Studies on testicular ultrastructural and hormonal changes in type-2 diabetic rats treated with highly active antiretroviral therapy conjugated silver nanoparticles.

AIM: This study investigated the impact of highly active antiretroviral therapy (HAART) loaded silver nanoparticles (AgNPs) as HAART-AgNPs on the sperm count, viability, serum hormonal profile, insulin-like growth factor I (IGF-1), and testicular ultrastructure. METHODS: Thirty-six adult male Sprague-Dawley rats were allocated into diabetic and non-diabetic groups (n = 18). The rats in the diabetic group were induced experimental type 2 diabetes using fructose and streptozotocin (frt-STZ). Animals in both groups were subdivided into three groups each, A-C and DF (n = 6), and received distilled water, HAART, and HAART-AgNP, respectively. FINDINGS: Treatment with HAART-AgNP displayed a significant increase (p < 0.05) in serum gonadotropin-releasing hormone (GnRH), follicle-stimulating hormone (FSH), luteinizing hormone (LH), and testicular IGF-1 in diabetic rats. Also, electron microscopy revealed ameliorated testicular ultrastructure upon administration of HAART-AgNP in diabetic rats that were previously marked with architectural and cellular alterations. In addition, treatment with HAART-AgNP significantly reduced (p < 0.05) the blood glucose levels of diabetic rats. In contrast, the treatment of non-diabetic rats with HAART caused a significant decrease (p < 0.05) in the sperm count, serum GnRH, and testicular IGF-1, however, this treatment induced ultrastructural changes and a significant increase (p < 0.05) in serum testosterone levels in diabetic and non-diabetic rats. SIGNIFICANCE: This study has demonstrated the beneficial impact of HAART-AgNP on the hypothalamic-pituitary-gonadal axis, IGF-1, and testicular architecture in male frt-STZ induced diabetic rats. This nanoconjugate could be a potential nano-drug candidate to cater for testicular dysfunction and metabolic derangements while managing HIV-infected male individuals.

Novel severe acute respiratory syndrome coronavirus 2 (SARS-COV-2) infection: Microbiologic perspectives and anatomic considerations for sanctuary sites.

INTRODUCTION: A significant chunk of global life - the economy, sports, aviation, academic, and entertainment activities - has significantly been affected by the ravaging outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-COV-2) with devastating consequences on morbidity and mortality in many countries of the world. METHODS: This review utilized search engines such as google scholar, PubMed, ResearchGate, and web of science to retrieve articles and information using keywords like "Coronavirus", "SARS-CoV-2", "COVID-19", "Origin of coronavirus and SARS-CoV-2", "microbiology of coronavirus", "microbiology of SARS-CoV-2", COVID-19", "Coronavirus reservoir sites", "Anatomic sanctuary sites and SARS-CoV-2", biological barriers and coronavirus", biological barrier and SARS-CoV-2". RESULTS: While this pandemic has caught the global scientific community at its lowest level of preparedness, it has inadvertently created a unified and wholesome approach towards developing potential vaccine (s) candidates by escalating clinical trial protocols in many countries of Europe, China and the United States. Interestingly, viral pathobiology continues to be an evolving aspect that potentially shows that the management of the current outbreak may largely depend on the discovery of a vaccine as the administration of known antiviral drugs are proving to offer some respite. Unfortunately, discontinuation and longtime administration of these drugs have been implicated in endocrine, reproductive and neurological disorders owing to the development of pathological lesions at anatomical sanctuary sites such as the brain and testis, as well as the presence of complex biological barriers that permit the entry of viruses but selective to the entrance of chemical substances and drugs. CONCLUSION: This review focuses on the microbiologic perspectives and importance of anatomical sanctuary sites in the possible viral rebound or reinfection into the system and their implications in viral re-entry and development of reproductive and neurological disorders in COVID-19 patients.

Momordica charantia mitigates hepatic injury following adjuvant treatment with antiretroviral drugs in diabetic animal models.

Momordica charantia (M. charantia) is a medicinal plant, used in traditional practice for treating diseases like hypertension and diabetes mellitus. This study investigated the possible hepato-protective effect of M. charantia following treatment with highly active antiretroviral therapy (HAART) in diabetic rats. 48 adult male Sprague Dawley rats were divided into seven groups (A-G) of 7 animals per group and treated according to protocols. Diabetes was induced with streptozotocin (STZ) by intraperitoneal injection (45 mg/kg body weight). The animals were euthanized on the 10th week with liver removed for examination and blood obtained via cardiac puncture and centrifuged to collect the sera. Blood glucose levels (BGL) were consistently and significantly raised (p < 0.05) in all groups not receiving the adjuvant M. charantia. Treatment with M. charantia reverses the increase in BGL to near normal. Markers of liver injury assayed showed significant increase (p < 0.05) in AST, ALP and ALT levels in groups not receiving M. charantia. Adjuvant HAART and M. charantia caused significant declines in the liver enzymes (p < 0.05). Serum GGT was not markedly altered. Treatment with M. charantia significantly restored liver enzymes elevations to near normal comparable to control. Histopathological observations ranged from severe hepatocellular distortions, necrosis and massive fibrosis following treatment of HAART in diabetic groups not receiving M. charantia. Treatment with M. charantia did not show any sign of hepatotoxicity as judged from the histological and biochemical observations.

