Germ cell-specific gene 2 accelerates cell cycle in epithelial ovarian cancer by inhibiting GSK3α-p27 cascade.

Epithelial ovarian cancer (EOC) is one of the most common malignant gynecological tumors with rapid growth potential and poor prognosis, however, the molecular mechanism underlying its outgrowth remained elusive. Germ cell-specific gene 2 (GSG2) was previously reported to be highly expressed in ovarian cancer and was essential for the growth of EOC. In this study, GSG2-knockdown cells and GSG2-overexpress cells were established through lentivirus-mediated transfection with Human ovarian cancer cells HO8910 and SKOV3. Knockdown of GSG2 inhibited cell proliferation and induced G2/M phase arrest in EOC. Interestingly, the expression of p27, a well-known regulator of the cell cycle showed a most significant increase after GSG2 knockdown. Further phosphorylation-protein array demonstrated the phosphorylation of GSK3αSer21 decreased in GSG2-knockdown cells to the most extent. Notably, inhibiting GSK3α activity effectively rescued GSG2 knockdown's suppression on cell cycle as well as p27 expression in EOC. Our study substantiates that GSG2 is able to phosphorylate GSK3α at Ser21 and then leads to the reduction of p27 expression, resulting in cell cycle acceleration and cell proliferation promotion. Thus, GSG2 may have the potential to become a promising target in EOC.

A membrane associated tandem kinase from wild emmer wheat confers broad-spectrum resistance to powdery mildew.

Crop wild relatives offer natural variations of disease resistance for crop improvement. Here, we report the isolation of broad-spectrum powdery mildew resistance gene Pm36, originated from wild emmer wheat, that encodes a tandem kinase with a transmembrane domain (WTK7-TM) through the combination of map-based cloning, PacBio SMRT long-read genome sequencing, mutagenesis, and transformation. Mutagenesis assay reveals that the two kinase domains and the transmembrane domain of WTK7-TM are critical for the powdery mildew resistance function. Consistently, in vitro phosphorylation assay shows that two kinase domains are indispensable for the kinase activity of WTK7-TM. Haplotype analysis uncovers that Pm36 is an orphan gene only present in a few wild emmer wheat, indicating its single ancient origin and potential contribution to the current wheat gene pool. Overall, our findings not only provide a powdery mildew resistance gene with great potential in wheat breeding but also sheds light into the mechanism underlying broad-spectrum resistance.

Deciphering The Emerging Role of Programmed Cell Death in Diabetic Wound Healing.

Diabetic wounds are characterized by delayed and incomplete healing. As one of the most common complications of diabetes, diabetic wounds can be fatal in some cases. Programmed cell death (PCD) is an active and ordered cell death mode determined by genes, including apoptosis, autophagy, pyroptosis, necroptosis, ferroptosis, and cuproptosis. It is currently believed that PCD plays a crucial role in diabetic wound healing. Diabetic hyperglycemic environments can lead to abnormal PCD in various cells during healing processes, thereby affecting the activity and function of cells and interfering with diabetic wound healing. Therefore, this review focuses on the new roles and mechanisms of PCD in diabetic wound healing. Moreover, the challenges and perspectives related to PCD in diabetic wound healing are presented, which will bring new insights to improve diabetic wound healing.

Osteoporotic bone loss from excess iron accumulation is driven by NOX4-triggered ferroptosis in osteoblasts.

Excess iron accumulation is a risk factor for osteopenia and osteoporosis, and ferroptosis is becoming well understood as iron-dependent form of cell death resulting from lipid peroxide accumulation. However, any pathological impacts of ferroptosis on osteoporosis remain unknown. Here, we show that ferroptosis is involved in excess-iron-induced bone loss and demonstrate that osteoporotic mice and humans have elevated skeletal accumulation of the NADPH oxidase 4 (NOX4) enzyme. Mechanistically, we found that the NOX4 locus contains iron-response element-like (IRE-like) sequences that are normally bound (and repressed) by the iron regulatory protein 1 (IRP1) protein. Binding with iron induces dissociation of IRP1 from the IRE-like sequences and thereby activates NOX4 transcription. Elevated NOX4 increases lipid peroxide accumulation and causes obvious dysregulation of mitochondrial morphology and function in osteoblasts. Excitingly, the osteoporotic bone loss which we initially observed in an excessive-iron accumulating mouse line (Hepc1-/-) was blocked upon treatment with the ferroptosis-inhibitor ferrostatin-1 (Ferr-1) and with the iron chelator deferoxamine (DFO), suggesting a potential therapeutic strategy for preventing osteoporotic bone loss based on disruption of ferroptosis.

