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| Effects on testis tubular compartment for the two types of control animals (Control plus vehicle; Control plus PDRN) and the two types of treated ones (CdCl 2 plus vehicle; CdCl 2 plus PDRN).
Source publication
Cadmium (Cd) impairs blood-testis barrier (BTB). Polydeoxyribonucleotide (PDRN), an adenosine A2A agonist, has positive effects on male reproductive system. We investigated the effects of PDRN on the morphological and functional changes induced by Cd in mice testes. Adult Swiss mice were divided into four groups: controls administered with 0.9% NaC...
Contexts in source publication
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... seminiferous epithelium and the extra tubular compartment exhibited normal features for both control groups (Figures 3A,B; Tables 1 and 2). By contrast, in testes of mice challenged with CdCl 2 the germinal epithelium showed a low Johnsen's score, some round spermatids and marked detachments from the basal membrane of both Sertoli cells and spermatogonia. ...
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... contrast, in testes of mice challenged with CdCl 2 the germinal epithelium showed a low Johnsen's score, some round spermatids and marked detachments from the basal membrane of both Sertoli cells and spermatogonia. An evident hemorrhagic extravasation and an interstitial edema were apparent in the extratubular compartment ( Figure 3C; Tables 1 and 2). In mice challenged with CdCl 2 and treated with PDRN, the seminiferous tubules had larger size and the germinal epithelium was better preserved, with a higher Johnsen's score and many spermatozoa. ...
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... mice challenged with CdCl 2 and treated with PDRN, the seminiferous tubules had larger size and the germinal epithelium was better preserved, with a higher Johnsen's score and many spermatozoa. However, milder edema and hemorrhagic extravasation were still present in the extratubular compartment ( Figure 3D; Tables 1 and 2). ...
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... TUNEL-positive germ cells were present in the seminiferous tubules from both control groups (Figures 4A,B; Table 1). ...
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... the contrary, after challenge with CdCl 2 a lot of TUNEL- positive germ cells were grouped along small peripheral districts of the seminiferous tubules ( Figure 4C; Table 1). ...
Citations
... Polydeoxyribonucleotide (PDRN) is a drug extracted from the gonads of trout, containing a mixture of polynucleotides [90,91]. It is a DNA fraction with a double-helix structure, comprising deoxyribonucleotides. Triggered by cellular enzymes, it supplies purines and pyrimidines [92]. ...
Wound management presents a significant global challenge, necessitating a comprehensive understanding of wound care products and clinical expertise in selecting dressings. Bioactive dressings (BD) represent a diverse category of dressings, capable of influencing wound healing through various mechanisms. These dressings, including honey, hyaluronic acid, collagen, alginates, and polymers enriched with polyhexamethylene biguanide, chitin, and chitosan derivatives, create a conducive environment for healing, promoting moisture balance, pH regulation, oxygen permeability, and fluid management. Interactive dressings further enhance targeted action by serving as substrates for bioactive agents. The continuous evolution of BDs, with new products introduced annually, underscores the need for updated knowledge in wound care. To facilitate dressing selection, a practical algorithm considers wound exudate, infection probability, and bleeding, guiding clinicians through the process. This algorithm aims to optimize wound care by ensuring the appropriate selection of BDs tailored to individual patient needs, ultimately improving outcomes in wound management.
... It is well known that the integrity of the BTB and its regular reorganization is necessary for a normal spermatogenesis, as it divides the seminiferous tubule into a basal compartment, where spermatogonia and primary spermatocytes are present, and an adluminal compartment, where all the other germinal cells are located [24]. BTB is made by adjacent Sertoli cells, connected by adherens and tight junctions; its integrity is based on the regular expression of transmembrane proteins, such as occludin, claudin-11 and N-cadherin [25]. In varicoceles, the activation of inflammatory pathways can induce the destruction of the BTB, thus producing male infertility [26]. ...