Efficacy of six artemisinin-based combination therapies in the attenuation of Plasmodium berghei-induced testicular toxicity in Swiss mice

Many artemisinin-based combination therapies (ACTs) have been approved for malaria treatment, yet reports indicate that some ACTs pose reversible testicular toxicity; however there is no comparative study of these ACTs on the testes in a curative malarial model. We investigated the ameliorative activity of six ACTs on Plasmodium berghei (PB) induced perturbations in testicular antioxidants, serum testosterone levels, sperm motility and the testes microanatomy. Forty male Swiss mice were divided into 8 groups of 5 each: Group 1 normal control (NC), uninfected and untreated, received placebo; group 2 was parasitized non-treated (PNT), while groups 3 - 8 received PB inoculum intraperitoneally. Initial parasitemia was established after 72 hours. Groups 3 - 8 thereafter received oral therapeutic doses of artesunate/amodiaquine (PBAA), artesunate/mefloquine (PBAM), artesunate/sulfadoxine-pyrimethamine (PBASP), artemisinin-piperaquine (PBAP), dihydroartemisinin/piperaquine (PBDP) and artemether/lumefantrine (PBAL) per kg body weight respectively. final parasitemia was performed 24 hours after last treatment, and animals euthanized. Result for parasitemia level was significantly (p < 0.05) declined in ACT-treated groups, except PBASP compared with PNT. Enzymatic antioxidants were significantly (p < 0.0001) altered in ACT-treated groups compared to PNT. Non-enzymatic antioxidants were significantly (p < 0.0001) increased in PBDP compared to NC and PNT. Progressive sperm motility significantly (p < 0.0001) declined in PNT, PBASP, PBAP and PBDP groups compared to NC. Testosterone showed decreasing trend in PBAP compared to PNT, and severe testicular distortions were demonstrated in PNT, PBASP, PBAP and PBDP. This study concludes that therapeutic doses of AA, AM and AL moderately protects against the deleterious effects of Plasmodium berghei-induced testicular toxicity in Swiss mice

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Testicular 3beta hydroxysteroid dehydrogenase in naringenin adjuvant under highly active antiretroviral therapy (HAART); preliminary data using Sprague-Dawley rats

HAART has brought relief to many living with HIV/AIDS, decreasing morbidity and mortality rates. In spite of these benefits, the treatment has been associated with reproductive disorders. This study is aimed at investigating the effects of Naringenin (Nar) on the expression of testicular 3ß-Hydroxysteroid dehydrogenase (3ß HSD) in HAART-treated Sprague-Dawley rats. 30 adult male Sprague-Dawley rats were randomly divided into six groups. The rats were fed with 30 mg/kg of HAART (Efavirenz+Embtricitabine+Tenofovir), 40mg/kg and 80 mg/kg of Nar and a combination of both HAART and Nar for a period of 70 days. Thereafter, the animals were euthanized and the testes processed. The results showed a significant decrease (p<0.05) in the expression of 3ß HSD in the HAART group compared to controls. However, the co-treatment of HAART with 40 mg/kg Nar increased significantly (p<0.05) the expression of 3ß HSD, compared to HAART and control. The relative volume fraction also showed significant increase (p<0.05) in germinal epithelium, lumen and Leydig cells of animals treated with 80 mg/kg Nar, and HAART+40 mg/kg Nar compared to control and HAART respectively. In conclusion, HAART is causes a deficiency in testicular 3ß HSD, thereby limiting spermatogenesis. However, co-treatment with 40 mg/kg Naringenin increases testicular 3ß HSD expression and enhances spermatogenesis

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Investigating Organ Toxicity Profile of Tenofovir and Tenofovir Nanoparticle on the Liver and Kidney: Experimental Animal Study.

