Retinoic acid mitigates the NSC319726-induced spermatogenesis dysfunction through cuproptosis-independent mechanisms.

Copper ionophore NSC319726 has attracted researchers' attention in treating diseases, particularly cancers. However, its potential effects on male reproduction during medication are unclear. This study aimed to determine whether NSC319726 exposure affected the male reproductive system. The reproductive toxicity of NSC319726 was evaluated in male mice following a continuous exposure period of 5 weeks. The result showed that NSC319726 exposure caused testis index reduction, spermatogenesis dysfunction, and architectural damage in the testis and epididymis. The exposure interfered with spermatogonia proliferation, meiosis initiation, sperm count, and sperm morphology. The exposure also disturbed androgen synthesis and blood testis barrier integrity. NSC319726 treatment could elevate the copper ions in the testis to induce cuproptosis in the testis. Copper chelator rescued the elevated copper ions in the testis and partly restored the spermatogenesis dysfunction caused by NSC319726. NSC319726 treatment also decreased the level of retinol dehydrogenase 10 (RDH10), thereby inhibiting the conversion of retinol to retinoic acid, causing the inability to initiate meiosis. Retinoic acid treatment could rescue the meiotic initiation and spermatogenesis while not affecting the intracellular copper ion levels. The study provided an insight into the bio-safety of NSC319726. Retinoic acid could be a potential therapy for spermatogenesis impairment in patients undergoing treatment with NSC319726.

TP53INP2 knockdown inhibits inflammatory response and apoptosis after spinal cord injury.

BACKGROUND: Spinal cord injury (SCI) is a traumatic neurological disorder with limited therapeutic options. Tumor protein p53-inducible nuclear protein 2 (TP53INP2) is involved in the occurrence and development of various diseases, and it may play a role during SCI via affecting inflammation and neuronal apoptosis. This study investigated the associated roles and mechanisms of TP53INP2 in SCI. METHODS: Mouse and lipopolysaccharide (LPS)-induced SCI BV-2 cell models were constructed to explore the role of TP53INP2 in SCI and the associated mechanisms. Histopathological evaluation of spinal cord tissue was detected by hematoxylin and eosin staining. The Basso, Beattie, and Bresnahan score was used to measure the motor function of the mice, while the spinal cord water content was used to assess spinal cord edema. The expression of TP53INP2 was measured using RT-qPCR. In addition, inflammatory factors in the spinal cord tissue of SCI mice and LPS-treated BV-2 cells were measured using enzyme-linked immunosorbent assay. Apoptosis and related protein expression levels were detected by flow cytometry and western blot analysis, respectively. RESULTS: TP53INP2 levels increased in SCI mice and LPS-treated BV-2 cells. The results of in vivo and in vitro experiments showed that TP53INP2 knockdown inhibited the inflammatory response and neuronal apoptosis in mouse spinal cord tissue or LPS-induced BV-2 cells. CONCLUSIONS: After spinal cord injury, TP53INP2 was upregulated, and TP53INP2 knockdown inhibited the inflammatory response and apoptosis.

GALNT2 targeted by miR-139-5p promotes proliferation of clear cell renal cell carcinoma via inhibition of LATS2 activation.

Polypeptide N-Acetylgalactosaminyltransferase (GALNTs) are critical enzymes that initiate mucin type-O glycosylation, and are closely associated with the occurrence and development of multiple cancers. However, the significance of GALNT2 in clear cell renal cell carcinoma (ccRCC) progression remains largely undetermined. Based on public multi-omics analysis, GALNT2 was strongly elevated in ccRCC versus adjoining nontumor tissues, and it displayed a relationship with poor overall survival (OS) of ccRCC patients. In addition, GALNT2 over-expression accelerated proliferation of renal cancer cell (RCC) lines. In contrast, GALNT2 knockdown using shRNAs suppressed cell proliferation, and this was rescued by LATS2 knockdown. Similarly, GALNT2 deficiency enhanced p-LATS2/LATS2 expression. LATS2 is activated by phosphorylation (p-LATS2) and, in turn, phosphorylate the downstream substrate protein YAP. Phosphorylated YAP (p-YAP) stimulated its degradation and cytoplasmic retention, as it was unable to translocate to the nucleus. This resulted in reduced cell proliferation. Subsequently, we explored the upstream miRNAs of GALNT2. Using dual luciferase reporter assay, we revealed that miR-139-5p interacted with the 3' UTR of GALNT2. Low miR-139-5p expression was associated with worse ccRCC patient outcome. Based on our experiments, miR-139-5p overexpression inhibited RCC proliferation, and this phenotype was rescued by GALNT2 overexpression. Given these evidences, the miR-139-5p-GALNT2-LATS2 axis is critical for RCC proliferation, and it is an excellent candidate for a new therapeutic target in ccRCC.

pH/ROS dual stimuli-responsive anionic flexible supramolecular organic frameworks for synergistic therapy.

