A rare germline BMP15 missense mutation causes hereditary ovarian immature teratoma in human.

Ovarian immature teratomas (OITs) are malignant tumors originating from the ovarian germ cells that mainly occur during the first 30 y of a female's life. Early age of onset strongly suggests the presence of susceptibility gene mutations for the disease yet to be discovered. Whole exon sequencing was used to screen pathogenic mutations from pedigrees with OITs. A rare missense germline mutation (C262T) in the first exon of the BMP15 gene was identified. In silico calculation suggested that the mutation could impair the formation of mature peptides. In vitro experiments on cell lines confirmed that the mutation caused an 84.7% reduction in the secretion of mature BMP15. Clinical samples from OIT patients also showed a similar pattern of decrease in the BMP15 expression. In the transgenic mouse model, the spontaneous parthenogenetic activation significantly increased in oocytes carrying the T allele. Remarkably, a mouse carrying the T allele developed the phenotype of OIT. Oocyte-specific RNA sequencing revealed that abnormal activation of the H-Ras/MAPK pathway might contribute to the development of OIT. BMP15 was identified as a pathogenic gene for OIT which improved our understanding of the etiology of OIT and provided a potential biomarker for genetic screening of this disorder.

Changes in T lymphocyte subsets in peripheral blood of patients with middle-advanced cervical cancer before and after nimotuzumab combined with concurrent chemoradiotherapy.

The current study sought to investigate the effect of nimotuzumab combined with concurrent chemoradiotherapy (CCRT + Nim) on T lymphocyte subsets in middle-advanced CC. Firstly, patients with middle-advanced CC were administered CCRT or CCRT + Nim. Next, levels of T lymphocytes in peripheral blood of CC patients pre- or post-treatment and healthy females were determined by flow cytometry. The short-term efficacy was evaluated, and overall survival (OS) and progression-free survival (PFS) of patients were recorded. In addition, the correlation of T lymphocyte subsets post-treatment with OS/PFS was assessed with Pearson analysis. CC patients exhibited decreased total T cells/T helper cells/CD4+/CD8+ ratio and increased T suppressor cells/Tregs in peripheral blood. Meanwhile, CCRT and CCRT + Nim improved T lymphocyte subset imbalance, with CCRT + Nim exhibiting better efficacy. CCRT + Nim exhibited better short-term efficacy and higher PFS than CCRT, with no evident difference in OS. The levels of total T cells/T helper cells/T suppressor cells/Tregs were not significantly-correlated with OS/PFS, and the CD4+/CD8+ ratio was correlated with PFS but not OS. Collectively, CCRT + nimotuzumab ameliorate the imbalance of T lymphocyte subsets in peripheral blood of middle-advanced CC patients, and the CD4+/CD8+ ratio after therapy is correlated with PFS.IMPACT STATEMENTWhat is already known on this subject? The utilisation of Nimotuzumab targeting epidermal growth factor receptor (EGFR) combined with concurrent chemoradiotherapy (CCRT) as an efficient treatment for middle-advanced cervical cancer (CC) has garnered the attention of numerous researchers over the years. T cells represent a major immune cell type in the tumour microenvironment and serve as the basis for maintaining cellular immune functions.What do the results of this study add? Our findings revealed that nimotuzumab combined with CCRT improves the abnormality of T lymphocyte subsets in peripheral blood of patients with middle-advanced CC, such that the CD4+/CD8+ ratio after treatment was significantly correlated with progression-free survival (PFS).What are the implications of these findings for clinical practice and/or further research? CCRT of CC may have a short-term negative impact on the peripheral T-cell immune micro-environment, and the combination of nimotuzumab, cisplatin-based chemotherapy, and radiotherapy enhances the frequency of Tregs in peripheral blood. Our findings illustrated that nimotuzumab combined with CCRT can improve the imbalance of T lymphocyte subsets in peripheral blood of patients with middle-advanced CC. A better understanding of the mechanisms of these therapies will optimise the selection of patients most likely to benefit from treatment, serving as a reference for further research on the relationship between EGFR-specific T cells and clinical benefit in patients treated with nimotuzumab in combination with CCRT.

Correction: Fan et al. Native Collagen II Relieves Bone Impairment through Improving Inflammation and Oxidative Stress in Ageing db/db Mice. Molecules2021, 26, 4942.