Tenofovir nanoparticles are novel therapeutic intervention in human immunodeficiency virus (HIV) infection reaching the virus in their sanctuary sites. However, there has been no systemic toxicity testing of this formulation despite global concerns on the safety of nano drugs. Therefore, this study was designed to investigate the toxicity of Tenofovir nanoparticle (NTDF) on the liver and kidney using an animal model. Fifteen adult male Sprague-Dawley (SD) rats maintained at the animal house of the biomedical resources unit of the University of KwaZulu-Natal were weighed and divided into three groups. Control animals (A) were administered with normal saline (NS). The therapeutic doses of Tenofovir (TDF) and nanoparticles of Tenofovir (NTDF) were administered to group B and C and observed for signs of stress for four weeks after which animals were weighed and sacrificed. Liver and kidney were removed and fixed in formal saline, processed and stained using H/E, PAS and MT stains for light microscopy. Serum was obtained for renal function test (RFT) and liver function test (LFT). Cellular measurements and capturing were done using ImageJ and Leica software 2.0. Data were analysed using graph pad 6, p values < 0.05 were significant. We observed no signs of behavioural toxicity and no mortality during this study, however, in the kidneys, we reported mild morphological perturbations widening of Bowman's space, and vacuolations in glomerulus and tubules of TDF and NTDF animals. Also, there was a significant elevation of glycogen deposition in NTDF and TDF animals when compared with control. In the liver, there were mild histological changes with widening of sinusoidal spaces, vacuolations in hepatocytes and elevation of glycogen deposition in TDF and NTDF administered animals. In addition to this, there were no significant differences in stereological measurements and cell count, LFT, RFT, weight changes and organo-somatic index between treatment groups and control. In conclusion, NTDF and TDF in therapeutic doses can lead to mild hepatic and renal histological damage. Further studies are needed to understand the precise genetic mechanism.

Antiretroviral Therapy and Alcohol Interactions: X-raying Testicular and Seminal Parameters Under the HAART Era.

The prevalence of alcohol use among HIV-infected patients undergoing antiretroviral (ARV) treatments has raised several concerns related to key therapeutic indices. These include drug interactions, compliance, efficacy and toxicity with the possibility of accelerated disease progression. Interaction of ARVs with alcohol can result in therapeutic failures or place patients at significant risk for toxicities. Research findings in this particular area are, however, limited and sometimes conflicting. This review focuses on alcohol and ARV interactions affecting testicular and spermatogenic indices. Antiretroviral drugs are known to negatively impact testicular functions via altered mitochondrial DNA and oxidative stress mechanisms. Interaction with alcohol can significantly affect seminal fluid concentration of ARVs. Habitual consumption of alcohol causes testicular hypofunction with potential for lowered fertility. Concomitant use of ARVs appears to act synergistically to exacerbate this toxicity. Alcohol also induces cytochrome P450 (CYPs) microsomal enzymes, which in turn affect ARVs metabolized by these enzymes. In the presence of ARVs with strong inhibitory activity, increased bioavailability with toxicities predominates. In addition, alcohol and ARVs have pronounced effects on membrane-associated drug transporters. Alcohol alters the properties of the lipid bilayer by changing membrane permeability and protein distribution. Since drug transporters critical to pharmacokinetics are integral membrane proteins, alcohol tends to diminish the activity of both the efflux and influx transporters. While excessive alcohol precipitates accelerated hypogonadism, future research needs to be directed to quantifying these effects of alcohol and ARVs in human testicular tissue.

Histo-morphological and seminal evaluation of testicular parameters in diabetic rats under antiretroviral therapy: interactions with Hypoxis hemerocallidea.

OBJECTIVES: Broad range of metabolic changes associated with highly active antiretroviral therapy (HAART) has been reported over decades including reproductive perturbations. The current study aimed at investigating the role of Hypoxis hemerocallidea (Hyp) in the seminal and morphometric alterations in the testes of streptozotocin-nicotinamide-induced diabetic rats under HAART. MATERIALS AND METHODS: Sixty-two adult male Sprague-Dawley rats were divided into A-H groups, containing 6 rats in the control group A and 8 rats in the treatment groups B-H. Diabetes was induced by intraperitoneal injection of nicotinamide (110 mg/kg BW) followed by streptozotocin (45 mg/kg BW). The animals were then subjected to various treatments with HAART, Hyp, and melatonin. RESULTS: weights (body and testicular), histological, histochemical, seminal fluid, and morphometric analyses were carried out. Sperm count and motility were reduced in HAART (P<0.05/0.003) and Hyp200 (P<.003) groups compared with normal and diabetic controls, respectively. Sperm count was higher (P<.003) in HAART+ Mel and HAART+Hyp100 groups. Morphometry showed the reduction in germinal epithelium height and basement membrane thickness (P<.003) in the Hyp100 group compared with diabetic controls. Adjuvant use of Hyp and melatonin with HAART did not significantly raise these indices (P>.05). Histological slides showed gross distortions in HAART, diabetic and HAART +Hyp groups with marked atrophy in tubules, germ cell loss and areas of focal depletion of the cell. PAS staining revealed detached basement membrane in diabetic groups with strong PAS-stain. CONCLUSION: The use of Hyp or melatonin does not ameliorate the testicular damages in diabetic animals under antiretroviral therapy.

