Zhejiang da xue xue bao. Yi xue ban = Journal of Zhejiang University. Medical sciences最新文献

Objectives: To investigate the effect of pachymic acid on brown/beige adipocyte differentiation and lipid metabolism in preadipocytes 3T3-L1 MBX.

Methods: The brown cocktail method was employed to induce 3T3-L1 MBX cells to differentiate into beige adipocytes. The impact of pachymic acid on the viability of 3T3-L1 MBX preadipocytes was evaluated using the CCK-8 assay. The formation of lipid droplets following treatment with pachymic acid was observed through oil red O staining, and the content of lipids in differentiated cells was determined. The expression levels of key browning genes, including uncoupling protein (Ucp) 1, the peroxisome proliferation-activating receptor gamma coactivator (Pgc)-1α, and the transcription factor containing PR domain 16 (Prdm16) were detected by quantitative reverse transcription polymerase chain reaction. The expression of sterol regulatory element binding protein (Srebp) 1c, acetyl-CoA carboxylase (Acc), fatty acid synthetase (Fas), and steroid-sensitive lipase (Hsl), fatty triglyceride hydrolase (Atgl), and carnitine palmitoyl transferase (Cpt) 1 of lipolysis-related genes were also examined.

Results: The 3T3-L1 MBX was induced in vitro to form beige adipocytes with high expression of key browning genes, including Ucp1, Pgc-1α, Prdm16, and beige adipose-marker genes, including Cd137, Tbx1, and Tmem26. The concentration range of 0-80 μM pachymic acid was non-cytotoxic to 3T3-L1 MBX. Pachymic acid treatment significantly inhibited the differentiation of 3T3-L1 MBX, resulting in a notable decrease in lipid accumulation content (P<0.01). Additionally, there was a marked increase in the expression of key browning genes and their proteins, such as Ucp1, Pgc-1α, and Prdm16, while the expressions of fat synthesis-related genes Srebp1c, Acc and Fas were significantly decreased (all P<0.05). The expressions of lipolysis-related genes, including Hsl, Atgl, and Cpt1, were significantly increased (all P<0.05). Besides, treating with 20 μmol/L pachymic acid showed the most pronounced effect.

Conclusions: Pachymic acid can inhibit fat synthesis and promote lipid decomposition by regulating the brown formation and lipid differentiation of 3T3-L1 MBX preadipocytes.

Objectives: To analyze the disease burden and trend from 1990 to 2020 of melanoma among middle-aged and elderly populations in China, and to predict the future trend from 2022 to 2035.

Methods: Data from the Global Burden of Disease Study (GBD) 2021 were utilized to collect incidence and mortality rates of melanoma, disability-adjusted life years (DALYs), and corresponding age crude rates among the middle-aged and elderly population in China. Additionally, the estimated annual percentage change (EAPC) was employed to assess the temporal trends. Age-period-cohort (APC) and Bayesian age-period-cohort (BAPC) models were utilized to compute age, period, and cohort effects on incidence and mortality rates of melanoma, as well as to predict future trends up to 2035.

Results: During 1990-2021, the incidence rate of melanoma for males was higher than that for females among the middle-aged and elderly population in China, and the overall incidence rate increased annually with an EAPC of 2.13 (1.90, 2.36), while the overall mortality rate and DALY rate showed a declining trend with an EAPC of －0.28 (－0.41, －0.15) and －0.54 (－0.68, －0.41),respectively. The results of the APC model analysis revealed that age effects on both incidence and mortality rates of melanoma in China's middle-aged and elderly population were significant, with both increasing with age. Period and cohort effects showed an upward trend for incidence rates but a downward trend for mortality rates. Moreover, the period and cohort effects for mortality rates were not significant among females. In the BAPC prediction model, the number of incidences of melanoma in middle-aged and elderly people in China would increase dramatically. By 2035, the number of incidence cases is expected to reach approximately 9600 (males) and 10 300 (females), corresponding to an incidence rate of 2.66/10⁵ and 2.67/10⁵, respectively; the number of deaths is projected to be about 2600 (males) and 3500 (females) by 2035, corresponding to a mortality rate of 0.72/10⁵ and 0.91/10⁵, respectively.

Conclusions: The disease burden of melanoma among the middle-aged and elderly population in China remains substantial and is expected to increase over the next decade.

Objectives: To investigate the protective effects and underlying mechanisms of Gynostemma pentaphyllum extract on motor dysfunction in mouse model of Parkinson's disease (PD).