NcRNA: key and potential in hearing loss.

Hearing loss has an extremely high prevalence worldwide and brings incredible economic and social burdens. Mechanisms such as epigenetics are profoundly involved in the initiation and progression of hearing loss and potentially yield definite strategies for hearing loss treatment. Non-coding genes occupy 97% of the human genome, and their transcripts, non-coding RNAs (ncRNAs), are widely participated in regulating various physiological and pathological situations. NcRNAs, mainly including micro-RNAs (miRNAs), long-stranded non-coding RNAs (lncRNAs), and circular RNAs (circRNAs), are involved in the regulation of cell metabolism and cell death by modulating gene expression and protein-protein interactions, thus impacting the occurrence and prognosis of hearing loss. This review provides a detailed overview of ncRNAs, especially miRNAs and lncRNAs, in the pathogenesis of hearing loss. We also discuss the shortcomings and issues that need to be addressed in the study of hearing loss ncRNAs in the hope of providing viable therapeutic strategies for the precise treatment of hearing loss.

Identification of a novel Calpain-2-SRC feed-back loop as necessity for ß-Catenin accumulation and signaling activation in hepatocellular carcinoma.

Rapid progression is the major cause of the poor prognosis of hepatocellular carcinoma (HCC); however, the underlying mechanism remained unclear. Here, we found Calpain-2 (CAPN2), a well-established protease that accelerates tumor progression in several malignancies, is overexpressed in HCC and acts as an independent predictor for poor outcomes. Furthermore, CAPN2 promoted the proliferation and invasion of HCC, and showed a positive correlation with the levels of invasion-related markers. Mechanistically, a novel CAPN2-SRC positive regulatory loop was identified upstream of ß-catenin to prevent its ubiquitination and degradation, and subsequently promoted HCC progression: CAPN2 could proteolyze PTP1B to form a truncation of approximately 42 kDa with increased phosphatase activity, resulting in reduced SRC Y530 phosphorylation and increased SRC kinase activity; meanwhile, CAPN2 itself was a bone fide substrate of SRC that was primarily phosphorylated at Y625 by SRC and exhibited increased proteolysis activity upon phosphorylation. Interestingly, the CAPN2-SRC loop could not only restrain most of cytoplasmic ß-catenin degradation by inhibiting GSK3ß pathway, but also prevented TRIM33-induced nuclear ß-catenin degradation even in ß-catenin-mutant cells. Present study identified a CAPN2-SRC positive loop responsible for intracellular ß-catenin accumulation and signaling activation, and targeting CAPN2 protease activity might be a promising approach for preventing HCC progression.

Evaluation of individualized treatment of nonproliferative diabetic retinopathy: a multicenter, randomized, parallel-controlled study.

OBJECTIVE: To evaluate the differences in the efficacy of stationary treatment and individualized treatment for patients with nonproliferative diabetic retinopathy (NPDR). METHODS: This study was a randomized, controlled, multicenter clinical trial. Participants with NPDR were randomized into the stationary treatment group or the individualized treatment group. The stationary treatment group was given the basic treatment and Qiming granules, and the individualized treatment group was given the basic treatment, Qiming granules, and individualized Chinese herbal medicines over a 12-week period. The individualized therapeutic formula was also changed over time to adjust to the changes in the clinical presentation of the patient. We conducted observations of fundus retinal exudation and hemorrhage, visual acuity, Traditional Chinese Medicine symptom scores and other indicators. RESULTS: A total of 140 participants with NPDR were randomized into the stationary treatment group or the individualized treatment group, and 132 participants completed this study. Following the 12-week treatment, significant improvements in both primary and secondary outcomes were observed in the stationary and individualized treatment groups. No remarkable difference in the primary outcomes between the two groups was observed. However, there was a significant difference in the Traditional Chinese Medicine symptom scores (18 ± 7 vs 15 ± 6; P < 0.05). There were no severe adverse effects. CONCLUSION: Compared with stationary treatment, individualized treatment is more effective at relieving the Traditional Chinese Medicine symptoms and improving vision and fundus lesions at 12 weeks post treatment.

