α-Ketoglutarate Improves Ovarian Reserve Function in Primary Ovarian Insufficiency by Inhibiting NLRP3-Mediated Pyroptosis of Granulosa Cells.

SCOPE: Premature ovarian insufficiency (POI) is a common female infertility problem, with its pathogenesis remains unknown. The NOD-like receptor family pyrin domain-containing 3 (NLRP3)-mediated pyroptosis has been proposed as a possible mechanism in POI. This study investigates the therapeutic effect of α-ketoglutarate (AKG) on ovarian reserve function in POI rats and further explores the potential molecular mechanisms. METHODS AND RESULTS: POI rats are caused by administration of cyclophosphamide (CTX) to determine whether AKG has a protective effect. AKG treatment increases the ovarian index, maintains both serum hormone levels and follicle number, and improves the ovarian reserve function in POI rats, as evidence by increased the level of lactate and the expression of rate-limiting enzymes of glycolysis in the ovaries, additionally reduced the expression of NLRP3, Gasdermin D (GSDMD), Caspase-1, Interleukin-18 (IL-18), and Interleukin-1 beta (IL-1ß). In vitro, KGN cells are treated with LPS and nigericin to mimic pyroptosis, then treated with AKG and MCC950. AKG inhibits inflammatory and pyroptosis factors such as NLRP3, restores the glycolysis process in vitro, meanwhile inhibition of NLRP3 has the same effect. CONCLUSION: AKG ameliorates CTX-induced POI by inhibiting NLRP3-mediated pyroptosis, which provides a new therapeutic strategy and drug target for clinical POI patients.

CircSCMH1 Accelerates Sorafenib Resistance in Hepatocellular Carcinoma by Regulating HN1 Expression via miR-485-5p.

Sorafenib (SOR) is the first-line chemotherapeutic therapy for hepatocellular carcinoma (HCC) treatment, but SOR resistance is a key factor affecting the therapeutic effect. Emerging studies have suggested that circular RNAs (circRNAs) play an important role in the development of drug resistance in HCC cells. This paper aimed to elucidate the potential role and molecular mechanism of circRNA Scm polycomb group protein homolog 1 (circSCMH1) in SOR-resistant HCC cells. CircSCMH1, microRNA-485-5p (miR-485-5p), and hematological and neurological expressed 1 (HN1) contents were detected by quantitative real-time polymerase chain reaction (qRT-PCR). Cell Counting Kit-8 (CCK8) assay was adopted to detect the SOR sensitivity of cells. Cell proliferation, migration, invasion, and apoptosis were assessed using colony formation, 5-Ethynyl-2'-deoxyuridine (EdU), transwell, and flow cytometry assays. Glucose metabolism was analyzed using commercial kits. HN1, B cell lymphoma-2 (Bcl-2), and Bcl-2-associated X (Bax) protein levels were assessed using western blot. Binding between miR-485-5p and circSCMH1 or HN1 was verified using a dual-luciferase reporter. Xenograft tumor model was used to explore the function of circSCMH1 in vivo. CircSCMH1 expression and HN1 abundances were increased, but the miR-485-5p level was reduced in SOR-resistant HCC tissues and cells. Deficiency of circSCMH1 enhanced SOR sensitivity by suppressing cell proliferation, migration, invasion, and glucose metabolism and inducing cell apoptosis in SOR-resistant HCC cell lines (Huh7/SOR and Hep3B/SOR). Mechanistically, circSCMH1 sponged miR-485-5p to positively regulate HN1 expression. Importantly, circSCMH1 depletion inhibited tumor growth and increased SOR sensitivity in vivo. CircSCMH1 promoted SOR resistance in HCC cells at least partly through upregulating HN1 expression by sponging miR-485-5p. These findings elucidated a new regulatory pathway of chemo-resistance in SOR-resistant HCC cells and provided a possible circRNA-targeted therapy for HCC.