The authors would like to correct spelling mistakes (undenatured type II collagen) in the title, as well as in the main manuscript including the tables and figures in the title paper [...].

Native Collagen II Relieves Bone Impairment through Improving Inflammation and Oxidative Stress in Ageing db/db Mice.

Ageing-related bone impairment due to exposure to hyperglycemic environment is scarcely researched. The aim was to confirm the improvement effects of undenatured type II collagen (UC II) on bone impairment in ageing db/db mice, and the ageing model was established by normal feeding for 48-week-old. Then, the ageing db/db mice were randomly assigned to UC II intervention, the ageing model, and the chondroitin sulfate + glucosamine hydrochloride control groups. After 12 weeks of treatment, femoral microarchitecture and biomechanical parameters were observed, biomarkers including bone metabolism, inflammatory cytokines, and oxidative stress were measured, and the gastrocnemius function and expressions of interleukin (IL) 1ß, receptor activator of nuclear factor (NF)-κB ligand (RANKL), and tartrate-resistant acid phosphatase (TRAP) were analyzed. The results showed that the mice in the UC II intervention group showed significantly superior bone and gastrocnemius properties than those in the ageing model group, including bone mineral density (287.65 ± 72.77 vs. 186.97 ± 32.2 mg/cm3), gastrocnemius index (0.46 ± 0.07 vs. 0.18 ± 0.01%), muscle fiber diameter (0.0415 ± 0.005 vs. 0.0330 ± 0.002 mm), and cross-sectional area (0.0011 ± 0.00007 vs. 0.00038 ± 0.00004 mm2). The UC II intervention elevated bone mineralization and formation and decreased bone resorption, inflammatory cytokines, and the oxidative stress. In addition, lower protein expression of IL-1ß, RANKL, and TRAP in the UC II intervention group was observed. These findings suggested that UC II improved bones impaired by T2DM during ageing, and the likely mechanism was partly due to inhibition of inflammation and oxidative stress.

Radioprotective Effect of Walnut Oligopeptides Against Gamma Radiation-Induced Splenocyte Apoptosis and Intestinal Injury in Mice.

Walnut oligopeptides (WOPs) intake is associated with the augment of the antioxidant defense system and immune system. The chief object of this study is to evaluate the radioprotective effect of walnut oligopeptides extracted from walnut seed protein against 60Coγ-irradiation induced damage in mice. Female BALB/c mice were administered WOPs through drinking water for 14 days until a single dose of whole-body 60Coγ-irradiation. The 30-day survival test was carried out in the first group (8 Gy), and the other two groups (3.5 Gy) were sacrificed at 3 days and 14 days post-irradiation. Blood and organ samples of mice in the three groups were collected, the histopathological analysis and immunohistochemistry were conducted. The number of peripheral blood leukocytes, bone marrow DNA content, inflammatory cytokines, antioxidant capacity, and intestinal permeability were measured. We found that the administration of WOPs augmented antioxidant defense system, accelerated hematopoietic recovery and showed the significant trend toward higher survival rate and less weight loss compared with non-administrated control mice. In addition, WOPs administration appeared to be important to limit IR-induced splenocyte apoptosis and inflammatory cascade as well as reduce intestine epithelial barrier dysfunction and promote epithelial integrity. These results suggest that pre and post-treatment of WOPs may help to ameliorate acute damage, which is induced by ionizing radiation in mice and accelerate its recovery.

The Protective Effect of Walnut Oligopeptides against Indomethacin-Induced Gastric Ulcer in Rats.

The aim of this study was to investigate the potential protective effects of walnut oligopeptides (WOPs) on indomethacin-induced gastric ulcers in rats. The rats were divided into the following groups: normal group, model group, omeprazole group (0.02 g/kg), and WOPs groups (0.22, 0.44, and 0.88 g/kg, respectively). After receiving gavage once per day for 30 consecutive days, the rats were injected intraperitoneally with indomethacin 48 mg/kg to induce gastric ulcers. Then, the serum inflammatory cytokines and gastric prostaglandin E2 (PGE2), oxidative stress-related indicators, and the RNA expression of COX-1 and COX-2 were measured. The results revealed that WOPs confer significant gastroprotection on gastric ulcers caused by indomethacin, regulating inflammatory cytokines, oxidative stress, and prostaglandins synthesis, and enhancing the expression of COX-1 and COX-2 in gastric tissue, thus exerting its protective effect on gastric mucosa. The gastroprotective mechanism may be related to the involvement of the arachidonic acid metabolism and upregulation of tryptophan, phenylalanine, tyrosine, and alpha-Linolenic acid metabolism synthesis in vivo.