MYSM1 induces apoptosis and sensitizes TNBC cells to cisplatin via RSK3-phospho-BAD pathway.

Breast cancer is one of the leading causes of mortality among women. Triple-negative breast cancer (TNBC) is responsible for a large percentage of all breast cancer deaths in women. This study demonstrated the function of Myb-like, SWIRM, and MPN domains 1 (MYSM1), an H2A deubiquitinase (DUB), in TNBC. MYSM1 expression was drastically decreased in breast cancer, especially in TNBC, suggesting a potential anticancer effect. Overexpressing and suppressing MYSM1 expression in TNBC cell lines led to significant biological changes in cell proliferation. Furthermore, MYSM1 overexpression increased cisplatin-induced apoptosis, which might be attributed to RSK3 inactivation and the subsequently decreased phosphorylation of Bcl-2 antagonist of cell death (BAD) (Ser 112). The findings suggest that MYSM1 is a potential target for regulating cell apoptosis and suppressing resistance to cisplatin in TNBC.

Functional characterization of powdery mildew resistance gene MlIW172, a new Pm60 allele and its allelic variation in wild emmer wheat.

Wild emmer wheat (Triticum dicoccoides, WEW) is an immediate progenitor of both the cultivated tetraploid and hexaploid wheats and it harbors rich genetic diversity against powdery mildew caused by Blumeria graminis f. sp. tritici (Bgt). A powdery mildew resistance gene MlIW172 originated from WEW accession IW172 (G-797-M) is fine mapped in a 0.048 centimorgan (cM) genetic interval on 7AL, corresponding to a genomic region spanning 233 kb, 1 Mb and 800 kb in Chinese Spring, WEW Zavitan, and T. urartu G1812, respectively. MlIW172 encodes a typical NLR protein NLRIW172 and physically locates in an NBS-LRR gene cluster. NLRIW172 is subsequently identified as a new allele of Pm60, and its function is validated by EMS mutagenesis and transgenic complementation. Haplotype analysis of the Pm60 alleles reveals diversifications in sequence variation in the locus and presence and absence variations (PAV) in WEW populations. Four common single nucleotide variations (SNV) are detected between the Pm60 alleles from WEW and T. urartu, indicative of speciation divergence between the two different wheat progenitors. The newly identified Pm60 alleles and haplotypes in WEW are anticipated to be valuable for breeding powdery mildew resistance wheat cultivars via marker-assisted selection.

Fine mapping of powdery mildew resistance gene MlWE74 derived from wild emmer wheat (Triticum turgidum ssp. dicoccoides) in an NBS-LRR gene cluster.

KEY MESSAGE: Powdery mildew resistance gene MlWE74, originated from wild emmer wheat accession G-748-M, was mapped in an NBS-LRR gene cluster of chromosome 2BS. Wheat powdery mildew, caused by Blumeria graminis f. sp. tritici (Bgt), is a globally devastating disease. Wild emmer wheat (Triticum turgidum var. dicoccoides) is a valuable genetic resource for improving disease resistance in common wheat. A powdery mildew resistance gene was transferred to hexaploid wheat line WE74 from wild emmer accession G-748-M. Genetic analysis revealed that the powdery mildew resistance in WE74 is controlled by a single dominant gene, herein temporarily designated MlWE74. Bulked segregant analysis (BSA) and molecular mapping delimited MlWE74 to the terminal region of chromosome 2BS flanking by markers WGGBD412 and WGGBH346 within a genetic interval of 0.25 cM and corresponding to 799.9 kb genomic region in the Zavitan reference sequence. Sequence annotation revealed two phosphoglycerate mutase-like genes, an alpha/beta-hydrolases gene, and five NBS-LRR disease resistance genes that could serve as candidates for map-based cloning of MlWE74. The geographical location analysis indicated that MlWE74 is mainly distributed in Rosh Pinna and Amirim regions, in the northern part of Israel, where environmental conditions are favorable to the occurrence of powdery mildew. Moreover, the co-segregated marker WGGBD425 is helpful in marker-assisted transfer of MlWE74 into elite cultivars.