Supramolecular organic frameworks (SOFs) have emerged as a promising class of organic porous materials with vast potential as nanocarriers for combination therapy. Here, we successfully construct an anionic flexible supramolecular organic framework (TPP-SOF) by leveraging multiple host-guest interactions. TPP-SOF is fabricated by the hierarchical orthogonal assembly between anionic water-soluble dimacrocyclic host (P5CD), porphyrin photosensitizers (TPP), and ROS-sensitive thioketal linked adamantane dimer (Ada-S-Ada). TPP-SOF exhibits pH-dependent activation of 1O2 production, which further facilitates the cleavage of Ada-S-Ada linker and promotes the disintegration of the framework. Moreover, leveraging electrostatic and hydrophobic interactions, the anionic TPP-SOF serves as an effective platform for loading cationic photosensitizer IR780 and chemotherapeutic prodrug PhenPt(IV), leading to the formation of supramolecular nanoparticles (IR780/Pt@TPP-SOF) for synergistic therapy. The obtained nanoparticles exhibit good stability, efficient generation of 1O2, and photothermal performance. In vitro and in vivo studies indicate that IR780/Pt@TPP-SOF exhibits remarkable synergistic chemo/PDT/PTT effects under 808 and 660 nm light irradiation. This study showcases a deep insight for the development of SOFs and a new approach for delivering cationic drugs and constructing synergistic combination therapy systems. STATEMENT OF SIGNIFICANCE: In this work, a pH/ROS-responsive anionic flexible supramolecular organic framework, TPP-SOF, was innovatively designed by the hierarchical orthogonal assembly, to co-deliver cationic photosensitizer IR780 and prodrug PhenPt(IV) for synergistic cancer therapy. The drug-loaded TPP-SOF is termed IR780/Pt@TPP-SOF, in which the photoactivity of porphyrin within TPP-SOF could be activated under acidic conditions, the 1O2 generated by the photosensitizers could break the thioketal bonds in Ada-S-Ada, leading to the disassembly of the framework and releasing the drugs. This supramolecular drug delivery system displays good biocompatibility and exhibits remarkable synergistic chemo/PDT/PTT effects.

Eucommiae cortex polysaccharides attenuate gut microbiota dysbiosis and neuroinflammation in mice exposed to chronic unpredictable mild stress: Beneficial in ameliorating depressive-like behaviors.

BACKGROUND: Chronic stress alters gut microbiota composition, as well as induces inflammatory responses and behavioral deficits. Eucommiae cortex polysaccharides (EPs) have been reported to remodel gut microbiota and ameliorate obesogenic diet-induced systemic low-grade inflammation, but their role in stress-induced behavioral and physiological changes is poorly understood. METHODS: Male Institute of Cancer Research (ICR) mice were exposed to chronic unpredictable stress (CUMS) for 4 weeks and then supplemented with EPs at a dose of 400 mg/kg once per day for 2 weeks. Behavioral test-specific antidepressant and anxiolytic effects of EPs were assessed in FST, TST, EPM, and OFT. Microbiota composition and inflammation were detected using 16S ribosomal RNA (rRNA) gene sequencing, quantitative RT-PCR, western blot, and immunofluorescence. RESULTS: We found that EPs ameliorated gut dysbiosis caused by CUMS, as evidenced by increasing the abundance of Lactobacillaceae and suppressing the expansion of the Proteobacteria, thereby mitigating intestinal inflammation and barrier derangement. Importantly, EPs reduced the release of bacterial-derived lipopolysaccharides (LPS, endotoxin) and inhibited the microglia-mediated TLR4/NFκB/MAPK signaling pathway, thereby attenuating the pro-inflammatory response in the hippocampus. These contributed to restoring the rhythm of hippocampal neurogenesis and alleviating behavioral abnormalities in CUMS mice. Correlation analysis showed that the perturbed-gut microbiota was strongly correlated with behavioral abnormalities and neuroinflammation. LIMITATIONS: This study did not clarify the causal relationship between EPs remodeling the gut microbiota and improved behavior in CUMS mice. CONCLUSIONS: EPs exert ameliorative effects on CUMS-induced neuroinflammation and depression-like symptoms, which may be strongly related to their beneficial effects on gut microbial composition.

Dysregulation of Notch-FGF signaling axis in germ cells results in cystic dilation of the rete testis in mice.