Varicocele is one of the main causes of infertility in men, thus representing an important clinical problem worldwide. Inflammation contributes mainly to its pathogenesis, even if the exact pathophysiological mechanisms that correlate varicocele and infertility are still unknown. In addition, oxidative stress, apoptosis, hypoxia, and scrotal hyperthermia seem to play important roles. So far, the treatment of varicocele and the care of the fertility-associated problems still represent an area of interest for researchers, although many advances have occurred over the past few years. Recent experimental animal studies, as well as the current epidemiological evidence in humans, demonstrated that many functional foods of natural origin and nutraceuticals that are particularly abundant in the Mediterranean diet showed anti-inflammatory effects in varicocele. The aim of the present narrative
review is to mainly evaluate recent experimental animal studies regarding the molecular mechanisms of varicocele and the state of the art about possible therapeutic approaches. As the current literature demonstrates convincing associations between diet, food components and fertility, the rational intakenof nutraceuticals, which are particularly abundant in foods typical of plant-based eating patterns, may be a reliable therapeutic supportive care against varicocele and, consequently, could be very useful in the cure of fertility-associated problems in patients.
... Aside from directly inducing structural damage in the testis, oxidative stress can also stimulate apoptosis in different models [68][69][70]. It was also discovered that germ cell apoptosis could be caused by a Cdinduced decrease in testosterone levels [15]. ...
Testicular damage is considered a severe complication of cadmium (Cd) exposure which is associated with tissue oxidative stress damage, inflammation, and apoptosis. The present study investigated the antioxidant, anti-inflammatory, and anti-apoptotic activities of apocynin (APO) and carvedilol (CVD) against Cd-induced acute testicular damage. Rats were allocated into five groups as follows: normal control (received vehicle), Cd control group (2 mg/kg, i.p), APO-treated group (25 mg/kg, P.O.), CVD-treated group (10 mg/kg, P.O.), and combination group (APO + CVD). Blood, serum, and tissue samples were withdrawn for hematological, biochemical, molecular, and histological analyses. The present results confirmed testicular damage after cd exposure as indicated by alteration of serum hormonal levels, hematological defects, histopathological changes, and loss of steroidogenic functions. Besides, Cd injection-induced up-regulation of NADPH oxidase, MDA, NF-κB, IRF3, MPO, pro-inflammatory cytokines, Bax, and cleaved caspase-3 expression concomitant with down-regulation of Nrf2, GSH, SOD, and Bcl2 expression. Interestingly, pretreatment with APO and/or CVD significantly relieved Cd-induced testicular damage at cellular and molecular levels. Notably, the combined protective effect of APO plus CVD was higher than the protective effect of each drug alone. Overall, combined APO and CVD could serve as a good candidate for protection against Cd-induced testicular damage via suppression of inflammatory response and modulation of the redox-sensitive pathway.
... All the while, reproductive health is a public health concern worldwide. Research evidence suggests that environmental contaminants may potentially cause reproductive health problems (Liu et al. 2022;Squadrito et al. 2016). Environmental toxicants (such as heavy metals, pesticides, and persistent organic pollutants) were confirmed to contribute to producing fertility disorders (Alharbi et al. 2018;Rani et al. 2020;Rehman et al. 2018). ...
... The blood-testis barrier (BTB) is mainly formed from specialized junctions between the Sertoli cells in the testicular seminiferous tubules. Research confirmed that environmental pollutants could affect reproductive health by disrupting the BTB (Liu et al. 2022;Squadrito et al. 2016). To investigate if PBDE-209 affects the integrity of BTB, we observed the testicular ultrastructure using the TEM. ...
Many materials use polybrominated diphenyl ethers (PBDEs) as flame retardants. As one of the most common congeners of PBDEs, decabromodiphenyl ether (PBDE-209) is reported to harm reproductive health. However, little is known research on attenuating the reproductive toxicity induced by PBDE-209. The present study aimed to investigate the effects of hesperidin against PBDE-209-induced reproductive toxicity in male mice. Pubertal male C57BL/6 J mice were exposed to PBDE-209 groups (20, 100, 500 mg/kg·bw) and hesperidin groups (100 mg/kg·bw PBDE-209 + 100 mg/kg·bw hesperidin) for 8 weeks. The results showed that PBDE-209 increased the amount of abnormal morphological sperms and decreased the sex hormone levels. PBDE-209 induced the histopathological lesions of seminiferous tubules and blood-testis barrier in mice testis. Expressions of apoptosis-associated proteins and mRNA (Bax, Bcl-2, etc.) were altered by the PBDE-209 treatment. PBDE-209 prominently increased the malondialdehyde (MDA) levels, the biomarker of oxidative stress. Hesperidin treatment partly alleviated PBDE-209-induced histopathological lesions and apoptosis in mice testis. These findings suggested that hesperidin partly protects against PBDE-induced reproductive toxicity in pubertal mice. We conclude that more work needs to be done to explore the appropriate dosage of hesperidin or find other drugs to protect against the reproductive toxicity of PBDEs.