LINC02561 promotes metastasis in HCC via HIF1-α/NDRG1/UPF1 axis.

In the entire world, hepatocellular carcinoma (HCC) is one of the most frequent cancers that lead to death. Experiments on the function of long non-coding RNAs in the emergence of malignancies, including HCC, are ongoing. As a crucial RNA monitoring mechanism in eucaryotic cells, nonsense-mediated mRNA decay (NMD) can recognize and destroy mRNAs, which has an premature termination codons (PTC) in the open reading frame to prevent harmful buildup of truncated protein products in the cells. Nonsense transcript regulator 1 (Up-frameshift suppressor 1, UPF1), as a highly conserved RNA helicase and ATPase, plays a key role in NMD. Our laboratory screened out the highly expressed lncRNA LINC02561 in HCC from the TCGA database. Further research found that LINC02561 enhanced the invasion and transition abilities of liver cancer cells by regulating the protein N-Myc downstream regulated 1 (NDRG1). Hypoxia inducible factor-1 (HIF-1α) can bonded to LINC02561 promoters under hypoxic conditions, thereby promoting the upregulation of LINC02561 expression in liver cancer cells. LINC02561 competes with NDRG1 mRNA to bind UPF1, thereby preventing the degradation of NDRG1 mRNA to facilitate NDRG1 protein level. Taken together, the HIF1α-LINC02561-UPF1-NDRG1 regulatory axis could be an entirely novel target of liver cancer-related treatment.

Alpha-ketoglutarate ameliorates induced premature ovarian insufficiency in rats by inhibiting apoptosis and upregulating glycolysis.

RESEARCH QUESTION: What are the effects of alpha-ketoglutarate (α-KG) treatment on the ovarian morphology and ovarian reserve function of rats with cyclophosphamide (CTX)-induced premature ovarian insufficiency (POI)? DESIGN: Thirty female Sprague Dawley rats were randomly allocated to a control group (n = 10) and a POI group (n = 20). Cyclophosphamide was administered for 2 weeks to induce POI. The POI group was then divided into two groups: a CTX-POI group (n = 10), administered normal saline, and a CTX-POI + α-KG group (n = 10), administered α-KG 250 mg/kg per day for 21 days. Body mass and fertility was assessed at the end of the study. Serum samples were collected for hormone concentration measurement, and biochemical, histopathological, TUNEL, immunohistochemical and glycolytic pathway analyses were conducted for each group. RESULTS: The α-KG treatment increased body mass and ovarian index of rats, partially normalized their disrupted estrous cycles, prevented follicular loss, restored ovarian reserve, and increased pregnancy rate and litter sizes of rats with POI. It significantly reduced serum concentration of FSH (P < 0.001), increased that of oestradiol (P<0.001) and reduced apoptosis of granulosa cells (P = 0.0003). Moreover, α-KG increased concentrations of lactate (P = 0.015) and ATP (P = 0.025), reduced that of pyruvate (P<0.001) and increased expression of rate-limiting enzymes of glycolysis in the ovary. CONCLUSIONS: α-KG treatment ameliorates the deleterious effects of CTX on the fertility of female rats, possibly by reducing the apoptosis of ovarian granulosa cells and restoring glycolysis.

Nicotinamide mononucleotide improves spermatogenic function in streptozotocin-induced diabetic mice via modulating the glycolysis pathway.

