to evaluate the expression of PD-L1 in 109 non-small cell lung cancer (NSCLC) tissues and para-tumor tissues. Associations between expressed PD-L1 and tumor ...histological types, degree of differentiation, and lymph node metastasis were calculated, and overall survival was assessed. Meanwhile, immunohistochemistry and immunofluorescence double labeling technique were performed to detect the expressions of PD-L1, CD1α, and CD83 on TIDC of 20 lung cancer tissues, and the expression of PD-L1 in CD1α
+
DCs and CD83
+
DCs and their significances were also explored. We found that the expression rate of PD-L1 in NSCLC was associated with histological types and overall survival. Patients with either adenocarcinoma or survival time after surgery less than 3 years showed higher expression rate of PD-L1. Furthermore, Cox model analysis indicated that PD-L1 might be regarded as a poor prognostic factor. PD-L1 could be also detected in CD1α
+
immature DC in NSCLC, indicating that as a class of key anti-tumor immunocyte in tumor microenvironment, DC expressing PD-L1 itself might play an important role in keeping its immature status and contributing to tumor cells immune escape and disease progression.
Comorbidities are common in children with epilepsy, with nearly half of the patients having at least one comorbidity. Attention deficit hyperactivity disorder (ADHD) is a psychiatric disorder ...characterized by hyperactivity and inattentiveness level disproportional to the child's developmental stage. The burden of ADHD in children with epilepsy is high and can adversely affect the patients' clinical outcomes, psychosocial aspects, and quality of life. Several hypotheses were proposed to explain the high burden of ADHD in childhood epilepsy; the well-established bidirectional connection and shared genetic/non-genetic factors between epilepsy and comorbid ADHD largely rule out the possibility of a chance in this association. Stimulants are effective in children with comorbid ADHD, and the current body of evidence supports their safety within the approved dose. Nonetheless, safety data should be further studied in randomized, double-blinded, placebo-controlled trials. Comorbid ADHD is still under-recognized in clinical practice. Early identification and management of comorbid ADHD are crucial to optimize the prognosis and reduce the risk of adverse long-term neurodevelopmental outcomes. The identification of the shared genetic background of epilepsy and ADHD can open the gate for tailoring treatment options for these patients through precision medicine.
Hemophilia is a genetic disorder linked to the sex chromosomes, resulting in impaired blood clotting due to insufficient intrinsic coagulation factors. There are approximately one million individuals ...worldwide with hemophilia, with hemophilia A being the most prevalent form. The current treatment for hemophilia A involves the administration of clotting factor VIII (FVIII) through regular and costly injections, which only provide temporary relief and pose inconveniences to patients. In utero transplantation (IUT) is an innovative method for addressing genetic disorders, taking advantage of the underdeveloped immune system of the fetus. This allows mesenchymal stromal cells to play a role in fetal development and potentially correct genetic abnormalities. The objective of this study was to assess the potential recovery of coagulation disorders in FVIII knockout hemophilia A mice through the administration of human amniotic fluid mesenchymal stromal cells (hAFMSCs) via IUT at the D14.5 fetal stage. The findings revealed that the transplanted human cells exhibited fusion with the recipient liver, with a ratio of approximately one human cell per 10,000 mouse cells and produced human FVIII protein in the livers of IUT-treated mice. Hemophilia A pups born to IUT recipients demonstrated substantial improvement in their coagulation issues from birth throughout the growth period of up to 12 weeks of age. Moreover, FVIII activity reached its peak at 6 weeks of age, while the levels of FVIII inhibitors remained relatively low during the 12-week testing period in mice with hemophilia. In conclusion, the results indicated that prenatal intrahepatic therapy using hAFMSCs has the potential to improve clotting issues in FVIII knockout mice, suggesting it as a potential clinical treatment for individuals with hemophilia A.
Dravet syndrome (DS), also known as severe myoclonic epilepsy of infancy, is a rare and drug-resistant form of developmental and epileptic encephalopathies, which is both debilitating and challenging ...to manage, typically arising during the first year of life, with seizures often triggered by fever, infections, or vaccinations. It is characterized by frequent and prolonged seizures, developmental delays, and various other neurological and behavioral impairments. Most cases result from pathogenic mutations in the sodium voltage-gated channel alpha subunit 1 (
) gene, which encodes a critical voltage-gated sodium channel subunit involved in neuronal excitability. Precision medicine offers significant potential for improving DS diagnosis and treatment. Early genetic testing enables timely and accurate diagnosis. Advances in our understanding of DS's underlying genetic mechanisms and neurobiology have enabled the development of targeted therapies, such as gene therapy, offering more effective and less invasive treatment options for patients with DS. Targeted and gene therapies provide hope for more effective and personalized treatments. However, research into novel approaches remains in its early stages, and their clinical application remains to be seen. This review addresses the current understanding of clinical DS features, genetic involvement in DS development, and outcomes of novel DS therapies.
Introduction
Kefir is an acidic and alcoholic fermented milk product with multiple health‐promoting benefits. A previous study demonstrated that kefir enhanced calcium absorption in intestinal Caco‐2 ...cells. In this study, kefir‐fermented peptide‐1 (KFP‐1) is isolated from the kefir peptide fraction, and its function as a calcium‐binding peptide is characterized.
Methods and Results
KFP‐1 was identified as a 17‐residue peptide with a sequence identical to that of κ‐casein (residues 138–154) in milk protein. KFP‐1 is demonstrated to promote calcium influx in Caco‐2 and IEC‐6 small intestinal cells in a concentration‐dependent manner. TRPV6, but not L‐type voltage‐gated calcium channels, is associated with the calcium influx induced by KFP‐1. An in vitro calcium binding assay indicates that the full‐length KFP‐1 peptide has a higher calcium‐binding capacity than the two truncated KFP‐1 peptides, KFP‐1∆C5 and KFP‐1C5. Alexa Fluor 594 labeling shows that KFP‐1 is taken up by Caco‐2 cells and interacts with calcium ions and TRPV6 protein. Moreover, KFP‐1 is found moderately resistant to pepsin and pancreatin digestions and enhanced calcium uptake by intestinal enterocytes in vivo.
Conclusion
These data suggest that KFP‐1, a novel calcium‐binding peptide, binds extracellular calcium ions and enters Caco‐2 and IEC‐6 cells, and promotes calcium uptake through TRPV6 calcium channels. The present study is of great importance for developing kefir‐derived metal ion‐binding peptides as functional nutraceutical additives.
Proposed mechanism of action of KFP‐1 for promoting calcium influx in intestinal epithelial cells. Based on the experimental data, it is hypothesized that KFP‐1 increased of intracellular calcium uptake in Caco‐2 cell through TRPV6 calcium channel, but not L‐type VGCC. Therefore, KFP‐1 can transmit dietary calcium from the luminal space of intestinal tract to the circulation system.
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