Graphical abstract
... An important reduction in male fertility has been associated with occupational exposure to Cd [40], whereas varicocele and other reproductive disorders account for only 23% of damaged reproductive conditions [4]. As a consequence of Cd exposure, severe hemorrhage, edema, necrosis of Leydig cells and decreased testosterone concentrations in the plasma and testes, reduced junctions of germ cells in the seminiferous tubules and a loss of integral membrane proteins at the Sertoli cell interface of the blood-testis barrier (BTB), a reduction in the count and motility of sperm have been observed [41][42][43][44][45][46][47]. Furthermore, Cd is also classified as a potential human carcinogen by the International Agency for Research on Cancer [48]: in fact, Leydig cells death or even cancer were demonstrated [49]. ...
... Even if the causes of Cd-induced reproductive toxicity have been not yet fully elucidated [50], several mechanisms have been demonstrated, such as oxidative stress [34,51], DNA changes [52], apoptosis [53], inflammation [54], disruption of the BTB [45,46,55] and hormonal imbalance [44,56]. ...
... After Cd challenge, BTB integrity is lost, owing to an evident increase in transforming growth factor (TGF)-β3, the most abundant form of TGF-β in the testis, produced by Sertoli cells, spermatogonia and early spermatocytes. TGF-β3 induces harmful effects in the tight junctions of Sertoli cells, owing to a decreased content in occludin, zonula occludens (ZO)-1, N-cadherin and claudin-11 [44][45][46]50]. In vitro studies showed that a correlation existed between tightness of the junctions and testosterone concentration [131]. ...
Cadmium (Cd) is a widespread heavy metal and a ubiquitous environmental toxicant. For the general population, the principal causes of Cd exposure are cigarette smoking, air pollution and contaminated water and food consumption, whereas occupational exposure usually involves humans working in mines or manufacturing batteries and pigments that utilize Cd. The aim of the present review is to evaluate recent data regarding the mechanisms of Cd-induced testicular structural and functional damages and the state of the art of the therapeutic approaches. Additionally, as the current literature demonstrates convincing associations between diet, food components and men's sexual health, a coherent nutraceutical supplementation may be a new valid therapeutic strategy for both the prevention and alleviation of Cd-induced testicular injury. The toxic effects on testes induced by Cd include many specific mechanisms, such as oxidative stress, inflammation and apoptosis. As no specific therapy for the prevention or treatment of the morbidity and mortality associated with Cd exposure is available, the development of new therapeutic agents is requested. Dietary strategies and the use of nutraceuticals, particularly abundant in fresh fruits, beans, vegetables and grains, typical of the Mediterranean diet, are recommended against Cd-induced testicular injury.
... In decades, laboratory experiments suggest that male gonad is a considerable target of MC-LR. The blood-testis barrier (BTB) is mainly composed of tight junctions (TJs), adherent junctions, and gap junctions (Squadrito et al., 2016). TJs which are observed between Sertoli cells play a pivot role in BTB integrity (Zhou et al., 2018). ...
... MC-LR has recently been proved to be taken up by Sertoli cells, leading to male reproductive system dysfunction . TJs which are the primary junctions of BTB play critical roles in an immunological barrier of host animals (Squadrito et al., 2016). MC-LR can destroy the integrity of the BTB by regulating TJs (Zhou et al., 2020). ...