Spermatogenic dysfunction is one of the major secondary complications of diabetes; however, the underlying mechanisms remain ill-defined, and there is no available drug or strategy for the radical treatment of diabetic spermatogenic dysfunction. Therefore, the objective of this study is to investigate the protective effects of nicotinamide mononucleotide (NMN) on testicular spermatogenic function in streptozotocin (STZ)-induced diabetic mice. The results show that oral administration of NMN significantly increases the body and testis weight and the number of sperms. Moreover, the abnormal sperm count and the rate of sperm malformation are significantly decreased compared with the saline-treated diabetic mice. Histological analysis reveals that NMN treatment significantly increases the area and diameter of seminiferous tubules, accompanied by an increased number of spermatogenic cells and sperms. Immunohistochemistry and qRT-PCR results show that NMN increases Bcl-2 expression and decreases Bax expression in the testis. NMN also increases the protein expression of Vimentin and the mRNA expressions of WT1 and GATA4. In addition, qRT-PCR, western blot analysis and immunohistochemistry results also show that NMN increases the expressions of glycolysis-related rate-limiting enzymes including HK2, PKM2, and LDHA. In summary, this study demonstrates the protective effects of NMN on the testis in an STZ-induced diabetic mice model. NMN exerts its protective effects via reducing spermatogenic cell apoptosis by regulating glycolysis of Sertoli cells in diabetic mice. This study provides an experimental basis for the future clinical application of NMN in diabetes-induced spermatogenic dysfunction.

Clinical Significance and Correlation Decomposition of Cord Blood NO, Activin A Levels, and MCA/UA with Fetal Distress.

The clinical significance and correlation of cord blood NO, activin A levels, and middle cerebral artery (MCA)/umbilical artery (UA) with fetal distress are explored. 120 puerperae who delivered in the obstetrics department of our hospital from January 2021 to January 2022 are selected as the examination subjects. According to the diagnostic criteria of fetal distress, they are divided into 70 cases of fetal distress and 50 cases of normal delivery. The parameters of umbilical cord blood NO, activin A, UA, and MCA are contrast between the two sets, then the diagnostic value of umbilical cord blood NO and activin A combined with UA and MCA in fetal distress is analyzed. The experimental results show cord blood NO and activin A combined with UA and MCA have a high diagnostic value for fetal distress, and there is an extensive correlation with the occurrence of fetal distress, which provides a reliable clinical diagnosis of fetal distress in a timely manner.

Mogroside V Improves Follicular Development and Ovulation in Young-Adult PCOS Rats Induced by Letrozole and High-Fat Diet Through Promoting Glycolysis.

Polycystic ovary syndrome (PCOS) is a heterogeneous endocrine disorder characterized by hyperandrogenism, ovulatory dysfunction, and polycystic ovaries. In this study, we induced a young-adult PCOS rat model by oral administration of letrozole combined with a high-fat diet and then treated with mogroside V (MV) to evaluate the protective effects of MV on endocrine and follicle development in young-adult PCOS rats. MV (600 mg/kg/day) administration not only significantly reduced the body weight and ovary weight, but also attenuated the disrupted estrous cycle and decreased the level of testosterone. MV restored the follicular development, especially by increasing the number of corpus luteum and the thickness of the granular layer in young-adult POCS rats. Moreover, metabolomics showed that MV markedly increased the levels of D-Glucose 6-phosphate, lactate and GTP, while decreased the level of pyruvate. Bioinformatic analysis revealed that MV recovered multiple metabolism-related processes including gluconeogenesis, glycolysis and glucose metabolic process. Further real-time quantitative PCR analysis showed that MV upregulated the expression of lactate dehydrogenase A (Ldha), hexokinase 2 (Hk2) and pyruvate kinase M2 (Pkm2). Western blotting and immunohistochemistry analysis showed that MV restored the expression of lactate dehydrogenase A (Ldha), hexokinase 2 (Hk2) and pyruvate kinase M2 (Pkm2). Collectively, these findings indicated that MV could effectively improve the ovarian microenvironment by upregulating the expression of LDHA, HK2 and PKM2 in granulosa cells and enhancing lactate and energy production, which may contribute to follicle development and ovulation of young-adult PCOS rats.

Effect of spermidine on ameliorating spermatogenic disorders in diabetic mice via regulating glycolysis pathway.

