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The Journal of Clinical Investigation Apr 2024The adoptive transfer of T cell receptor-engineered (TCR-engineered) T cells (ACT) targeting the HLA-A2-restricted cancer-testis epitope NY-ESO-1157-165 (A2/NY) has...
The adoptive transfer of T cell receptor-engineered (TCR-engineered) T cells (ACT) targeting the HLA-A2-restricted cancer-testis epitope NY-ESO-1157-165 (A2/NY) has yielded favorable clinical responses against several cancers. Two approaches to improve ACT are TCR affinity optimization and T cell coengineering to express immunomodulatory molecules that can exploit endogenous immunity. By computational design we previously developed a panel of binding-enhanced A2/NY-TCRs including A97L, which augmented the in vitro function of gene-modified T cells as compared with WT. Here, we demonstrated higher persistence and improved tumor control by A97L-T cells. In order to harness macrophages in tumors, we further coengineered A97L-T cells to secrete a high-affinity signal regulatory protein α (SiRPα) decoy (CV1) that blocks CD47. While CV1-Fc-coengineered A97L-T cells mediated significantly better control of tumor outgrowth and survival in Winn assays, in subcutaneous xenograft models the T cells, coated by CV1-Fc, were depleted. Importantly, there was no phagocytosis of CV1 monomer-coengineered T cells by human macrophages. Moreover, avelumab and cetuximab enhanced macrophage-mediated phagocytosis of tumor cells in vitro in the presence of CV1 and improved tumor control upon coadministration with A97L-T cells. Taken together, our study indicates important clinical promise for harnessing macrophages by combining CV1-coengineered TCR-T cells with targeted antibodies to direct phagocytosis against tumor cells.
Topics: Animals; Humans; Mice; Antigens, Differentiation; Antigens, Neoplasm; CD47 Antigen; Cell Line, Tumor; HLA-A2 Antigen; Immunotherapy, Adoptive; Macrophages; Phagocytosis; Receptors, Antigen, T-Cell; Receptors, Immunologic; T-Lymphocytes; Xenograft Model Antitumor Assays; Male; Female
PubMed: 38828721
DOI: 10.1172/JCI161660 -
Archives of Razi Institute Dec 2023Cloves possess antimicrobial and antioxidant activities, among other roles, they can play. This study investigated the effect of clove oil (CLO) on testicular and...
Cloves possess antimicrobial and antioxidant activities, among other roles, they can play. This study investigated the effect of clove oil (CLO) on testicular and epididymal changes induced by cadmium chloride (CdCl). A total of 25 rats were randomly assigned to five groups of five rats. Group A was allowed feed and water . Group B was given 20mg/kg of CdCl, group C was given 20mg/kg of CdCl and 10mg/kg of CLO, group D was given 20mg/kg of CdCl and 20mg/kg of CLO, and group E was given 20mg/kg of CdCl and 20mg/kg of Di Methyl Sulphur Oxide. After the experiment, the animals were sacrificed by cervical dislocation after 24 hours of fasting. The testes and epididymis were harvested, while the right epididymis was homogenized for sperm analysis. The results revealed a significant decrease in progressive motility in group B, while a significant increase was observed in CLO-treated groups (P<0.05). In addition, group B showed a significant reduction in percentage progressive, an increase in percentage non-motile, and a decrease in sperm count. The histological studies showed that the control group displayed normal testicular and epididymal histo-architecture, while the Cadmium group (B) showed a progressive degeneration of the cells and tissues, alleviated by the high dose of CLO in both the testes and epididymis. In conclusion, the current research demonstrated that testicular and epididymal damage induced by Cadmium could decrease fertility, and CLO may be used in alleviating the deleterious effects of CdCl.
Topics: Animals; Male; Epididymis; Rats; Testis; Rats, Wistar; Clove Oil; Cadmium Chloride; Dimethyl Sulfoxide; Random Allocation; Cadmium
PubMed: 38828169
DOI: 10.32592/ARI.2023.78.6.1728 -
Scientific Reports May 2024Testicular torsion carries the ominous prospect of inducing acute scrotal distress and the perilous consequence of testicular atrophy, necessitating immediate surgical...