Walnut (Juglans regia L.) Oligopeptides Alleviate Alcohol-Induced Acute Liver Injury through the Inhibition of Inflammation and Oxidative Stress in Rats.

The study was aimed at investigating the effects of walnut oligopeptides (WOPs) on alcohol-induced acute liver injury and its underlying mechanisms. Male Sprague Dawley (SD) rats were randomly assigned to six groups: normal control, alcohol control, whey protein (440 mg/kg.bw), and three WOPs (220 mg/kg.bw, 440 mg/kg.bw, 880 mg/kg.bw) groups. After 30 days of gavage, ethanol with a volume fraction of 50%, administered at a dose of 7 g/kg.bw., caused acute liver injury. A righting reflex experiment and a blood ethanol concentration evaluation were then performed. Serum biochemical parameters, inflammatory cytokines, liver alcohol metabolism enzymes, oxidative stress biomarkers, liver nuclear factor-κB (NF-κB p65), and cytochrome P4502E1 expression were determined. The results revealed that the intervention of 440 mg/kg and 880 mg/kg WOPs could alleviate the degree of intoxication, decrease blood ethanol concentration, alleviate alcohol-induced hepatic steatosis, enhance the activity of hepatic ethanol metabolizing enzymes and antioxidant capacity, reduce lipid oxidation products and pro-inflammatory factor contents, and inhibit the expression of NF-κBp65 in the livers of rats. The outcomes of the study suggest that WOPs have beneficial effects on liver damage caused by acute ethanol binge drinking, with the high-dose WOPs (880 mg/kg.bw) exerting the most pronounced hepatoprotective effect.

The Effects of Peanut Oligopeptides on Exercise-Induced Fatigue in Mice and Its Underlying Mechanism.

The aim of this study was to clarify the anti-fatigue effect of peanut oligopeptides (POPs) in mice and to investigate its possible underlying mechanism. A total of 150 male ICR mice were randomly assigned into five groups: control, whey protein (0.50 g/kg·bw), and three peanut peptide groups (0.25, 0.50, and 1.00 g/kg·bw). All the mice were treated with intra-gastric administration for 30 days. Following the intervention, a weight-loaded swimming test, blood lactate concentration, glycogen content, the activities of antioxidant factors and energy metabolism enzymes, and the function of mitochondria in the skeletal muscle were examined. The results show that POP intervention significantly prolonged the exhaustive swimming time, decreased blood lactate concentration levels, regulated the process of energy metabolism, and increased the level of antioxidant enzymes, muscle glycogen, and expressions of mtTFA and NRF-1 in the mitochondria of the gastrocnemius muscle. The results suggest that POPs produce an anti-fatigue effect in the animals, and they may exert this effect through the mechanism of improving the animals' antioxidant capacity to reduce oxidative damage levels and regulating the process of energy metabolism.

Beneficial Effects of Walnut Oligopeptides on Muscle Loss in Senescence-Accelerated Mouse Prone-8 (SAMP8) Mice: Focusing on Mitochondrial Function.

Aging-related muscle loss is a hallmark of aging and is the cause of some negative outcomes. An optimized diet and supplements have a positive effect in slowing down the process of muscle loss. This study was designed to evaluate the beneficial effects of walnut oligopeptides (WOPs) on aging-related muscle loss and explore the possible underlying mechanism in Senescence-Accelerated Mouse Prone 8 (SAMP8) Mice. SAMP8 mice were randomly divided into four groups (n = 15/group), including one group which was the SAMP8 age control group and three groups those were WOP intervention groups. Meanwhile, Senescence Accelerated Resistant Mouse 1 (SAMR1) mice (n = 12), which had normal senescence rates, were used as model controls. During the six-month intervention period, the age control and normal control groups were given sterilized water, while the three WOP intervention groups were given WOP solution with low (110 mg/kg·bw), medium (220 mg/kg·bw) and high concentrations (440 mg/kg·bw), respectively. The results showed that WOPs could significantly increase muscle mass and improve physical performance (wire hang and catwalk behavioral tests) in aging mice. Moreover, WOPs could significantly reduce the levels of IL-1ß, IL-6 and TNF-α in serum and gastrocnemius tissues and increase the mitochondrial DNA content, as well as the expression levels of AMPK, PGC-1α, NRF-1 and TFAM in the gastrocnemius muscle of aging mice, which was speculated to be the specific mechanism related to mitochondrial function improvement and inflammation reduction. These results indicate that WOPs can improve aging-related muscle loss, in term of both muscle mass and physical performance, and WOP supplements seems to be potentially effective in elderly individuals.