Diabetes mellitus (DM), a high incidence metabolic disease, is related to the impairment of male spermatogenic function. Spermidine (SPM), one of the biogenic amines, was identified from human seminal plasma and believed to have multiple pharmacological functions. However, there exists little evidence that reported SPM's effects on moderating diabetic male spermatogenic function. Thus, the objective of this study was to investigate the SPM's protective effects on testicular spermatogenic function in streptozotocin (STZ)-induced type 1 diabetic mice. Therefore, 40 mature male C57BL/6 J mice were divided into four main groups: the control group (n = 10), the diabetic group (n = 10), the 2.5 mg/kg SPM-treated diabetic group (n = 10) and the 5 mg/kg SPM-treated diabetic group (n = 10), which was given intraperitoneally for 8 weeks. The type 1 diabetic mice model was established by a single intraperitoneal injection of STZ 120 mg/kg. The results showed that, compare to the control group, the body and testis weight, as well the number of sperm were decreased, while the rate of sperm malformation was significantly increased in STZ-induced diabetic mice. Then the testicular morphology was observed, which showed that seminiferous tubule of testis were arranged in mess, the area and diameter of which was decreased, along with downregulated anti-apoptotic factor (Bcl-2) expression, and upregulated pro-apoptotic factor (Bax) expression in the testes. Furthermore, testicular genetic expression levels of Sertoli cells (SCs) markers (WT1, GATA4 and Vimentin) detected that the pathological changes aggravated observably, such as the severity of tubule degeneration increased. Compared to the saline-treated DM mice, SPM treatment markedly improved testicular function, with an increment in the body and testis weight as well as sperm count. Pro-apoptotic factor (Bax) was down-regulated expression with the up-regulated expression of Bcl-2 and suppression of apoptosis in the testes. What's more, expression of WT1, GATA4, Vimentin and the expressions of glycolytic rate-limiting enzyme genes (HK2, PKM2, LDHA) in diabetic testes were also upregulated by SPM supplement. The evidence derived from this study indicated that the SMP's positive effect on moderating spermatogenic disorder in T1DM mice's testis. This positive effect is delivered via promoting spermatogenic cell proliferation and participating in the glycolytic pathway's activation.

Circ_0058058 Drives the Malignant Phenotypes and Immune Evasion of Pancreatic Cancer by the MicroRNA-557-Dependent Regulation of PDL1.

OBJECTIVES: Pancreatic cancer (PC) is one of the most deadly malignancies in the world. Recently, circular RNAs play crucial roles in PC progression. However, the functions of circ_0058058 in PC are barely known. METHODS: The expression of circ_0058058, microRNA-557-5p (miR-557), and programmed cell death receptor ligand 1 (PDL1) was detected by quantitative real-time polymerase chain reaction. Functional experiments were implemented to disclose the effect of circ_0058058 deficiency on PC cell proliferation, apoptosis, invasion, angiogenesis, and immune escape. The binding relationship between miR-557 and circ_0058058 or PDL1 was identified by dual-luciferase reporter assay and RNA immunoprecipitation assay. In vivo assay was used to disclose the impact of circ_0058058 silencing on tumor formation in vivo. RESULTS: Circ_0058058 was highly expressed in PC tissues and cell lines. Knockdown of circ_0058058 repressed cell proliferation, invasion, angiogenesis, and immune escape while contributed to apoptosis in PC cells. Mechanically, circ_0058058 worked as a molecular sponge of miR-557 to regulate PDL1 expression. Moreover, circ_0058058 showed a promotional effect on tumor growth in vivo. CONCLUSIONS: Our findings suggested that circ_0058058 served as miR-557 sponge to upregulate PDL1, thereby triggering PC proliferation, invasion, angiogenesis, and immune escape.

Phylogenetic analysis reveals the new genus Amoenoboletus from Asia and New Zealand.

