Prediction of formation abrasiveness under the action of a PDC bit based on the fractal dimension of a rock surface.

During rock drilling, a drill bit will wear as it breaks the rock. However, there is no uniform grading standard for rock abrasiveness. To solve this problem, the wear mechanisms of a polycrystalline diamond compact (PDC) bit and the formation it is drilling into are analyzed in depth, and an abrasiveness evaluation method based on the fractal dimension of the rock surface topography is established. Initially, a three-dimensional digital model is generated from a scanning electron microscope image of the rock after drilling; next, an evaluation of the irregularities on the rock surface is performed using an adapted Weierstrass-Mandelbrot (W-M) function to ascertain the fractal dimensionality. Then, the microcontact characteristics of the contact surface between the formation and the PDC bit are analyzed, and the distribution of the microconvex contact points of the two-body friction pair in a region is obtained. Because the sliding friction between the drill bit and the rock produces a large amount of heat, according to the contact area formula of the friction surface and heat conduction theory, the temperature rise and overall temperature distribution of the formation and PDC bit under the condition of sliding friction are revealed, and the real contact area between the formation and the drill bit within a certain temperature range is obtained. Finally, the evaluation index of rock abrasiveness under sliding conditions is established by adopting the wear weight loss of the rock cutting tool per unit volume as the index of rock abrasiveness, and the model is verified by a microdrilling experiment. The research in this paper is highly important for improving the rock-breaking efficiency and bit service life during drilling.

Hernandezine promotes cancer cell apoptosis and disrupts the lysosomal acidic environment and cathepsin D maturation.

Hernandezine (Her), a bisbenzylisoquinoline alkaloid extracted from Thalictrum flavum, is recognized for its range of biological activities inherent to this herbal medicine. Despite its notable properties, the anti-cancer effects of Her have remained largely unexplored. In this study, we elucidated that Her significantly induced cytotoxicity in cancer cells through the activation of apoptosis and necroptosis mechanisms. Furthermore, Her triggered autophagosome formation by activating the AMPK and ATG5 conjugation systems, leading to LC3 lipidation. Our findings revealed that Her caused damage to the mitochondrial membrane, with the damaged mitochondria undergoing mitophagy, as evidenced by the elevated expression of mitophagy markers. Conversely, Her disrupted autophagic flux, demonstrated by the upregulation of p62 and accumulation of autolysosomes, as observed in the RFP-GFP-LC3 reporter assay. Initially, we determined that Her did not prevent the fusion of autophagosomes and lysosomes. However, it inhibited the maturation of cathepsin D and increased lysosomal pH, indicating an impairment of lysosomal function. The use of the early-stage autophagy inhibitor, 3-methyladenine (3-MA), did not suppress LC3II, suggesting that Her also induces noncanonical autophagy in autophagosome formation. The application of Bafilomycin A1, an inhibitor of noncanonical autophagy, diminished the recruitment of ATG16L1 and the accumulation of LC3II by Her, thereby augmenting Her-induced cell death. These observations imply that while autophagy initially plays a protective role, the disruption of the autophagic process by Her promotes programmed cell death. This study provides the first evidence of Her's dual role in inducing apoptosis and necroptosis while also initiating and subsequently impairing autophagy to promote apoptotic cell death. These insights contribute to a deeper understanding of the mechanisms underlying programmed cell death, offering potential avenues for enhancing cancer prevention and therapeutic strategies.

Low­calorie sweetener D­psicose promotes hydrogen peroxide­mediated apoptosis in C2C12 myogenic cells favoring skeletal muscle cell injury.

Diet and exercise are the most effective approaches used to induce weight loss. D­psicose is a low­calorie sweetener that has been shown to reduce weight in obese individuals. However, the effect of D­psicose on muscle cells under oxidative stress, which is produced during exercise, requires further investigation. The present study aimed to determine the effects of D­psicose on C2C12 myogenic cells in vitro. Hydrogen peroxide (H2O2) was used to stimulate the generation of intracellular reactive oxygen species (ROS) in muscle cells to mimic exercise conditions. Cell viability was analyzed using a MTT assay and flow cytometry was used to analyze the levels of apoptosis, mitochondrial membrane potential (MMP), the generation of ROS and the cell cycle distribution following treatment. Furthermore, protein expression levels were analyzed using western blotting and cell proliferation was determined using a colony formation assay. The results of the present study revealed that D­psicose alone exerted no toxicity on C2C12 mouse myogenic cells. However, in the presence of low­dose (100 µM) H2O2­induced ROS, D­psicose induced C2C12 cell injury and significantly decreased C2C12 cell viability in a dose­dependent manner. In addition, the levels of apoptosis and the generation of ROS increased, while the MMP decreased. MAPK family molecules were also activated in a dose­dependent manner following treatment. Notably, the combined treatment induced G2/M phase arrest and reduced the proliferation of C2C12 cells. In conclusion, the findings of the present study suggested that D­psicose may induce toxic effects on muscle cells in a simulated exercise situation by increasing ROS levels, activating the MAPK signaling pathway and disrupting the MMP.