Does Hypoxis hemerocallidea mitigate renal histopathological injuries following highly active antiretroviral therapy? An experimental animal study.

BACKGROUND: Nephrotoxicity has become an important public health problem following the success recorded with highly active antiretroviral therapy, and there is paucity of literature reporting the attenuating influence of plant-based adjuvants that can mitigate the effects. METHODS: Sixty three adult male Sprague-Dawley rats were divided into 9 groups (A-I) and treated as follows: group A received HAART cocktail (lamivudine, stavudine and nevirapine), group B received HAART and Hypoxis hemerocallidea (HH) extract (200 mg/kg), group C received HAART and HH (100 mg/kg), group D received HAART and vitamin C, group E received HAART and vitamin E, group F received HAART, vitamin C and vitamin E, group G received HH extract (100 mg/kg), group H received HH extract (200 mg/kg), and group I received saline as placebo. After 56 days, animals were euthanized, kidneys harvested and prepared for H&E staining and blood samples were collected for BUN and serum creatinine analyses. RESULTS: The results from histological slides showed distorted glomerular and epithelial components with extensive loss of Bowman's capillary integrity in HAART-treated group. Adjuvant treatment with HH both high and low doses did not show any remarkable attenuating influence. However, HH100mg/kg-alone treated group showed improved histological layout as compared to the higher dose. Co-administration of HAART and vitamins C and E did not improve the parameters examined. The serum creatinine and BUN levels were significantly increased (P<0.05) following HAART with observable increase in kidney body weight ratio. SCR levels in group D was significantly reduced (P<0.05) but elevated in groups B, C, G and H (P<0.001). Groups B and C, as well as groups F and H recorded higher BUN values (P<0.05). CONCLUSIONS: Adjuvant treatment with HH extract did not attenuate the nephrotoxicity of HAART in this model.

Coconut Oil Extract Mitigates Testicular Injury Following Adjuvant Treatment with Antiretroviral Drugs.

Increased access to highly active antiretroviral therapy (HAART) has made the management of drug toxicities an increasingly crucial component of HIV. This study investigated the effects of adjuvant use of coconut oil and HAART on testicular morphology and seminal parameters in Sprague- Dawley rats. Twelve adult male Sprague-Dawley rats, weighing 153~169 g were distributed into four groups (A-D) and treated as follows: A served as control (distilled water); B (HAART cocktail- Zidovudine, Lamivudine and Nevirapine); C (HAART + Virgin coconut oil 10 mL/kg) and D (Virgin coconut oil 10 mL/kg). After 56 days of treatment, animals were killed and laparotomy to exercise the epididymis for seminal fluid analyses done whilst testicular tissues were processed for histomorphometric studies. Result showed a significant decline in sperm motility (P < 0.05) and count (P < 0.0001) in HAART-treated animals while there was insignificant changes in other parameters in groups C and D except count that was reduced (P < 0.0001) when compared with controls. Histomorphological studies showed HAART caused disorders in seminiferous tubular architecture with significant (P < 0.01) decline in epithelial height closely mirrored by extensive reticulin framework and positive PAS cells. Adjuvant Virgin coconut oil + HAART resulted in significant decrease in seminiferous tubular diameter (P < 0.05), but other morphometric and histological parameters were similar to control or Virgin coconut oil alone (which showed normal histoarchitecture levels). While derangements in testicular and seminal fluid parameters occurred following HAART, adjuvant treatment with Virgin coconut oil restored the distortions emanating thereof.

Highly active antiretroviral therapy (HAART) and testicular morphology: current status and a case for a stereologic approach.

As antiretroviral therapy becomes increasingly accessible, the associated improvements in the health, quality of life, and survival of patients are anticipated to influence the fertility determinants of patients, specifically young males, within the reproductive axis. Therefore, the understanding of testicular histology in patients with HIV/AIDS undergoing therapeutic management is essential, because the sexual route is one of the main means of transmission of HIV, which is localized primarily in the germ cells of the testes. It is also important to determine whether any changes have occurred in the testicular histologic patterns in the course of the HIV/AIDS therapy. This review highlights the views of experts that current therapy and prolongation of survival in HIV/AIDS patients are associated with a shift in the histologic findings of testes toward a more pronounced loss of germ cells. There have been attempts to use stereologic size and number estimators to quantify the volume or number of biologically significant reference spaces and objects from their appearance on two-dimensional sections without introducing bias from inappropriate assumptions, models, or correction formulas. Therefore, morphologic changes related to altered distribution of highly active retroviral therapy within the testis and the consequent endocrine perturbations characteristic of a potential complication of antiretroviral treatment regimens can be analyzed in stereologic dimensions.