The Asia-Pacific region is renowned to harbor nearly half of the global hot spots of biodiversity. Accordingly, many endemic species of boletes have already been recorded from this geographic region. However, the majority of the specific descriptions of reported boletoid species follow classical concepts of taxonomy, and by comparison only a few taxa have been corroborated by modern molecular techniques. In this study, we focused on specimens in a new clade uncovered by our previous studies. By careful reexamination of macroscopic and microscopic characters of Boletus granulopunctatus, originally described from Japan, and Xerocomus mcrobbii, originally described from New Zealand, we discovered a new genus and species Amoenoboletus miraculosus from Sabah, Malaysia. In addition, three new combinations in Amoenoboletus are proposed, and a dichotomous key to species in the genus is provided. The phylogenetically close relationship among Amoenoboletus species suggests a tight geographic correlation in the Asia-Pacific region.

Effect of Low-Frequency Electric Pulse Technique Combined with Carboprost Methylate Suppositories on Recovery of Gastrointestinal Function and Postoperative Complications of Patients with Scarred Uterus Undergoing Secondary Cesarean Section.

The study aims to explore the effect of low-frequency electric pulse technique combined with carboprost methylate suppositories on recovery of gastrointestinal function and postoperative complications of patients with scarred uterus undergoing secondary cesarean section (C-section). The clinical data of 120 patients with scarred uterus undergoing secondary C-section treated in our hospital from February 2019 to February 2020 were retrospectively analyzed, and the patients were equally divided into experimental and control groups according to their admission order, where each group included 60 patients. After the operation, patients in the control group received routine nursing and conducted breastfeeding, and carboprost methylate suppositories were used for postoperative hemostasis. Those in the experimental group received low-frequency electric pulse technique for comprehensive treatment to compare their coagulation function indicators, recovery of gastrointestinal function, incidence rates of postoperative complications, and involution of uterus. No significant between-group differences in patients' general information such as gestational weeks, gravidity, and number of times receiving C-section were observed (P > 0.05). Compared with the control group after the operation, patients in the experimental group obtained significantly better coagulation function indicators (P < 0.001) and presented better gastrointestinal function recovery (P < 0.001), significantly lower incidence rates of postpartum hemorrhage, retention of urine, deep venous thrombosis of lower limb, rupture of uterus, and endometrial cavity fluid (P < 0.05), and significantly better involution of uterus (P < 0.001). In conclusion, combining low-frequency electric pulse technique with carboprost methylate suppositories can lower the incidence rates of postoperative complications for patients with scarred uterus undergoing secondary C-section, improve their coagulation function, promote the recovery of gastrointestinal function, and present the desirable involution of uterus, which should be promoted in practice.

Four New Species of Hemileccinum (Xerocomoideae, Boletaceae) from Southwestern China.

The genus Hemileccinum belongs to the subfamily Xerocomoideae of the family Boletaceae. In this study, phylogenetic inferences of Hemileccinum based on sequences of a single-locus (ITS) and a multi-locus (nrLSU, tef1-α, rpb1, rpb2) were conducted. Four new species, namely H. abidum, H. brevisporum, H. ferrugineipes and H. parvum were delimited and proposed based on morphological and molecular evidence. Descriptions and line-drawings of them were presented, as well as their comparisons to allied taxa. Our study shed new light on the recognition of the genus. The pileipellis of the species in this genus should mostly be regarded as (sub)epithelium to hyphoepithelium, because the pileipellis of most studied species here is composed of short inflated cells in the inner layer (subpellis) and filamentous hyphae in outer layer (suprapellis). The basidiospores of the studied species, including the type species, H. impolitum, have a warty surface.

Resveratrol Improves Follicular Development of PCOS Rats by Regulating the Glycolytic Pathway.