Methods: Eighty C57BL/6 male mice were randomly divided into five groups: control group, PD model group, levodopa treatment group (positive control group), low-dose GP treatment group (LD-GP group), and high-dose GP treatment group (HD-GP group), with 16 mice per group. The PD model was induced by injection of 6-hydroxydopamine into the substantia nigra pars reticulata in mice of last 5 groups. Two weeks after 6-hydroxydopamine modeling, mice in positive control group received introperitoneal injection of levodopa 10 mg·kg^－1·d^－1, mice in LD-GP and HD-GP groups received oral 100 mg·kg^－1·d^－1 or 200 mg·kg^－1·d^－1 for 3 weeks, respectively. After 3-week-treatment, the effects of GP on motor dysfunction in 6-OHDA-induced PD mice were assessed using open field and CatWalk gait tests, while the effects on muscle strength were evaluated by forelimb grip strength. Immunofluorescence staining was used to detect the number of tyrosine hydroxylase (TH) positive neurons. The levels of dopamine and serotonin in midbrain were determined by enzyme-linked immunosorbent assay. In addition, Western blotting was performed to detect the expression of mitogen-activated protein kinase (MAPK) family proteins such as p- extracellular signal-regulated kinase (ERK)1/2, p-p38 and p-c-Jun N-terminal kinase (JNK)1/2 , and mitochondrial apoptosis pathway proteins such as B-cell lymphoma (Bcl)-2, Bcl-2 associated X protein (Bax), and cleaved- cysteine aspartic acid specific protease (caspase)-3.

Results: Behavioral experiments showed that GP significantly improved the spontaneous activity and motor coordination of PD mice (P<0.05). And the forelimb grip strength was also increased by GP treatment (P<0.05), compared with PD model group. In addition, compared with model group, the number of TH-positive neurons in substantia nigra pars reticulata region, the levels of dopamine and serotonin in midbrain and the expression of p-ERK1/2 were significantly increased by GP treatment (all P<0.05), whereas the expression of p-p38 and p-JNK1/2, the ratio of Bax/Bcl-2 and cleaved-caspase 3/caspase 3 were significantly decreased (all P<0.05).

Conclusions: The results indicate that GP might increase dopamine and serotonin levels in midbrain and promoted the survival of dopaminergic neurons in substantia nigra pars reticulata by regulating the expression of phosphorylation of MAPK family proteins and the expression of mitochondrial apoptosis-related proteins, and then ameliorate motor deficits in PD mice.

As the central organ of metabolism, the liver plays a pivotal role in the regulation of the synthesis and metabolism of various nutrients within the body. Ferroptosis, as a newly discovered type of programmed cell death caused by the accumulation of iron-dependent lipid peroxides, is involved in the physiological and pathological processes of a variety of acute and chronic liver diseases. Ferroptosis can accelerate the pathogenetic process of acute liver injury, metabolic associated fatty liver disease, alcoholic liver disease, viral hepatitis, and autoimmune hepatitis; while it can slower disease progression in advanced liver fibrosis and hepatocellular carcinoma. This suggests that targeted regulation of ferroptosis may impact the occurrence and development of various liver diseases. This article reviews the latest research progress of ferroptosis in various liver diseases, including acute liver injury, metabolic associated fatty liver disease, alcoholic liver disease, viral hepatitis, autoimmune hepatitis, liver fibrosis and hepatocellular carcinoma. It aims to provide insights for the prevention and treatment of acute and chronic liver diseases through targeting ferroptosis.

It is reported that iron metabolism and ferroptosis can influence the occurrence and development of myeloid tumors, which can serve as therapeutic targets. Dysregulation of iron metabolism is present in a variety of myeloid neoplasms. The prognosis of acute myeloid leukemia is related to differential expression of molecules related to iron metabolism. The prognosis of myelodysplastic syndrome patients with iron overload is poor. Myeloproliferative neoplasms are often characterized by the coexistence of iron deficiency and erythrocytosis, which can be treated by targeting hepcidin. Myeloid tumor cells are susceptible to oxidative damage caused by the accumulation of reactive oxygen species and are sensitive to ferroptosis. Ferroptosis has anti-tumor effect in acute myeloid leukemia and myelodysplastic syndrome. Targeting ferroptosis can reverse imatinib resistance in chronic myeloid leukemia. This article reviews the characteristics of iron metabolism in the development and progression of myeloid neoplasms, as well as the mechanism of ferroptosis, to provide a basis for the development of new therapeutic strategies.

Recent studies have shown that iron metabolism dysregulation and lipid peroxidation-induced ferroptosis, triggered by oxidative stress, play a key role in the development of aortic dissection. Dysregulated iron metabolism leads to excessive production of hydroxyl radicals due to abnormal iron levels and heme metabolism, while lipid peroxidation is linked to system Xc^－ dysfunction and accumulation of phospholipid hydroperoxides. These factors synergistically disrupt aortic homeostasis and drive ferroptosis in vascular cells, including endothelial and smooth muscle cells. Furthermore, disruptions in ferroptosis-related genes, along with risk factors such as smoking, epigenetic modifications such as protein methylation, and abnormalities in immune cells, particularly T cells, are closely linked to aortic dissection. Several small molecules and nanomaterials have shown potential in inhibiting ferroptosis in this context. This review elucidates the roles of ferroptosis in aortic dissection and proposes strategies for its targeted prevention and treatment.