Testicular torsion carries the ominous prospect of inducing acute scrotal distress and the perilous consequence of testicular atrophy, necessitating immediate surgical intervention to reinstate vital testicular perfusion, notwithstanding the paradoxical detrimental impact of reperfusion. Although no drugs have secured approval for this urgent circumstance, antioxidants emerge as promising candidates. This study aspires to illustrate the influence of eprosartan, an AT1R antagonist, on testicular torsion in rats. Wistar albino rats were meticulously separated into five groups, (n = 6): sham group, eprosartan group, testicular torsion-detorsion (T/D) group, and two groups of T/D treated with two oral doses of eprosartan (30 or 60 mg/kg). Serum testosterone, sperm analysis and histopathological examination were done to evaluate spermatogenesis. Oxidative stress markers were assessed. Bax, BCL-2, SIRT1, Nrf2, HO-1 besides cleaved caspase-3 testicular contents were estimated using ELISA or qRT-PCR. As autophagy markers, SQSTM-1/p62, Beclin-1, mTOR and AMPK were investigated. Our findings highlight that eprosartan effectively improved serum testosterone levels, testicular weight, and sperm count/motility/viability, while mitigating histological irregularities and sperm abnormalities induced by T/D. This recovery in testicular function was underpinned by the activation of the cytoprotective SIRT1/Nrf2/HO-1 axis, which curtailed testicular oxidative stress, indicated by lowering the MDA content and increasing GSH content. In terms of apoptosis, eprosartan effectively countered apoptotic processes by decreasing cleaved caspase-3 content, suppressing Bax and stimulating Bcl-2 gene expression. Simultaneously, it reactivated impaired autophagy by increasing Beclin-1 expression, decreasing the expression of SQSTM-1/p62 and modulate the phosphorylation of AMPK and mTOR proteins. Eprosartan hold promise for managing testicular dysfunction arising from testicular torsion exerting antioxidant, pro-autophagic and anti-apoptotic effect via the activation of SIRT1/Nrf2/HO-1 as well as Beclin-1/AMPK/mTOR pathways.
Topics: Male; Animals; Sirtuin 1; Thiophenes; Rats; TOR Serine-Threonine Kinases; Autophagy; NF-E2-Related Factor 2; Testis; Beclin-1; Rats, Wistar; Imidazoles; Spermatic Cord Torsion; Acrylates; Signal Transduction; Oxidative Stress; Heme Oxygenase (Decyclizing); AMP-Activated Protein Kinases; Spermatogenesis; Apoptosis; Testosterone; Antioxidants
PubMed: 38822026
DOI: 10.1038/s41598-024-62740-6 -
Frontiers in Endocrinology 2024It is well known that metabolic disorders, including type 1 diabetes (T1D), are often associated with reduced male fertility, mainly increasing oxidative stress and...
BACKGROUND
It is well known that metabolic disorders, including type 1 diabetes (T1D), are often associated with reduced male fertility, mainly increasing oxidative stress and impairing the hypothalamus-pituitary-testis (HPT) axis, with consequently altered spermatogenesis and reduced sperm parameters. Herein, using a rat model of T1D obtained by treatment with streptozotocin (STZ), we analyzed several parameters of testicular activity.
METHODS
A total of 10 adult male Wistar rats were divided into two groups of five: control and T1D, obtained with a single intraperitoneal injection of STZ. After 3 months, the rats were anesthetized and sacrificed; one testis was stored at -80°C for biochemical analysis, and the other was fixed for histological and immunofluorescence analysis.
RESULTS
The data confirmed that T1D induced oxidative stress and, consequently, alterations in both testicular somatic and germ cells. This aspect was highlighted by enhanced apoptosis, altered steroidogenesis and Leydig cell maturity, and impaired spermatogenesis. In addition, the blood-testis barrier integrity was compromised, as shown by the reduced levels of structural proteins (N-cadherin, ZO-1, occludin, connexin 43, and VANGL2) and the phosphorylation status of regulative kinases (Src and FAK). Mechanistically, the dysregulation of the SIRT1/NRF2/MAPKs signaling pathways was proven, particularly the reduced nuclear translocation of NRF2, affecting its ability to induce the transcription of genes encoding for antioxidant enzymes. Finally, the stimulation of testicular inflammation and pyroptosis was also confirmed, as highlighted by the increased levels of some markers, such as NF-κB and NLRP3.
CONCLUSION
The combined data allowed us to confirm that T1D has detrimental effects on rat testicular activity. Moreover, a better comprehension of the molecular mechanisms underlying the association between metabolic disorders and male fertility could help to identify novel targets to prevent and treat fertility disorders related to T1D.
