Men with diabetes frequently experience spermatogenic dysfunction, which is the most significant sign that diabetes has harmed their ability to reproduce. The effect of various doses of the hydro-alcoholic extract of Nerium oleander leaves on the pituitary-gonadal axis, sperm motility and number, antioxidant system, changes in testicular tissue structure, and spermatogenesis in healthy and diabetic rats has been examined in the current study. Eighty male rats that had been streptozotocin-induced diabetic and healthy were divided into eight groups: (1) control, (2) Nerium (50 mg/kg), (3) Nerium (100 mg/kg), (4) Nerium (200 mg/kg), (5) DM (6) DM+Nerium (50 mg/kg), (7) DM+Nerium (100 mg/kg) and (8) DM+Nerium (200 mg/kg) and were administered orally for 48 days consecutive. Following the studies, analysis of the testicular tissues\' antioxidant capacity as well as sperm parameters, Johnsen\'s scoring and morphometric evaluation, histology, biochemical and stereology studies were performed.The outcomes showed that Nerium 50 and 100 mg/kg considerably enhanced the testicular morphology, sperm parameters, and reproductive organs to varying degrees in diabetic rats. After Nerium 50 mg/kg administration, glutathione peroxidase (GPX) and catalase (CAT) levels in the testicular tissue were increased whereas malondialdehyde (MDA) levels were markedly decreased. Nerium may help protect against diabetic-induced spermatogenic dysfunction in male rats by enhancing the activities of antioxidant enzymes in lower dosages.

BACKGROUND: Nerium oleander is used to treat liver-associated chronic metabolic diseases in traditional medicinal systems across the globe. The hepatoprotective effects of oleander are mentioned in Indian and Chinese traditional medicinal literature.
OBJECTIVE: The present study aimed to investigate the cellular mechanisms behind the hepatoprotective effects of a non-toxic dose of oleander (NO).
METHODS: The hepatoprotective effects of NO were tested against lipopolysaccharide (LPS)-treated HepG2 cells. Oxidative stress response was studied using cellular enzymatic assays, and gene expression was analyzed using qRT-PCR. HepG2 cells were pretreated with TAK-242 (pharmacological inhibitor of TLR4) to decipher the anti-inflammatory mechanisms of NO. Cell-free metabolites were analyzed using GCMS and were subjected to pathway enrichment analysis.
RESULTS: NO reduced systemic inflammation, serum lipid peroxidation byproducts, and glucose without affecting serum transaminase levels and hepatic histopathological features. NO attenuated the inflammation-induced loss of antioxidant enzyme activities and mRNA expressions of toll-like receptor-4 (TLR4)/nuclear factor κβ (NFκβ)-dependent inflammatory genes. In TAK-242 pretreated cells, LPS was unable to induce inflammatory and oxidative responses. However, NO treatment in TAK-242 pretreated cells with LPS stimulation further reduced the signs of inflammation and improved hepatoprotective activities. A comparative analysis of the intracellular global metabolome from HepG2 cells with and without NO treatment indicated NO-mediated favorable modulation of intracellular metabolic pathways that support cytoprotective activities.
CONCLUSIONS: NO protects HepG2 cells from LPS-induced oxidative and inflammatory injury. The hepatoprotective effects of NO are mediated by a TLR4-independent process and through a favorable modulation of the intracellular global metabolome that supports cytoprotection.

Natural cardiac glycosides have positive inotropic heart effects but at high, toxic doses they can cause life-threatening cardiac arrhythmias. Here we present the first Croatian case of a 16-year-old girl who attempted suicide by eating dried oleander leaves, which contain natural cardiac glycosides, and her treatment with a specific antidote. The girl presented with an oedema of the uvula indicating local toxicity, severe bradycardia, first-degree atrioventricular block, drowsiness, and vomiting. Having taken her medical history, we started treatment with atropine, intravenous infusion of dextrose-saline solution and gastroprotection, but it was not successful. Then we introduced digoxin-specific Fab antibody fragments and within two hours, the patient\'s sinus rhythm returned to normal. Cases of self-poisoning with this oleander are common in South-East Asia, because it is often used as a medicinal herb, and digoxin-specific Fab fragments have already been reported as effective antidote against oleander poisoning there. Our case has taught us that it is important to have this drug in the hospital pharmacy both for digitalis and oleander poisoning.
Prirodni srčani glikozidi imaju pozitivan inotropni učinak na srce. U visokim, toksičnim dozama mogu prouzročiti za život opasne srčane aritmije. Predstavljamo prvi hrvatski slučaj pokušaja samoubojstva 16-godišnje djevojke konzumiranjem oleandrovih suhih listova, koji sadrže prirodne srčane glikozide, i liječenje specifičnim protuotrovom. Djevojka je također imala edem uvule kao znak lokalne toksičnosti. Svi podatci dobiveni su analizom dokumentacije iz medicinskoga kartona. U djevojke se javila značajna bradikardija, atrioventrikularni blok prvog stupnja, pospanost i povraćanje. Početno liječenje atropinom, intravenskom infuzijom fiziološke otopine i 5 % glukoze uz gastroprotekciju nisu bili učinkoviti. Pacijentica je zatim liječena digoksin-specifičnim Fab imunoglobulinskim fragmentima. Unutar dva sata od primjene lijeka srčani se ritam promijenio u normalni sinusni ritam. Ovo je rijedak slučaj pokušaja suicida samootrovanjem na našim prostorima. Slučajevi samootrovanja ovom biljkom česti su u jugoistočnoj Aziji jer se ondje često koristi kao biljni proizvod za samoliječenje. Digoksin specifični Fab fragmenti su protuotrov za predoziranje digoksinom, kao i za akutnu intoksikaciju ovom biljkom. Važno je imati ovaj lijek u bolničkoj ljekarni kako za intoksikaciju digitalisom tako i za otrovanje ovom biljkom.