Numb (Nb) and Numb-like (Nbl) are functionally redundant adaptor proteins that critically regulate cell fate and morphogenesis in a variety of organs. We selectively deleted Nb and Nbl in testicular germ cells by breeding Nb/Nbl floxed mice with a transgenic mouse line Tex101-Cre. The mutant mice developed unilateral or bilateral cystic dilation in the rete testis (RT). Dye trace indicated partial blockages in the testicular hilum. Morphological and immunohistochemical evaluations revealed that the lining epithelium of the cysts possessed similar characteristics of RT epithelium, suggesting that the cyst originated from dilation of the RT lumen. Spermatogenesis and the efferent ducts were unaffected. In comparisons of isolated germ cells from mutants to control mice, the Notch activity considerably increased and the expression of Notch target gene Hey1 significantly elevated. Further studies identified that germ cell Fgf4 expression negatively correlated the Notch activity and demonstrated that blockade of FGF receptors mediated FGF4 signaling induced enlargement of the RT lumen in vitro. The crucial role of the FGF4 signaling in modulation of RT development was verified by the selective germ cell Fgf4 ablation, which displayed a phenotype similar to that of germ cell Nb/Nbl null mutant males. These findings indicate that aberrant over-activation of the Notch signaling in germ cells due to Nb/Nbl abrogation impairs the RT development, which is through the suppressing germ cell Fgf4 expression. The present study uncovers the presence of a lumicrine signal pathway in which secreted/diffusible protein FGF4 produced by germ cells is essential for normal RT development.

The role of long non-coding RNAs and downstream signaling pathways in leukemia progression.

The study of long non-coding RNAs (lncRNA) is a newly established field and our knowledge about them is rapidly growing. These kinds of RNAs are unchanged parts of the genome throughout evolution, that modulate cell growth, differentiation, and apoptosis during diverse physiological and pathological processes including leukemia development. They have the capability to be useful biomarkers for the diagnosis, clinical typing, prognosis, as well as potential therapeutic targets. In this study, we summarized the role of lncRNAs in the expression and function of white blood cells and oncogenic transformation into four main types of leukemia.

Erratum: MiR-4295 promotes cell growth in bladder cancer by targeting BTG1.

[This corrects the article on p. 4892 in vol. 8, PMID: 27904689.].

WITHDRAWN: MiR-6838 Promotes Growth and Invasion in Bladder Cancer Via Suppression of Rb.

Ahead of Print article withdrawn by publisher..

Effectiveness and safety of unilateral pedicle screw fixation in transforaminal lumbar interbody fusion (TLIF): a systematic review and meta-analysis.

PURPOSE: To evaluate the effectiveness and safety of unilateral pedicle screw fixation in transforaminal lumbar interbody fusion (TLIF) by comparing with bilateral pedicle screw fixation. MATERIALS AND METHODS: PubMed, EMBASE, and the Cochrane Central Register of Controlled Trial database were used to search and identify clinical prospective trials that evaluated the efficacy and safety of unilateral fixation as compared with bilateral fixation in TLIF surgery. The methodological qualities of studies were assessed using the PEDro (Physiotherapy Evidence Database) score and Newcastle-Ottawa Scale. RESULTS: Fourteen prospective studies comprising 954 participants were analyzed. Data synthesis show lower fusion rate (P = 0.03) and more cage migration (P = 0.04) in unilateral group compared to bilateral group. There was no significant difference in visual analog scale (VAS), Oswestry Disability Index (ODI), the Short Form 36 Health Survey (SF-36) physical component score (PCS), and length of hospital stay between unilateral and bilateral groups. The unilateral group had shorter operative time (P < 0.00001) and less blood loss (P = 0.0007). CONCLUSIONS: Based on this systematic review and meta-analysis, the unilateral fixation in TLIF may achieve a similar clinical outcome and reduce blood loss and operative time when compared with that in bilateral fixation. However, the unilateral fixation may produce lower fusion rate and more cage migration than bilateral fixation in TLIF.

MiR-4295 promotes cell growth in bladder cancer by targeting BTG1.

microRNAs (miRNAs) have been demonstrated to contribute to tumor progression and metastasis, and have been proposed to be key regulators of diverse biological processes. In this study, we report that miR-4295 is deregulated in bladder cancer tissues and cell lines. To characterize the role of miR-4295 in bladder cancer cells, we performed functional assays. The overexpression of miR-4295 significantly promoted bladder cancer cell proliferation, colony formation, and migration. Moreover, its downregulation induced cell cycle arrest and apoptosis of bladder cancer cells. Furthermore, a luciferase reporter assay and rescue experiment indicated that miR-4295 directly targets BTG1 by binding its 3'UTR. In conclusion, these results demonstrate that miR-4295 acts as an oncogene and may be a potential biomarker for bladder cancer diagnosis and treatment.

[Bilateral ureteral polyps in children: a case report].

Fibroepithelial polyp of the ureter is a benign tumor of mesodermal origin that rarely occurs in children. The most common presenting symptoms are hematuria and flank pain by obstruction of the urinary tract. The etiology of this tumor is still not clear. It occurs more frequently in boys and often arises in the proximal ureter and the ureteropelvic junction. The preoperative diagnosis is difficult. We present here the case of a 11-year-old boy who had fibroepithelial polyps as the cause of the left flank ureteropelvic junction obstruction at pyeloplasty, and had the same condition on the right flank 5 years ago. We used polypectomy and pyeloureterostomy to treat the boy. No major intraoperative or preoperative complications developed.