Topics: Animals; Male; Oxidative Stress; Rats; NF-E2-Related Factor 2; Rats, Wistar; NLR Family, Pyrin Domain-Containing 3 Protein; Testis; Diabetes Mellitus, Type 1; Diabetes Mellitus, Experimental; Spermatogenesis; Signal Transduction; Germ Cells; Spermatozoa
PubMed: 38818504
DOI: 10.3389/fendo.2024.1399256 -
Frontiers in Pharmacology 2024Testicular torsion is a critical urologic condition for which testicular detorsion surgery is considered irreplaceable as well as the golden method of reversal. However,...
Testicular torsion is a critical urologic condition for which testicular detorsion surgery is considered irreplaceable as well as the golden method of reversal. However, the surgical treatment is equivalent to a blood reperfusion process, and no specific drugs are available to treat blood reperfusion injuries. Salidroside (SAL) is one of the main effective substances in rhodiola, which has been shown to have antioxidant and antiapoptosis activities. This study was designed to determine whether SAL exerted a protective effect on testicular ischemia-reperfusion (I/R) injury. In this study, the I/R injury model of the testes and reoxygenation (OGD/R) model were used for verification, and SAL was administered at doses of 100 mg/kg and 0.05 mmol/L, respectively. After the experiments, the testicular tissue and TM4 Sertoli cells were collected for histopathologic and biochemical analyses. The results revealed that SAL improves the structure of testicular tissue and regulates the oxidation-antioxidation system. To further understand the molecular mechanisms of SAL in treating testicular I/R injuries, transcriptomics and metabonomics analyses were integrated. The results show that the Nfr2/HO-1/GPX4/ferroptosis signaling pathway is enriched significantly, indicating that it may be the main regulatory pathway for SAL in the treatment of testicular I/R injuries. Thereafter, transfection with Nrf2 plasmid-liposome was used to reverse verify that the Nfr2/HO-1/GPX4/ferroptosis signaling pathway was the main pathway for SAL anti-testicular I/R injury treatment. Thus, it is suggested that SAL can protect against testicular I/R injuries by regulating the Nfr2/HO-1/GPX4 signaling pathway to inhibit ferroptosis and that SAL may be a potential drug for the treatment of testicular I/R injuries.
PubMed: 38818379
DOI: 10.3389/fphar.2024.1377836 -
Journal of Cancer 2024Stomach adenocarcinoma (STAD) is the fifth most common cancer and the third leading cause of cancer-related deaths worldwide. Cancer-testis antigens (CTAs) participate...
Stomach adenocarcinoma (STAD) is the fifth most common cancer and the third leading cause of cancer-related deaths worldwide. Cancer-testis antigens (CTAs) participate in the pathogenesis and development of multiple cancers and are aberrantly overexpressed in various types of cancer. This study aimed to develop a CTA-related gene signature (CTARSig) to predict prognosis in STAD patients and explore its underlying mechanisms. We performed differential and prognostic analyses of CTA-related genes and constructed a CTA-related signature (CTARSig) along with a novel nomogram to predict the prognosis of patients with STAD based on the Cox and The Least Absolute Shrinkage and Selection Operator. CTARSig was further validated in an external cohort (GSE84437). Additionally, univariate and multivariate Cox regression, as well as receiver operating characteristic (ROC) analyses, were performed to assess the CTARSig systematically. Single-sample gene set enrichment analysis and ESTIMATE were used to characterise the Tumor Immune Microenvironment (TIME) in patients with STAD. Furthermore, Gene Set Variation Analysis, Kyoto Encyclopedia of Genes and Genomes, and Gene Ontology analyses revealed the biological functions and signalling pathways associated with CTARSig. Finally, the human gastric cancer cell lines, HCG-27 and AGS, were used for and experiments, respectively, to further validate the role of ELOVL4. Eleven CTA-related genes were identified to construct the CTARSig. Kaplan-Meier curves, independent prognostic analysis, and ROC curves revealed that CTARSig could better predict survival in patients with STAD. Moreover, in our study, we demonstrated that ELOVL4 is upregulated in gastric cancer tissues and that its high expression is associated with poor survival. Additionally, and experiments demonstrated that ELOVL4 promotes the metastatic and invasive potential of STAD cells, suggesting it may be a potential therapeutic target for STAD. In this study, a novel signature associated with CTAs was constructed for STAD, which may be a good predictor of patient prognosis. Thus, ELOVL4 may be a potential therapeutic target for gastric cancer. This study provides new insights into the potential roles of CTAs in gastric cancer.
PubMed: 38817874
DOI: 10.7150/jca.91842 -
International Journal of Endocrinology 2024The mechanism of steroidogenesis and spermatogenesis impairment in men with type 2 diabetes remains unclear. We aimed to explore the local changes of steroidogenesis and...