It has been confirmed that exposure to various metal pollutants can induce neurotoxicity, which is closely associated with the occurrence and development of neurological disorders. Ferroptosis is a form of cell death in response to metal pollutant exposure and it is closely related to oxidative stress, iron metabolism and lipid peroxidation. Recent studies have revealed that ferroptosis plays a significant role in the neurotoxicity induced by metals such as lead, cadmium, manganese, nickel, and antimony. Lead exposure triggers ferroptosis through oxidative stress, iron metabolism disorder and inflammation. Cadmium can induce ferroptosis through iron metabolism, oxidative stress and ferroptosis related signaling pathways. Manganese can promote ferroptosis through mitochondrial dysfunction, iron metabolism disorder and oxidative stress. Nickel can promote ferroptosis by influencing mitochondrial function, disrupting iron homeostasis and facilitating lipid peroxidation in the central nervous system. Antimony exposure can induce glutathione depletion by activating iron autophagy, resulting in excessive intracellular iron deposition and ultimately causing ferroptosis. This article reviews the effects of metal pollutants on ferroptosis-related indicators and discusses the specific mechanisms by which each metal triggers ferroptosis. It provides a reference for identifying targets for preventing neurotoxicity and for developing treatment strategies for neurological disorders.

Ferroptosis is a form of regulated cell death, which is dependent on iron metabolism imbalance and characterized by lipid peroxidation. Ferroptosis plays a crucial role in various pathological processes. Studies have shown that the occurrence of ferroptosis is closely associated with the progression of hepatocellular carcinoma (HCC). Ferroptosis is involved in regulating the lipid metabolism, iron homeostasis, mitochondrial metabolism, and redox processes in HCC. Additionally, ferroptosis plays a key role in HCC tumor immunity by modulating the phenotype and function of various immune cells in the tumor microenvironment, affecting tumor immune escape and progression. Ferroptosis-induced lipid peroxidation and oxidative stress can promote the polarization of M1 macrophages and enhance the pro-inflammatory response in tumors, inhibiting immune suppressive cells such as myeloid-derived suppressor cells and regulatory T cells to disrupt their immune suppression function. The regulation of expression of ferroptosis-related molecules such as GPX4 and SLC7A11 not only affects the sensitivity of tumor cells to immunotherapy but also directly influences the activity and survival of effector cells such as T cells and dendritic cells, further enhancing or weakening host antitumor immune response. Targeting ferroptosis has demonstrated significant clinical potential in HCC treatment. Induction of ferroptosis by nanomedicines and molecular targeting strategies can directly kill tumor cells or enhance antitumor immune responses. The integration of multimodal therapies with immunotherapy further expands the application of ferroptosis targeting as a cancer therapy. This article reviews the relationship between ferroptosis and antitumor immune responses and the role of ferroptosis in HCC progression from the perspective of tumor immune microenvironment, to provide insights for the development of antitumor immune therapies targeting ferroptosis.

Objectives: To evaluate the immunogenicity and osteogenic ability of animal-derived bone graft material decellularized with supercritical carbon dioxide.

Methods: Porcine femurs were randomly divided into two groups after preliminary treatment, and decellularized with conventional method (control group) or supercritical carbon dioxide (experimental group). Allogenic demineralized bone matrix was used as positive control. Clearance rate of galactose-α-1, 3-galactose (α-Gal) antigen was determined by enzyme-linked immunosorbent assay and residual DNA was detected by a fluorescence method. Nine SPF-grade male athymic nude mice of 6 weeks old were randomly divided into experimental, control and positive control groups. Samples were implanted over biceps femoris muscle of athymic nude mice. The explants were collected 4 weeks post implantation. Hematoxylin and eosin (HE) staining and immunohistochemistry were applied to determine the osteogenic ability and bone tissue-associated protein expressions of the implants.

Results: The clearance rates of α-Gal antigen in the experimental group and the control group were (99.09±0.26)% and (30.18±2.02)%, respectively (t=58.67, P<0.01). The residual DNA of the experimental, control and positive control groups were (13.49±0.07), (15.20±0.21) and (14.70±0.17) ng/mg. The residual DNA in the experimental group was significantly lower than that in the control group (t=－13.41, P<0.01) and positive control group (t=－11.30, P<0.01). HE staining results showed that multiple bone formation centers with active osteogenesis and rich bone marrow were observed in experimental group 4 weeks after implantation, but only a small number of bone formation centers were observed in the control and positive control groups, with no obvious osteoblasts present. Immunohistochemistry results indicated that the expressions of alkaline phosphatase, Runt-related transcription factor 2, collagen typeⅠand osteocalcin in the experimental group showed an increasing trend compared with those in the control and positive control groups.

Conclusions: Compared with clinically used allogenic demineralized bone matrix and bone graft material decellularized with conventional method, bone graft material decellularized with supercritical carbon dioxide exhibits lower immunogenicity and better osteogenic ability.