SCOPE: Polycystic ovary syndrome (PCOS) is a common endocrine and metabolic disorder that can cause infertility; however, the underlying mechanisms remain ill-defined, and there are no available drugs or strategies for the treatment of PCOS. This study examined the therapeutic effect of resveratrol in a rat model of PCOS. METHODS AND RESULTS: PCOS is induced in rats by administration of letrozole and a high fat diet to determine whether resveratrol has a protective effect. Oral administration of resveratrol significantly decreased body weight, as well as the serum levels of testosterone and follicle stimulating hormone. Resveratrol improved the estrous cycle by restoring the thickness and number of granular cells. Resveratrol increased the levels of lactate and ATP, decreased pyruvate levels, and restored the glycolytic process, upregulating LDHA, HK2, and PKM2. Resveratrol also upregulated SIRT2, thereby modulating the expression of rate-limiting enzymes of glycolysis. CONCLUSION: Resveratrol suppressed damage to the ovaries in PCOS rats by restoring glycolytic activity, providing potential targets for the treatment of PCOS.

MiR-1207-5p targets PYCR1 to inhibit the progression of prostate cancer.

Prostate cancer, the most common non-cutaneous male cancer, is a public health problem with a third prevalence worldwide. PYCR1 and miR-1207-5p dysregulations were found in cancer progression. Our study aims to reveal the biological role of miR-1207-5p-PYCR1 axis in prostate cancer progression. First, we investigated the expression of miR-1207-5p in prostate cancer tissues and cell lines by RT-qPCR. Next, we confirmed miR-1207-5p targeting PYCR1 by luciferase assay. CCK-8 assay, BrdU assay, flow cytometry, and tanswell assay were applied for examining cell proliferation, apoptosis, and invasion in prostate cancer cells, respectively. In the present study, decreased miR-1207-5p expression was obviously observed in prostate cancer tissues and cells. Upregulation of miR-1207-5p hampered cellular proliferation and invasion, while enhanced cellular apoptosis. In addition, upregulation of PYCR1 elevated cell proliferation and invasion, but repressed apoptosis of prostate cancer cells. Moreover, miR-1207-5p inhibited the expression of PYCR1 to repress prostate cancer tumorigenesis. MiR-1207-5p inhibited the expression of PYCR1 to repress the progression of prostate cancer by inhibiting cell growth and elevating cell apoptosis. Overall, our study clarifies the biological role of miR-1207-5p-PYCR1 axis in prostate cancer progression, which might be effective biomarkers for clinical treatment of prostate cancer.

Six1 Promotes Epithelial-Mesenchymal Transition in Bronchial Epithelial Cells via the TGFß1/Smad Signalling Pathway.

INTRODUCTION: The homeodomain transcription factor sine oculis homeobox homolog 1 (Six1) plays a crucial role in embryogenesis and is not expressed in normal adult tissue but is expressed in many pathological processes, including airway remodelling in asthma. The current study aimed to reveal the effects of Six1 in regulating the airway remodelling and its possible mechanism. METHODS: A mouse model of ovalbumin-induced asthma-associated airway wall remodelling and a bronchial epithelial cell (16HBE) model of transforming growth factor ß1 (TGFß1)-induced epithelial-mesenchymal transition (EMT) were used to investigate the role of Six1. Then, 16HBE cells were transformed with Six1 expression vectors and treated with a TGFß1 pathway inhibitor to determine the role of Six1 in EMT. The effect of Six1 and its possible mechanism were assessed by immunohistochemistry, RT-PCR, and Western blot. RESULTS: Six1 expression was elevated in the lungs in an OVA mouse model of allergic asthma and in 16HBE cells treated with TGFß1. Six1 overexpression promoted an EMT-like phenotype with a decreased protein expression of E-cadherin and increased protein expression of α-smooth muscle actin (α-SMA) as well as fibronectin in 16HBE cells; these effects appeared to promote TGFß1 and phospho-Smad2 (pSmad2) production, which are the main products of the TGFß1/Smad signalling pathway, which could be reduced by a TGFß1 inhibitor. CONCLUSION: These data reveal that Six1 and TGFß1 are potentially a part of an autocrine feedback loop that induces EMT, and these factors can be reduced by blocking the TGFß1/Smad signalling pathway. As such, these factors may represent a promising novel therapeutic target for airway remodelling in asthma.

FGFR-TKI resistance in cancer: current status and perspectives.