OBJECTIVE
The mechanism of steroidogenesis and spermatogenesis impairment in men with type 2 diabetes remains unclear. We aimed to explore the local changes of steroidogenesis and spermatogenesis in the testis of db/db mice. . We performed single-cell RNA sequencing analysis in the testis of db/db and C57BL/6J mice. The differentially expressed genes were then confirmed by real-time PCR. The histopathological characteristics of testis in db/db mice and C57BL/6J control were also performed.
RESULTS
The 20-week-old db/db mice had significantly higher blood glucose and body weight (both < 0.001). The serum testosterone levels (4.4 ± 0.8 vs. 9.8 ± 0.7 ng/ml, =0.001) and weight of the testis (0.16 ± 0.01 vs. 0.24 ± 0.01 g, < 0.001) were significantly lower in db/db mice than that in C57BL/6J controls. db/db mice had a lower cross-sectional area of seminiferous tubules and thickness of the cell layer (both < 0.05). The numbers of Sertoli cells and Leydig cells decreased in db/db mice (both < 0.01). Single-cell RNA sequencing analysis showed that compared with the control group, the percentage of spermatogonia was significantly higher in the db/db mouse ( < 0.001), while the proportions of spermatocytes, round and elongating spermatids, and sperms were all lower in the db/db mouse ( all < 0.001). The most differentially expressed genes were found in round spermatids ( = 86), which were not found in spermatogonia, spermatocyte, and sperm. Igfbp5 was the most significantly decreased gene in Leydig cells of the db/db mouse, while the expression of Cd74, H2-Aa, and H2-Eb1 was elevated. Ccl7 and Ptgds were the most significantly increased and decreased genes in Sertoli cells of the db/db mouse.
CONCLUSIONS
The present study indicates spermiogenesis and steroidogenesis defects in db/db mice. The mechanism of steroidogenesis impairment in the testis of db/db mice deserves further investigation.
PubMed: 38817616
DOI: 10.1155/2024/8797972 -
BMC Urology May 2024Congenital inguinal hernia, hydrocele and undescended testis (UDT) are associated with patent processus vaginalis. The smooth muscles present in the processus vaginalis... (Comparative Study)
Comparative Study
BACKGROUND
Congenital inguinal hernia, hydrocele and undescended testis (UDT) are associated with patent processus vaginalis. The smooth muscles present in the processus vaginalis aid in the descent of the testis and undergo programmed cell death after testicular descent leading to obliteration. The persisting amount of smooth muscle in the processus vaginalis influences the clinical outcome as inguinal hernia, hydrocele or UDT. Therefore, a study was conducted to evaluate the processus vaginalis in these three conditions to observe the presence and phenotype of smooth muscle cells and the presence of myofibroblasts.
MATERIALS AND METHODS
The processus vaginalis sacs in patients with inguinal hernia, hydrocele and UDT were examined using light microscopy for the presence and distribution of smooth muscle cells and immunohistochemical staining for vimentin, desmin, and α-smooth muscle actin (SMA) to identify the smooth muscle phenotype. Transmission electron microscopy was also performed in all the sacs to observe the presence of myofibroblasts.
RESULTS
Seventy-eight specimens of processus vaginalis (from seventy-four patients), distributed as 47%, 27%, and 26% as inguinal hernia, hydrocele and UDT respectively, were included in the study. The sacs from inguinal hernia and hydrocele had significantly more presence of smooth muscles distributed as multiple smooth muscle bundles (p < 0.001). Desmin and SMA staining of smooth muscle cells was observed in significantly more sacs from hydrocele, followed by inguinal hernia and UDT (p < 0.001). The sacs from UDT had a significant presence of striated muscles (p = 0.028). The sacs from inguinal hernia had a significant presence of myofibroblasts, followed by hydrocele and UDT (p < 0.001) and this significantly correlated with the light microscopy and immunohistochemical features. The processus vaginalis sacs from four female patients did not differ statistically from the male inguinal hernia sacs in any of the above parameters.
CONCLUSION
The processus vaginalis sacs in pediatric inguinal hernia, hydrocele and undescended testis differ in the presence, distribution and phenotype of smooth muscles and the presence of myofibroblasts. The clinical presentations in these entities reflect these differences.
Topics: Humans; Male; Testicular Hydrocele; Hernia, Inguinal; Infant; Cryptorchidism; Child, Preschool; Myocytes, Smooth Muscle; Child; Myofibroblasts; Infant, Newborn
PubMed: 38816716
DOI: 10.1186/s12894-024-01449-0 -
Reproductive Toxicology (Elmsford, N.Y.) Aug 2024Paracetamol is suggested to have endocrine disrupting properties possibly affecting fetal programming of reproductive health that might lead to impaired semen quality...