The molecular mechanism of a novel derivative of BTO-956 induced apoptosis in human myelomonocytic lymphoma cells.

Acute myeloid leukemia (AML) is a malignant cancer of the hematopoietic system. Although the effectiveness of arsenic compounds has been recognized and applied clinically, some patients are still found resistant to this chemotherapy. In this study, we investigated that a synthetic thyroid hormone analog (TA), 2-iodo-4-nitro-1-(o-tolyloxy) benzene, had a strong apoptosis effect on U937 cells. U937 cells were treated with TA, and examinted the generation of reactive oxygen species (ROS), dysfunction of mitochondria, expression of pro-apoptosis and anti-apoptosis, and cleavage of caspase-3 and Poly (ADP-ribose) polymerase (PARP). Further, it is also evaluated that insight molecular mechanism and signaling pathways involved in the study. It is found that TA significantly induced apoptosis in U937 cells through production of ROS, dysfunction of mitochondria, and activation of caspase cascade. It was also observed that MAPK signaling pathway including ERK, JNK, and P38 signals are involved in the induction of apoptosis. Moreover, marked activation of autophagy and ER stress markers such as LC3, P62, Beclin1 and GRP78, CHOP were observed, respectively. Pretreatment with ER stress inhibitor tauroursodeoxycholic acid (TUDCA) and autophagy inhibitor 3-Methyladenine (3-MA) have successfully attenuated and aggravated TA-induced apoptosis, respectively. We further confirmed the active involvement of ER stress and autophagy signals. In conclusion, TA induced apoptosis through ER stress and activation of autophagy, and the latter is not conducive to TA-induced cell death. Our results may provide a new insight into the strategic development of novel therapy for the treatment of AML.

Melatonin triggers the anticancer potential of phenylarsine oxide via induction of apoptosis through ROS generation and JNK activation.

Melatonin, a safe endogenous hormone and a natural supplement, has recently been recognized to have antiproliferative effects and the ability to sensitize cells to other anticancer therapies. Phenylarsine oxide (PAO) has anticancer potential but it is considered as a toxic agent. In this study we combined melatonin to reduce the toxicity while securing the anti-cancer effects of PAO. Cell viability was determined by MTT assay, whereas cytotoxic assays were performed using an LDH cytotoxicity assay kit. Cell cycle analysis, Annexin V/PI staining, the mitochondrial membrane potential (MMP), mitochondrial calcium and reactive oxygen species (ROS) generation were analyzed using flow cytometry. Sytox stained cells were visualized by fluorescence microscopy and the expression of proteins was detected by western blotting. Melatonin increased the anticancer potential of PAO by decreasing the cell viability and increasing LDH release in various cancer cells. The mode of cell death was determined to be typical apoptosis, as evidenced by Annexin V/PI-stained cells, PARP cleavage, and caspase-3 activation, and with significant modulations in the expression of proapoptotic, antiapoptotic and cell cycle-related proteins. ROS generation played a critical role in induction of cell death by this combined treatment, which is validated by reversal of cytotoxicity upon cotreatment with NAC. Furthermore, the activation of MAPKs, especially JNK, contributed to the induction of cell death, accompanied by endoplasmic reticulum stress and autophagy, affirmed by the abrogation of cytotoxicity after JNK-IN-8 and TUDCA application. Melatonin showed promising potential as a chemotherapeutic agent in combination with PAO to achieve a better anticancer response.

Aluminum chloride causes 5-fluorouracil resistance in hepatocellular carcinoma HepG2 cells.