Fibroblast growth factor receptors (FGFRs) play key roles in promoting the proliferation, differentiation, and migration of cancer cell. Inactivation of FGFRs by tyrosine kinase inhibitors (TKI) has achieved great success in tumor-targeted therapy. However, resistance to FGFR-TKI has become a concern. Here, we review the mechanisms of FGFR-TKI resistance in cancer, including gatekeeper mutations, alternative signaling pathway activation, lysosome-mediated TKI sequestration, and gene fusion. In addition, we summarize strategies to overcome resistance, including developing covalent inhibitors, developing dual-target inhibitors, adopting combination therapy, and targeting lysosomes, which will facilitate the transition to precision medicine and individualized treatment.

Overexpression of CENPF is associated with progression and poor prognosis of lung adenocarcinoma.

Background and aim: The molecular signatures of lung adenocarcinoma (LUAD) are not well understood. Centromere protein F (CENPF) has been shown to promote oncogenesis in many cancers; however, its role in LUAD has not been illustrated. We explored the role of CENPF in LUAD. Methods: CENPF expression level was investigated in public online database firstly, the prognosis of CENPF in LUAD were also assessed by Kaplan-Meier analysis. Then quantitative reverse transcription-polymerase chain reaction (qRT-PCR) was performed using 13 matched pairs of clinical LUAD tissue samples. Subsequently, the impact of CENPF expression on cell proliferation, cell cycle, apoptosis, colony formation was investigated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT), flow cytometric analysis and colony formation assay, respectively. Finally, experimental xenograft lung cancer model of nude mice armpit of right forelimb to determine the effect of CENPF on LUAD tumorigenesis. Results: CENPF mRNA expression was significantly elevated in LUAD tissues compared with adjacent non-tumor lung tissues in Gene Expression Profiling Interactive Analysis (GEPIA) (P < 0.001). Up-regulated CENPF was remarkably positively associated with pathological stage, relapse free survival (RFS) as well as overall survival (OS) of LUAD patients. Besides, CENPF knockdown greatly suppressed A549 cell proliferation, induced S phase arrest, promoted apoptosis and decreased colony numbers of LUAD cells. Furthermore, knockdown of CENPF significantly inhibited the tumor growth of the LUAD cells in an experimental xenograft lung cancer model of nude mice armpit of right forelimb. Conclusion: Taken together, these results demonstrated that CENPF may serve as a potential biomarker of prognostic relevance and a potential therapeutic target for LUAD.

BDNF and nicotine dependence: associations and potential mechanisms.

Smoking is the leading preventable cause of death worldwide and tobacco addiction has become a serious public health problem. Nicotine is the main addictive component of tobacco, and the majority of people that smoke regularly develop nicotine dependence. Nicotine addiction is deemed to be a chronic mental disorder. Although it is well known that nicotine binds to the nicotinic acetylcholine receptors (nAChRs) and activates the mesolimbic dopaminergic system (MDS) to generate the pleasant and rewarding effects, the molecular mechanisms of nicotine addiction are not fully understood. Brain-derived neurotrophic factor (BDNF) is the most prevalent growth factor in the brain, which regulates neuron survival, differentiation, and synaptic plasticity, mainly through binding to the high affinity receptor tyrosine kinase receptor B (TrkB). BDNF gene polymorphisms are associated with nicotine dependence and blood BDNF levels are altered in smokers. In this review, we discussed the effects of nicotine on BDNF expression in the brain and summarized the underlying signaling pathways, which further indicated BDNF as a key regulator in nicotine dependence. Further studies that aim to understand the neurobiological mechanism of BDNF in nicotine addcition would provide a valuable reference for quitting smoking and developing the treatment of other addictive substances.

Durable benefit from immunotherapy and accompanied lupus erythematosus in pancreatic adenocarcinoma with DNA repair deficiency.