Paracetamol is suggested to have endocrine disrupting properties possibly affecting fetal programming of reproductive health that might lead to impaired semen quality and changes in reproductive hormones. In this longitudinal study, we included 1058 young adult men born 1998-2000 into the Danish National Birth Cohort with follow-up at 18-21 years of age. The exposure, maternal intake of paracetamol, was modelled in three ways: dichotomized, trimester-specific, and as duration of exposure categorized into: short (1-2 weeks), medium (3-9 weeks) or long duration (>9 weeks) vs. no intake. Outcomes included semen characteristics, self-measured testis volume, and reproductive hormone levels. We used negative binominal regression to estimate the percentage difference and 95% confidence interval (CI) for each outcome. In total, 547 (48%) sons were prenatally exposed to paracetamol due to maternal intake at least once. Maternal intake of paracetamol during pregnancy was not associated with any of the biomarkers in the dichotomized or trimester-specific exposure models. For duration of exposure, sons of mothers with long duration of maternal intake of paracetamol showed tendencies towards lower semen concentration (-14% [95% CI: -31%; 8%]), a higher proportion of nonprogressive and immotile spermatozoa (8% [95% CI: -4%; 21%]) and higher DNA Fragmentation Index (16% [95% CI: -1%; 36%]) compared to son of mothers with no intake. Maternal intake of paracetamol during pregnancy was not clearly associated with biomarkers of male fecundity in adult sons. However, it cannot be ruled out that long duration of maternal intake of paracetamol might be associated with impaired semen characteristics.
Topics: Acetaminophen; Humans; Male; Female; Pregnancy; Young Adult; Biomarkers; Adolescent; Prenatal Exposure Delayed Effects; Fertility; Analgesics, Non-Narcotic; Longitudinal Studies; Denmark; Testis; Semen Analysis
PubMed: 38815769
DOI: 10.1016/j.reprotox.2024.108626 -
Turkish Journal of Medical Sciences 2023To investigate the effects of acetylsalicylic acid (ASA) and the use of ultrasound elastography on testicular torsion.
BACKGROUND/AIM
To investigate the effects of acetylsalicylic acid (ASA) and the use of ultrasound elastography on testicular torsion.
MATERIALS AND METHODS
Herein, 6 equal groups of rats were formed (n: 48): control group, sham group, torsion/detorsion (T/D)-1 h group, T/D-1 h + ASA group, T/D-8 h group, and T/D-8 h + ASA group. Testicular torsion was created by rotating the left testis 720° clockwise. At 30 min before torsion, 100 mg/kg of ASA was injected intraperitoneally. Elastography was performed at 8 and 24 h. After orchiectomy, specimens were collected for histopathological evaluation.
RESULTS
When comparing the left testicular volume (LV) parameters obtained from the elastography applied at 8 h, significant differences were observed between the following group pairs: the sham and T/D-8 h groups, T/D-1 h and T/D-8 h groups, and T/D-1 h + ASA and T/D-8 h groups (p = 0.004, p = 0.023, and p = 0.026, respectively). The mean LVS (velocity) (stiffness assessment) of the groups was similar at 8 h. When comparing the LV parameters at 24 h, significant differences were found between the T/D-1 h and T/D-8 h groups and between the T/D-8 h and T/D-8 h + ASA groups (p = 0.008 and p = 0.004, respectively). For the LVS mean values at 24 h, significant differences were found between the control and sham groups, sham and T/D-1 h groups, sham and T/D-8 h groups, and sham and T/D-8 h + ASA groups (p = 0.009, p = 0.021, p = 0.027, and p = 0.009, respectively).Histopathological evaluation showed a decrease in the morphological grades and an increase in the mean testicular injury scores in the T/D-1 h + ASA group compared to the T/D-1 h group. The T/D-8 h + ASA group had a higher morphological grade than the T/D-8 h group, whereas their mean testicular injury scores were similar.
CONCLUSION
ASA treatment for testicular torsion was shown to be ineffective. Elastography can be a complementary method to Doppler ultrasonography in the diagnosis of testicular torsion and can guide surgeons in their approach to surgery.
Topics: Male; Spermatic Cord Torsion; Animals; Aspirin; Elasticity Imaging Techniques; Rats; Testis; Disease Models, Animal; Anti-Inflammatory Agents, Non-Steroidal
PubMed: 38813515
DOI: 10.55730/1300-0144.5729