Chemoresistance is one of the major obstacles in chemotherapy-based hepatocellular carcinoma (HCC) intervention. Aluminum (Al) is an environmental pollutant that plays a vital role in carcinogenesis, tumorigenesis, and metastasis. However, the effect of Al on chemoresistance remains unknown. 5-Fluorouracil (5-FU) is a widely used antitumor drug. Therefore, we investigated the effects of aluminum chloride (AlCl3 ) on the chemoresistance of HepG2 cells to 5-FU and explored the underlying mechanisms of these effects. The results demonstrated that AlCl3 pretreatment attenuated 5-FU-induced apoptosis through Erk activation and reversed 5-FU-induced cell cycle arrest by downregulating p-Chk2Thr68 levels. In addition, AlCl3 markedly increased the levels of proteins associated with cell migration, such as MMP-2 and MMP-9. Further investigation demonstrated that an Erk inhibitor (U0126) reversed the AlCl3 -induced decrease in apoptosis, enhancement of cell cycle progression, promotion of cell migration, and attenuation of oxidative stress. In summary, AlCl3 induced chemoresistance to 5-FU in HepG2 cells. The present study suggests a potential influence of AlCl3 on 5-FU therapy. These findings may help others to understand and properly address the resistance of HCC to chemotherapeutic agents.

Protective effect of dihydromyricetin on hyperthermia-induced apoptosis in human myelomonocytic lymphoma cells.

Dihydromyricetin (DMY) is a traditional herbal medicine, with a wide range of biological activities. Extreme hyperthermia (HT) can suppress the immune system; thus, protection of the immune system is beneficial in heat-related diseases, including heatstroke. In our study, we revealed the protective effect of DMY against HT-induced apoptosis and analysed the underlying molecular mechanisms. We incubated human myelomonocytic lymphoma U937 cells at 44 °C for 30 min with or without DMY and followed by further incubation for 6 h at 37 °C. Cell viability was determined by the CCK-8 assay. DMY did not cause any cytotoxic effects in U937 cells even at high doses. HT treatment alone induced significant apoptosis, which was detected by DNA fragmentation and Annexin V/PI double staining. Mitochondrial dysfunction was identified by loss of mitochondrial membrane potential (MMP) during heat stimulation. Apoptotic related proteins were involved, truncated Bid and caspase-3 were upregulated, and Mcl-1 and XIAP were downregulated. We also identified the related signalling pathways, such as the MAPK and PI3K/AKT pathways. However, changes in HT were dramatically reversed when the cells were pretreated with DMY before exposure to HT. Overall, MAPKs and PI3K/AKT signalling, mitochondrial dysfunction, and caspase-mediated pathways were involved in the protective effect of DMY against HT-induced apoptosis in U937 cells, which was totally reversed by DMY pretreatment. These findings indicate a new clinical therapeutic strategy for the protection of immune cells during heatstroke.

Mechanistic study of nonivamide enhancement of hyperthermia-induced apoptosis in U937 cells.

Hyperthermia is one therapeutic tool for damaging and killing cancer cells, with minimal injury to normal tissues. However, its cytotoxic effects alone are insufficient for quantitative cancer cell death. To overcome this limitation, several studies have explored non-toxic enhancers for hyperthermia-induced cell death. Capsaicin may be applicable as a therapeutic tool against various types of cancer. In the present study, we employed nonivamide, a less-pungent capsaicin analogue, to investigate its possible enhancing effects on hyperthermia-induced apoptosis; moreover, we analyzed its molecular mechanism. Treatment of U937 cells at 44 °C for 15 min, combined with nonivamide 50 µM, revealed enhancement of apoptosis. Significant increases in reactive oxygen species generation, mitochondrial dysfunction, and cleaved caspase-3 were observed during the combined treatment; these were accompanied by an increase in pro-apoptotic Bcl-2 family proteins and a decrease in anti-apoptotic Bcl-2 proteins. In addition, significant increases in p-JNK and p-p38 were detected, following the combined treatment. In conclusion, nonivamide enhanced hyperthermia-induced apoptosis via a mitochondrial-caspase dependent pathway. The underlying mechanism may include elevation of intracellular reactive oxygen species, mitochondrial dysfunction, and increased activation of JNK and p38.

Baicalin Augments Hyperthermia-Induced Apoptosis in U937 Cells and Modulates the MAPK Pathway via ROS Generation.