Walnut Oligopeptide Delayed Improved Aging-Related Learning and Memory Impairment in SAMP8 Mice.

Aging-related learning and memory decline are hallmarks of aging and pose a significant health burden. The effects of walnut oligopeptides (WOPs) on learning and memory were evaluated in this study. Sixty SAMP8 mice were randomly divided into four groups (15 mice/group), including one SAMP8 age-control group and three WOP-treated groups. SAMR1 mice (n = 15) that show a normal senescence rate were used as controls. The SAMP8 and SAMR1 controls were administered ordinary sterilized water, while the WOP-intervention groups were administered 110, 220, and 440 mg/kg·bw of WOPs in water, respectively. The whole intervention period was six months. The remaining 15 SAMP8 (4-month-old) mice were used as the young control group. The results showed that WOPs significantly improved the decline in aging-related learning/memory ability. WOPs significantly increased the expression of BDNF and PSD95 and decreased the level of APP and Aß1-42 in the brain. The mechanism of action may be related to an increase in the activity of antioxidant enzymes (SOD and GSH-Px), a reduction in the expression of inflammatory factors (TNF-α and IL-1ß) in the brain and a reduction in oxidative stress injury (MDA). Furthermore, the expression of AMPK, SIRT-1, and PGC-1α was upregulated and the mitochondrial DNA content was increased in brain. These results indicated that WOPs improved aging-related learning and memory impairment. WOP supplementation may be a potential and effective method for the elderly.

Protective Effects of Small-Molecule Oligopeptides Isolated from Tilapia Fish Scale on Ethanol-Induced Gastroduodenal Injury in Rats.

Peptic ulcer has a serious impact on people's health around the world, and traditional medicines can cause adverse reactions. This study investigated the protective effects of tilapia collagen oligopeptides (TCOPs) on gastroduodenal injury. Seventy-two specific pathogen-free (SPF) male Sprague Dawley (SD) rats were randomly divided into six groups according to body weight: normal control group, ethanol group, whey protein group (500 mg/kg BW), and three TCOPs dose groups (250, 500, 1000 mg/kg BW). After intragastric administration for 30 days, the acute gastroduodenal injury was induced by anhydrous ethanol (5 mL/kg, intragastrically) in all groups except the normal control group. Biomarkers in gastric and duodenal tissue and serum were measured. Furthermore, western blot was used to detect the expression of apoptosis-related proteins. The results showed that the administration with TCOPs significantly reduced gastric and duodenal ulcer index, increased gastric juice pH, superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH-Px) activities, along with the reduction of malondialdehyde (MDA) contents. TCOPs decreased tumor Necrosis Factor-α (TNF-α), interleukin-1ß (IL-1ß), and myeloperoxidase (MPO) levels, while interleukin- 10 (IL-10) levels were increased. Furthermore, pepsinogens 1 (PG1), pepsinogens 2 (PG2), gastrin (GAS), and the pepsinogen ratio (PGR) were decreased, the prostaglandin E2 (PGE2) and NO contents were increased after TCOPs intervention. Moreover, TCOPs up-regulated the expression of Bcl-2 and inhibited the expression of Bax and Caspase-3. In conclusion, TCOPs have protective effects on ethanol-induced gastroduodenal injury through gastrointestinal mucosal microcirculation promotion, antioxidation, anti-inflammation, and anti-apoptosis mechanisms.

Radioprotective Effect of Whey Hydrolysate Peptides against γ-Radiation-Induced Oxidative Stress in BALB/c Mice.