Preparation and Mechanism of Bio-Based Sodium Alginate Fibers with Flame Retardant and Antibacterial Properties.

Flame retardant and antibacterial sodium alginate (SA) fiber were fabricated using the bio-based flame retardant of phytic acid and DL-arginine successively, and then the morphological structures, combustion behavior, thermal stability, and mechanical as well as antibacterial properties of SA fiber were investigated carefully. It is found that when the additional amount of PADL (reaction products of phytic acid and DL-arginine) in SA composite fiber is 20 wt%, its limiting oxygen index (LOI) is 40.0 ± 0.3%, and UL-94 is V-0 grade. The combustion behavior of composite fiber shows that PADL can effectively reduce combustion heat and promote carbon formation. Its peak of HRR (pkHRR) is 5.9% of pure SA fiber, and the residual carbon increases from 23.0 ± 0.1% to 44.2 ± 0.2%. At the same time, the density of the residual carbon increases gradually. PADL can promote SA to form expanded carbon with increasing density, and isolate the heat and volatilization of combustible gases. The guanidine group of DL-arginine can interact with the cell membrane to kill bacteria, and the antibacterial property of SA composite fiber is increased by 30%. This study provides a very ecological, safe, environmentally friendly and simple method to prepare flame retardant and antibacterial SA composite fiber with bio-based materials.

Pt Edge-Doped MoS2 : Activating the Active Sites for Maximized Hydrogen Evolution Reaction Performance.

The demand of clean energy calls for efficient and low-cost hydrogen evolution reaction electrocatalysts. Fabricating hybrid catalysts from noble/non-noble catalysts is a practical route to reducing the consumption of noble metals and enhancing catalytic efficiency. Here, 2H-MoS2 is etched and edge-doped with Pt nanoparticles using focused ion beam and photoreduction techniques. Precise comparison of as-prepared samples demonstrates that the enhancement of catalytic performance can be controlled through tuning the catalyst defect length. On this basis, remarkably high performance is obtained by designing a specific defect array that is superior to commercial Pt/C with less Pt loading and higher mass activity. It has been proved by experimentation and COMSOL Multiphysics simulations that the promotion of catalytic activity not only benefits from the synergistic effect of Pt and edge active sites, but also contributes to the increased potential at the edges of the designed defect. This study sheds light on the mechanism of understanding nanoscale edge-doped hybrid catalysts and provides a feasible strategy for the full utilization of noble metals.

TTK is a potential therapeutic target for cisplatin-resistant ovarian cancer.

BACKGROUND: Drug resistance and recurrence are main contributors to the poor prognosis of ovarian cancer. Cisplatin is a platinum compound which is widely used in the treatment of various solid tumors including ovarian cancer. Up to now, the mechanism of cisplatin resistance in ovarian cancer is unclear. Threonine and tyrosine kinase (TTK), an integral part of the spindle assembly checkpoint, may be a potential new target associated with chemotherapy sensitivity. RESULTS: TTK was up-regulated in the cisplatin-resistant ovarian cancer cell line. Down-regulation of TTK could recover the sensitivity of cisplatin-resistant ovarian cancer cells to cisplatin treatment. Mechanistically, the PI3K/AKT signaling pathway was activated in cisplatin-resistant cells, and this pathway would be affected by TTK expression. Furthermore, TTK was highly expressed in the tissues of ovarian cancer patients, especially those acquired resistance to cisplatin. CONCLUSIONS: Our study revealed that TTK may be a promising therapeutic target for cisplatin-resistant ovarian cancer.

pH/H2O2 Dual-Responsive Chiral Mesoporous Silica Nanorods Coated with a Biocompatible Active Targeting Ligand for Cancer Therapy.