Quercetin has numerous functions including antioxidant and anti-inflammatory effects. The beneficial effect of quercetin against microcystin-LR (MC-LR)-induced testicular tight junctions (TJs) defects in vitro and in vivo were investigated. Significant reductions in transepithelial electrical resistance, occludin, and zonula occludens-1(ZO-1) levels were detected in the MC-LR-treated TM4 cells, and quercetin attenuated these effects. Interestingly, quercetin suppressed MC-LR-induced phosphorylation of protein kinase B (AKT). It effectively inhibited the accumulation of reactive oxygen species (ROS) in cells stimulated by MC-LR. In addition, ROS inhibitors blocked the TJ damage that is dependent on the AKT signaling pathway induced by MC-LR. In conclusion, our results suggest that alleviates MC-LR-impaired TJs by suppressing the ROS-regulated activation of the AKT pathway.
... Cadmium (Cd) is a representative environmental pollutant, which has posed serious and urgent threats to public health (Oprea et al., 2014). The World Health Organization (WHO) lists Cd as a food pollutant, and it has also been classified as a human carcinogen with strong mutagenesis and genotoxicity by the International Agency for Research on Cancer (IARC) (Squadrito et al., 2017). In the environment, Cd enters human body mainly through digestive tract and respiratory tract (Benvenga et al., 2021). ...
Background
: Cadmium (Cd) is a representative pernicious metal, which has high biological toxicity. Its precaution through dietary administration is considered an important strategy. Considering that portulaca oleracea L. (Por.L) has antioxidant, anti-inflammatory and other high medicinal value, and purslane insoluble dietary fiber (PIDF) has good binding property to metal ions, they could be good methods for Cd-induced biotoxicity therapy.
Purpose
: To investigate the beneficial effects of Por.L or PIDF against Cd-induced subchronic toxicity and identify its underlying mechanisms.
Study design and Methods
: C57BL/6 male mice (n=12) were received 100 mg L⁻¹ CdCl2 in water for 8 weeks. Mice were divided into four groups: Control, Cd-treated, 8% Por.L + Cd, and 8% PIDF + Cd. Histological evaluation, inductively coupled plasma-mass spectrometry, western blotting analysis, quantitative real time-PCR, gas chromatography-mass spectrometry and 16S rDNA analysis were used in the study.
Results
: Por.L treatment was able to inhibit inflammation and accumulation of Cd, enhance the activity of antioxidant enzymes, increase beneficial bacterial species of Akkermansia and Faecalibaculum and suppress the production of inflammatory cytokines in the colon, such as TNF-α, IL-6, IL-1β and IFN-γ. PIDF mainly relieved the toxicity of Cd by increasing the production of short chain fatty acids with anti-inflammatory functions and repressing the liver and kidney inflammation mediated by the TLR4/ MyD88/NF-κB pathway.
Conclusion
: Our study has demonstrated that the antagonistic-Cd effects of Por.L might be mediated via chelation, antioxidation, regulation of intestinal microecology. Thus, our study provides a novel insight into Por.L as a promising function food for the anti-Cd biotoxicity. Por.L supplement could be considered as a potential coping strategy to alleviate hazardous effects in Cd-exposed humans.
... Then, the tissues were dehydrated with increasing alcohol concentrations. The dehydrated pieces were embedded in Durcupan ACM (Squadrito et al., 2017). Finally, the sections were obtained with a Reichert Jung Ultracut E. Semi-thin sections (1 µm) were stained with toluidine blue and examined with a light microscope. ...
Seahorses (Hippocampus spp.) are exceptional marine species considering their reproductive patterns and other features. Due to the iconic characteristics of these fishes, aquarium trade, and research efforts have increased in the last years. Consequently, novel rearing techniques have been developed; however, there is a need for improvements on a series of issues, namely reproduction success enhancement. The tropical species Hippocampus reidi is the most traded seahorse but many aspects of breeding and its impact on the quality of neonates are still poorly understood. In the present study, we assessed the effects of two pre-breeding diets on newborn quality and viability considering biochemical characteristics, energetic status, and ultrastructural aspects of muscular tissue. During the whole pre-breeding season (5 months), the breeders were fed on one of the following diets: M0 (adult non-enriched Artemia) and M5 (adult non-enriched Artemia + mysidaceans). From the onset of the reproduction period, all breeders were fed for 6 months on diet M5. Breeding success and energetic status (ATP, total adenylic nucleotides, AEC, and NAD) of newborns resulted considerably enhanced in treatment M5. However, initial differences in neonates quality did not affect further newborn performance (survival and growth until day 7 after male’s pouch release) while gaining access to high-quality preys (copepods). Besides, morphological alterations in muscle tissue were not observed. The reproduction in the species followed a capital–income continuum pattern characterized by an initial mixed capital-income period (until 70–100 days since the onset of the breeding season) followed by an income breeding period with progressive exhaustion of body reserves, especially in M0-newborns. Interestingly, the effects of pre-breeding diets were also noticed in the second half of the breeding period. Our results seemed to indicate that the requirements in essential fatty acids in H. reidi are lower than in other seahorse species (e.g., Hippocampus guttulatus). Globally, the results achieved revealed that high-quality pre-breeding diets enhanced reproduction success and would likely result advantageous to improve newborn endurance in conditions of moderate starvation or sub-optimal feeding.