BACKGROUND/AIMS: Hyperthermia is a widely used therapeutic tool for cancer therapy and a well-known inducer of apoptosis. Although the flavonoid compound baicalin (BCN) is a potent anticancer agent for several human carcinomas, it is less potent in the human U937 myelomonocytic leukemia cell line. To explore any enhancing effects of BCN on hyperthermia-induced apoptosis, this study investigated the combined effects and apoptotic mechanisms of hyperthermia and BCN in U937 cells. METHODS: U937 cells were heat treated at 44ºC for 12 min with or without pre-treatment with BCN (10-50 µM) and then incubated for 6 h at 37 ºC with 5% CO2 and 95% air. Cell viability was analyzed by Trypan blue exclusion assay. Apoptosis was examined by DNA fragmentation, fluorescence microscopy and flow cytometry. Generation of mitochondrial trans-membrane potential (MMP), mitochondrial calcium, and reactive oxygen species (ROS) was also detected by flow cytometry. The expression of proteins related to apoptosis and signaling pathways was determined by western blotting. RESULTS: Hyperthermia alone did not reduce cell viability or induce notable levels of apoptosis, but combined hyperthermia and BCN treatment markedly augmented apoptosis by upregulating proapoptotic proteins and suppressing antiapoptotic proteins, culminating in caspase-3 activation. Mitochondrial transmembrane potential was significantly decreased, and generation of reactive oxygen species (ROS) and suppression of antioxidant enzymes were marked. Furthermore, with the combined treatment, the phosphorylated forms of JNK and p38 showed increased expression, whereas AKT was dephosphorylated. JNK-IN-8 (a JNK inhibitor) and NAC (a ROS scavenger) abrogated the apoptotic effects of the combined treatment, significantly protecting the cells and indicating the involvement of high ROS generation and the MAPK pathway in the underlying molecular mechanism. CONCLUSION: This study provides compelling evidence that hyperthermia, in combination with BCN, is a promising therapeutic strategy for enhancement of apoptosis and suggest a promising therapeutic approach for cancer.

Potential hazards of fenvalerate in massive pollution influence the apoptosis sensitivity.

Fenvalerate (Fen), a synthetic pyrethroid insecticide, is widely used in agricultural, domestic and veterinary applications. Fen induces abnormal cell proliferation and apoptosis, which are linked to its hazardous effects. However, this view is controversial and the underlying molecular mechanisms remain elusive. In the present study, the effects of Fen on cadmium (Cd)-induced apoptosis and the associated molecular mechanisms were investigated in human myeloid leukemia U937 cells. U937 cells were treated with 50 µm cadmium chloride (CdCl2 ) with or without Fen pretreatment at 1-50 µm. Apoptosis was evaluated by externalization of phosphatidylserine on the plasma membrane. The expression levels of apoptosis-related proteins, including Bcl-2 family members were determined by western blot analysis. The results revealed that pretreatment with Fen at 20 µm for 12 hours significantly inhibited Cd-induced apoptosis. Decreased expression of pro-apoptotic Bcl-2 family proteins (Noxa and Bid) and increased expression of anti-apoptotic proteins (Bcl-xL, Mcl-1 and XIAP) were observed after combined treatment with Fen and CdCl2 . Phosphorylation of ERK and AKT was increased, while phosphorylation of JNK was decreased by the combined treatment, compared with CdCl2 treatment alone. In conclusion, Fen decreased apoptotic sensitivity induced by Cd in U937 cells. This effect was associated with activation of ERK and AKT, suppression of JNK and changes in expression of Bcl-2 family proteins and XIAP. The present findings suggest a potential influence of Fen on Cd toxicity via suppression of apoptosis. Fen decreased apoptotic sensitivity induced by Cd, and thus it may contribute carcinogenic risk and influence on cancer therapy.

Mantle Subduction and Uplift of Intracontinental Mountains: A Case Study from the Chinese Tianshan Mountains within Eurasia.

The driving mechanism that is responsible for the uplift of intracontinental mountains has puzzled geologists for decades. This study addresses this issue by using receiver function images across the Chinese Tianshan Mountains and available data from both deep seismic profiles and surface structural deformation. The near-surface structural deformation shows that the Tianshan crust experienced strong shortening during the Cenozoic. The receiver function image across the Tianshan Mountains reveals that the lithosphere of the Junggar Basin to the north became uncoupled along the Moho, and the mantle below the Moho subducted southwards beneath the northern part of the Tianshan Mountains, thereby thickening the overlying crust. Similar deep structures, however, are not observed under the Tarim Basin and the adjacent southern Tianshan Mountains. This difference in the deep structures correlates with geomorphological features in the region. Thus, a new model of mantle subduction, herein termed M-type subduction, is proposed for the mountain-building processes in intracontinental compressional settings. The available geomorphological, geological and seismic data in the literatures show that this model is probably suitable for other high, linear mountains within the continent.