Nano-drug delivery systems (nano-DDSs) with an existing specific interaction to tumor cells and intelligent stimulus-triggered drug delivery performance in a tumor microenvironment (TME) remain hotspots for effective cancer therapy. Herein, multifunctional pH/H2O2 dual-responsive chiral mesoporous silica nanorods (HA-CD/DOX-PCMSRs) were creatively constructed by first grafting phenylboronic acid pinacol ester (PBAP) onto the amino-functioned nanorods, then incorporating doxorubicin (DOX) into the mesoporous structure, and finally coating with the cyclodextrin-modified hyaluronic acid conjugate (HA-CD) through a weak host-guest interaction. Under a physiological environment, the gatekeeper CD could avoid the premature leakage of DOX and minimize the side effects to normal cells. After the uptake by the tumor cells, the H2O2-sensitive moieties of PBAP were exposed and a small amount of DOX was leaked along with the shift of the supramolecular switch HA-CD under the acidic condition. Notably, the self-supplying H2O2 mediated by the released DOX in turn accelerated the PBAP disintegration, further promoted the rapid release of DOX, and increased the DOX accumulation in tumor regions. Innovatively, this nano-DDS could simultaneously achieve the tumor-targeting ability via CD44 receptor-mediated endocytosis and pH/H2O2 dual responsiveness activated by the TME and hence exhibited superior antitumor efficacy. Furthermore, HA acting as the hydrophilic shell could improve the biocompatibility of this nano-DDS.

CALD1 is a prognostic biomarker and correlated with immune infiltrates in gastric cancers.

BACKGROUND: Caldesmon gene (CALD1) plays an important role in many cellular functions. Some researchers have found the correlation between CALD1 expression and prognosis of gastrointestinal cancer (GI), but the association with tumor-infiltrating lymphocytes (TILs) still unclear. METHODS: The expression of CALD1 in different human tumor was analyzed by Oncomine and Tumor Immune Estimation Resource (TIMER) databases. The correlations between CALD1 and prognosis in types cancer were explored by Kaplan-Meier plotter and Gene Expression Profiling Interactive Analysis (GEPIA) databases. The association between CALD1 expression and tumor immune cell infiltration was further analyzed via TIMER and GEPIA databases. RESULTS: The CALD1 expressions in types cancer between tumor tissues and adjacent normal tissues were significantly different. The high expression of CALD1 was related with poor overall survival (OS) of patients with gastric cancer, especially in gastric cancer patients at N1, N2 and N3 stages. The expression of CALD1 was positively associated with immune-infiltrated, such as CD8+T cells, CD4+T cells, macrophages, neutrophils, and dendritic cells (DCs) in gastric cancer. CONCLUSIONS: CALD1 was considerably a key role in prognosis of patients with gastric cancer. The expression level of CALD1 is significantly associated with immune-infiltrated in gastric cancer. Furthermore, CALD1 expression may be involved in regulating tumor-associated macrophages (TAMs), dendritic cells, exhausted T cells and regulatory T cells in gastric cancer. These findings suggest that CALD1 could be utilized as a marker of prognosis and immune infiltration in gastric cancer.

VHL regulates the sensitivity of clear cell renal cell carcinoma to SIRT4-mediated metabolic stress via HIF-1α/HO-1 pathway.

Clear cell renal cell carcinomas (ccRCC) reprogram carbon metabolism responses to hypoxia, thereby promoting utilization of glutamine. Recently, sirtuin 4 (SIRT4), a novel molecular has turned out to be related to alternating glutamine metabolism and modulating the tumor microenvironment. However, the role of SIRT4 in ccRCC remains poorly understood. Here, we illustrated that the expression of SIRT4 is markedly reduced in cancerous tissues, and closely associated with malignancy stage, grade, and prognosis. In ccRCC cells, SIRT4 exerted its proapoptotic activity through enhancing intracellular reactive oxygen species (ROS). Heme oxygenase-1 (HO-1) is part of an endogenous defense system against oxidative stress. Nevertheless, overexpression of SIRT4 hindered the upregulation of HO-1 in von Hippel-Lindau (VHL)-proficient cells and repressed its expression in VHL-deficient cells. This discrepancy indicated that competent VHL withstands the inhibitory role of SIRT4 on HIF-1α/HO-1. Functionally, overexpression of HO-1 counteracted the promotional effects of SIRT4 on ROS accumulation and apoptosis. Mechanistically, SIRT4 modulates ROS and HO-1 expression via accommodating p38-MAPK phosphorylation. By contrast, downregulation of p38-MAPK by SB203580 decreased intracellular ROS level and enhanced the expression of HO-1. Collectively, this work revealed a potential role for SIRT4 in the stimulation of ROS and the modulation of apoptosis. SIRT4/HO-1 may act as a potential therapeutic target, especially in VHL-deficient ccRCCs.