... A 2017 study confirmed that Om-PDRN prevents tissue damage in C57 BL/6J mice [38]. Concretely, the mice were challenged with Cd to induce the blood-testis barrier (BTB), resulting in a combination of tight junctions, adherent junctions, and gap junctions. ...
Polydeoxyribonucleotides (PDRNs) are a family of DNA-derived drugs with a molecular weight ranging from 50 to 1500 kDa, which are mainly extracted from the sperm cells of salmon trout or chum salmon. Many pre-clinical and clinical studies have demonstrated the wound healing and anti-inflammatory properties of PDRN, which are mediated by the activation of adenosine A2A receptor and salvage pathways, in addition to promoting osteoblast activity, collagen synthesis, and angiogenesis. In fact, PDRN is already marketed due to its therapeutic properties against various wound healing- and inflammation-related diseases. Therefore, this review assessed the most recent trends in marine organism-derived PDRN using the Google Scholar search engine. Further, we summarized the current applications and pharmacological properties of PDRN to serve as a reference for the development of novel PDRN-based technologies.
... In fact, male infertility with lower semen quality [7] and postponed puberty with reduced gonadal growth [8] were observed. In animals, and particularly in rodents [9], after experimental Cd exposure, testicular lesions were observed, such as a significant reduction in testis weight and testosterone levels, and structural changes in both seminiferous tubules and Leydig cells [10][11][12][13]. ...
... In addition to directly inducing structural damage in the testis, oxidative stress is also capable of stimulating apoptosis both in vitro [17] and in vivo [12,18]. In fact, Cd has been shown to increase the expression of proapoptotic factors such B cell-lymphoma (Bcl)-2-associated X protein (Bax), of the key regulatory protein p53, and of caspase-3 as well as to reduce that of the antiapoptotic Bcl-2 [11,[18][19][20][21]. ...
... Recent studies examining the exposure-effect assessment linked chronic Cd challenge with adverse effects in almost every organ and tissue where Cd accumulates [47,48]. In particular, numerous studies have demonstrated Cd-induced reproductive dysfunctions, such as reduction in testis and body weight, damage of the blood-testis barrier, reduced germ cell adhesion with increased loss of immature cells, testosterone reduction, low sperm count, and consequent subfertility or infertility [7,[11][12][13]. ...
It is known that cadmium damages testis structure and functionality. We examined the effects of nutraceuticals such as a flavonoid-rich extract of bergamot juice (BJe), alone or in association with curcumin (Cur) and resveratrol (Re), on mice testicular dysfunction caused by cadmium chloride (CdCl2). Controversial data on the protective effects of Cur and Re are available, while no evidence on the possible role of BJe exists. Adult male C57 BL/6J mice were administered with CdCl2 and treated with Cur, Re, or BJe alone or in combination for 14 days. Then, testes were removed and processed for molecular, structural, and immunohistochemical analyses. CdCl2 increased the mRNA of IL-1β, TNF-α, p53, and BAX while reduced that of Bcl-2 and induced tubular lesions and apoptosis of germinal cells. Cur, Re, and BJe at 40 mg/kg significantly improved all of these parameters and events, although BJe at 20 mg/kg showed a lower protective effect. The association of Cur, Re, and BJe at both doses of 50/20/20 and 100/20/40 mg/kg brought each parameter close to those of the control. Our results indicate that the nutraceuticals employed in this study and their associations exert a positive action against Cd-induced testicular injury, suggesting a possible protection of testis functionality in subjects exposed to environmental toxicants.