Radiation therapy is widely used in the treatment of tumor diseases, but it can also cause serious damage to the body, so it is necessary to find effective nutritional supplements. The main purpose of this study is to evaluate the protective effect of whey hydrolysate peptides (WHPs) against 60Coγ radiation damage in mice and explore the mechanism. BALB/c mice were given WHPs by oral gavage administration for 14 days. Then, some mice underwent a 30-day survival test after 8 Gy radiation, and other mice received 3.5 Gy radiation to analyze the changes in body weight, hematology and bone marrow DNA after three and 14 days. In addition, through further analysis of the level of oxidative stress and intestinal barrier function, the possible mechanism of the radioprotective effect of WHPs was explored. The study found WHPs can prolong survival time, restore body weight, and increase the number of peripheral blood white blood cells and bone marrow DNA content in irradiated mice. In addition, WHPs can significantly improve the antioxidant capacity, inhibit pro-inflammatory cytokines and protect the intestinal barrier. These results indicate that WHPs have a certain radioprotective effect in mice, and the main mechanism is related to reducing oxidative damage.

The Gastroprotective Effect of Small Molecule Oligopeptides Isolated from Walnut (Juglans regia L.) against Ethanol-Induced Gastric Mucosal Injury in Rats.

The study investigated the protective effect of walnut oligopeptides (WOPs) against ethanol-induced gastric injury using Sprague-Dawley (SD) rats. Rats were randomly divided into seven groups based on body weight (10/group), normal group, ethanol group, whey protein group (220 mg/kg body weight), omeprazole group (20 mg/kg body weight), and three WOPs groups (220, 440, 880 mg/kg body weight). After 30 days of treatment with WOPs, rats were given 5 ml/kg absolute ethanol by gavage to induce gastric mucosal injury. Gastric ulcer index (GUI) were determined and the following measured; gastric content pH, gastric mucin, endogenous pepsinogens (PG), prostaglandin E2 (PGE2), inflammatory cytokines, oxidative stress indicators, and the expression of apoptosis-related proteins were measured to evaluate the gastroprotective effect of WOPs. The results showed that the administration with WOPs markedly mitigated the hemorrhagic gastric lesions caused by ethanol in rats, and decreased the GUI, the gastric content pH, PG1, PG2, and NO levels, enhanced mucin and PGE2. Also, WOPs repressed gastric inflammation through the reduction of TNF-α, IL-6, IL-1ß and increase IL-10 levels, and revealed antioxidant properties with the enhancement of superoxide dismutase, glutathione, and catalase activity, while reduction of malondialdehyde. Moreover, WOPs treatment significantly down-regulated Bax, caspase-3 and nuclear factor-κB p65 (NF-κB p65) expression, while up-regulating the expression of Bcl-2 and inhibitor kappa Bα (IκBα) protein. These results indicated that WOPs have protective effects against ethanol-induced gastric mucosal injury in rats through anti-inflammatory, anti-oxidation, and anti-apoptosis mechanisms.

Jackfruit (Artocarpus heterophyllus Lam.) oligopeptides regulate immune responses via Th cell stimulation, cytokine secretion and antibody production.

This study aimed to observe the immunomodulatory effects of oligopeptides derived from jackfruit (Artocarpus heterophyllus Lam.) (JOPs). 200 female BALB/c mice in five groups were respectively given deionized water (control), whey protein (0.20 g per kg body weight (BW)) and JOPs at doses of 0.20, 0.40, and 0.80 g per kg BW by intragastric administration on a daily basis. 7 tests were conducted to determine the immunomodulatory effects of JOPs on immune organ indexes, cellular and humoral immune responses, macrophage phagocytosis, and natural killer (NK) cell activity. Spleen T lymphocyte sub-populations and serum cytokine and immunoglobulin levels were tested to study how JOPs improved the immune system. We found that JOPs could significantly enhance innate and adaptive immune responses in mice by the improvement of cell-mediated and humoral immunity, macrophage phagocytosis capacity and NK cell activity. The immunomodulatory effects may be based on increased T and Th cell percentages, serum interleukin (IL)-1α, IL-10, tumor necrosis factor (TNF)-α, production of immunoglobulin (Ig) M, IgG, and IgA, and depressed interferon (IFN)-γ secretion. These results suggest that dietary JOPs could be valuable as potential immunomodulators.