BACKGROUND: Clinical trials showed limited benefit of anti-PD-1 (programmed cell death 1) monotherapy in pancreatic adenocarcinoma patients and immune-related adverse events caused by immune checkpoint inhibitors were rarely reported in pancreatic adenocarcinoma. Here, we report the first case of durable benefit along with systemic lupus erythematosus following immunotherapy in mismatch repair-proficient pancreatic cancer. CASE PRESENTATION: We describe a 57-year-old woman with resected stage ⅢB pancreatic cancer who underwent several lines of conventional chemotherapy after multiple lymph node metastases. When the disease progressed again, the patient received an off-label treatment with pembrolizumab (100 mg every 3 weeks). After four cycles of immunotherapy treatment, CA19-9 level rapidly decreased to normal and the lymph node metastases reduced dramatically in volume, demonstrating a partial response to the therapy by RECIST 1.1 criteria. She continued on pembrolizumab and a total of eight cycles of administration she had received. Her lesions showed consistent reduction in size even when the medication had been stopped. Actually the patient experienced durable benefit from anti-PD-1 therapy for more than 4 years and she is still in good condition without tumor relapses to date. Besides, she was diagnosed with systemic lupus erythematosus 2 months after the last dose of pembrolizumab. Molecular profiling identified two deleterious PALB2 alterations including a germline mutation (PALB2 c.3114-1G>A) and a somatic mutation (PALB2 c.2514+1G>C) in this patient, suggesting the potential of DNA homologous recombination deficiency. Multiplex immunohistochemistry and RNA-seq results revealed a brisk immune cell infiltration in her resected primary lesion. Additionally, humanleukocyte antigen (HLA) typing assay identified two previously reported systemic lupus erythematosus risk alleles HLA-DRB1*15:01 and HLA-DQB1*06:02 in this patient. CONCLUSIONS: The deleterious mutations of PALB2 closely related to homologous recombination deficiency or alterations of DNA damage response and repair genes might be promising biomarkers for predicting efficacy of immune checkpoint inhibitors in pancreatic adenocarcinoma. Genetic correlation behind immunotherapy-induced systemic lupus erythematosus and associated mechanism remain to be elucidated.

Role of GRK4 in the regulation of the renal ETB receptor in hypertension.

The endothelin receptor type B (ETBR) regulates water and electrolyte balance and blood pressure, in part, by inhibiting renal sodium transport. Our preliminary study found that the ETBR-mediated diuresis and natriuresis are impaired in hypertension with unknown mechanism. Persistently increased activity of G protein-coupled receptor kinase 4 (GRK4), caused by increased expression or genetic variants (eg, GRKγ142V), impairs the ability of the kidney to excrete a sodium load, in part, by impairing renal dopamine D1 receptor function through persistent phosphorylation. Our present study found that although renal ETBR expression was not different between Wistar-Kyoto (WKY) and spontaneously hypertensive rats (SHRs), renal ETBR phosphorylation was higher in SHRs. The role of hyper-phosphorylation in impaired ETBR-function was supported by results in human (h) GRK4γ transgenic mice. Stimulation of ETBR by BQ3020-induced natriuresis in human (h) GRK4γ wild-type (WT) mice. However, in hGRK4γ 142V transgenic mice, the renal ETBR was hyperphosphorylated and ETBR-mediated natriuresis and diuresis were not evident. There were co-localization and co-immunoprecipitation of ETBR and GRK4 in renal proximal tubule (RPT) cells from both WKY and SHRs but was greater in the latter than the former group. SiRNA-mediated downregulation of GRK4 expression, recovered the impaired inhibitory effect of ETBR on Na+ -K+ -ATPase activity in RPT cells from SHR. In vivo downregulation of renal GRK4 expression, via ultrasound-targeted microbubble destruction, decreased ETBR phosphorylation and restored ETBR-mediated natriuresis and diuresis in SHRs. This study provides a mechanism by which GRK4, via regulation of renal ETBR function, participates in the pathogenesis of hypertension.