RBOH1-dependent H2O2 mediates spermine-induced antioxidant enzyme system to enhance tomato seedling tolerance to salinity-alkalinity stress.

Salinity-alkalinity stress is a limiting factor in tomato production in the world. Plants perceive salinity-alkalinity stress by activating signaling pathways to increase plant tolerance (Xu et al., 2020). Here, we investigated whether spermine (Spm) induces respiratory burst oxidase homolog 1 (RBOH1) and hydrogen peroxide (H2O2) signaling in response to salinity-alkalinity stress in tomato. The results showed that exogenous Spm induced the expression of RBOH1 and the accumulation of H2O2 under normal condition. Accordingly, we tested the function of H2O2 signal in tomato seedlings and found that exogenous H2O2 increased the expression levels of Cu/Zn-superoxide dismutase (Cu/Zn-SOD), catalase 1 (CAT1), cytosolic ascorbate peroxidase (cAPX), and glutathione reductase 1 (GR1) and the activities of SOD (EC 1.15.1.1), CAT (EC 1.11.1.6), ascorbate peroxidase (APX; EC 1.11.1.11), and GR (EC 1.6.4.2) in tomato seedlings under salinity-alkalinity stress. DMTU increased the malondialdehyde (MDA) content and relative electrical conductivity, and the relative water content (RWC), and accelerated leaf yellowing in tomato seedlings under salinity-alkalinity stress, even though we sprayed Spm on tomato leaves. We also found that RBOH1 silencing decreased the expression levels of Cu/Zn-SOD, CAT1, cAPX, and GR1 and the activities of SOD, CAT, APX, and GR when tomato seedlings were under salinity-alkalinity stress. Exogenous Spm did not increase RWC and decrease MDA content in RBOH1 silencing tomato seedlings under salinity-alkalinity stress.

GSG2 Promotes Development and Predicts Poor Prognosis of Ovarian Cancer.

PURPOSE: Ovarian cancer is one of the most common malignant tumors in gynecology, whose treatment was seriously limited by the unclear understanding of molecular mechanism in disease development. GSG2, also known as Haspin, is a novel molecule found to be involved in human cancers. MATERIALS AND METHODS: In this study, immunohistochemical analysis was used to detect GSG2 expression in ovarian cancer tissues and corresponding normal tissues. Statistical analysis was performed to construct relationship between GSG2 and tumor characteristics as well as prognosis. Ovarian cell model with GSG2 knockdown was constructed through lentivirus-mediated transfection of shRNA, which was used in MTT assay, colony formation assay and flow cytometry for investigating the role of GSG2 in ovarian cancer. A human apoptosis antibody array was used to identify potential downstream apoptosis-related proteins of GSG2. RESULTS: The results demonstrated the upregulation of GSG2 in ovarian cancer, whose expression was positively related to tumor grade and AJCC stage, and negatively correlated with patients' prognosis. Moreover, knockdown of GSG2 inhibited ovarian cancer development through suppressing cell growth and inducing cell apoptosis. Further exploration revealed that a variety of apoptosis-related and PI3K signaling pathway-related proteins may be implicated in the GSG2 induced regulation of ovarian cancer. CONCLUSION: In summary, it was illustrated that GSG2 was involved in the development of ovarian cancer, which has the potential to become therapeutic target and prognostic indicator in ovarian cancer treatment.