UNASSIGNED: Nerium oleander is a toxic plant containing cardiac glycosides throughout all its parts, thereby posing severe health risks upon ingestion. The clinical manifestations of oleander poisoning closely resemble those of digoxin toxicity, encompassing a spectrum of gastrointestinal symptoms, neuropsychiatric disorders, and cardiac disturbances. This scientific case report describes a case of accidental intoxication resulting from the consumption of an oleander leaves infusion misidentified as bay laurel leaves.
UNASSIGNED: An 84-year-old patient consumed an oleander leaves infusion, and after four hours experienced gastrointestinal symptoms. He contacted the poison control center (PCC) and was advised to go to the emergency department (ED). Upon arrival, the patient presented stable vital signs without cardiac irregularities. The PCC recommended the administration of activated charcoal, vigilant monitoring, including electrocardiography (ECG). Subsequent ECGs assessments revealed the presence of third-degree atrioventricular block; in consultation with the PCC, digoxin-specific antibodies and external pacing were necessary. The patient was discharged on the eighth day in good hemodynamic condition, and outpatient follow-up visits showed clinical stability.
UNASSIGNED: This study offers insights for the management of similar cases. The limitations of conventional assays in measuring oleander cardiac glycosides were observed, emphasizing reliance on clinical evaluation. The patient\'s trajectory, remaining asymptomatic despite severe ECG changes post-ingestion, underscores the importance of prolonged clinical monitoring.

The Nerium oleander extract PBI 05204 (PBI) and its cardiac glycoside constituent oleandrin have direct anti-viral properties. Their effect on the immune system, however, is largely unknown. We used an in vitro model of human peripheral blood mononuclear cells to document effects under three different culture conditions: normal, challenged with the viral mimetic polyinosinic:polycytidylic acid Poly I:C, and inflamed by lipopolysaccharide (LPS). Cells were evaluated for immune activation marks CD69, CD25, and CD107a, and culture supernatants were tested for cytokines. Both PBI and oleandrin directly activated Natural Killer (NK) cells and monocytes and triggered increased production of cytokines. Under viral mimetic challenge, PBI and oleandrin enhanced the Poly I:C-mediated immune activation of monocytes and NK cells and enhanced production of IFN-γ. Under inflammatory conditions, many cytokines were controlled at similar levels as in cultures treated with PBI and oleandrin without inflammation. PBI triggered higher levels of some cytokines than oleandrin. Both products increased T cell cytotoxic attack on malignant target cells, strongest by PBI. The results show that PBI and oleandrin directly activate innate immune cells, enhance anti-viral immune responses through NK cell activation and IFN-γ levels, and modulate immune responses under inflamed conditions. The potential clinical impact of these activities is discussed.

BACKGROUND: Nerium oleander L. is ethnopharmacologically used for diabetes. Our aim was to investigate the ameliorative effects of ethanolic Nerium flower extract (NFE) in STZ-induced diabetic rats.
METHODS: Seven random groups including control group, NFE group (50 mg/kg), diabetic group, glibenclamide group and NFE treated groups (25 mg/kg, 75 mg/kg, and 225 mg/kg) were composed of forty-nine rats. Blood glucose level, glycated hemoglobin (HbA1c), insulin level, liver damage parameters and lipid profile parameters were investigated. Antioxidant defense system enzyme activities and reduced glutathione (GSH) and malondialdehyde (MDA) contents and immunotoxic and neurotoxic parameters were determined in liver tissue. Additionally, the ameliorative effects of NFE were histopathologically examined in liver. mRNA levels of SLC2A2 gene encoding glucose transporter 2 protein were measured by quantitative real time PCR.
RESULTS: NFE caused decrease in glucose level and HbA1c and increase in insulin and C-peptide levels. Additionally, NFE improved liver damage biomarkers and lipid profile parameters in serum. Moreover, lipid peroxidation was prevented and antioxidant enzyme activities in liver were regulated by NFE treatment. Furthermore, anti-immunotoxic and anti-neurotoxic effects of NFE were determined in liver tissue of diabetic rats. Histopathogically, significant liver damages were observed in the diabetic rats. Histopathological changes were decreased partially in the 225 mg/kg NFE treated group. SLC2A2 gene expression in liver of diabetic rats significantly reduced compared to healthy rats and NFE treatment (25 mg/kg) caused increase in gene expression.
CONCLUSIONS: Flower extract of Nerium plant may have an antidiabetic potential due to its high phytochemical content.

Nerium oleander L. is a medicinal plant, used for the treatment of cancers and hyperglycemia across the world, especially in Indian sub-continent, Turkey, Morocco, and China. Although clinical studies supporting its pharmacological effects remain critically underexplored, accidental and intentional consumption of any part of the plant causes fatal toxicity in animals and humans. While the polyphenolic fraction of oleander leaves has been attributed to its pre-clinical pharmacological activities, the presence of diverse cardiac glycosides (especially oleandrin) causes apoptosis to cancer cells in vitro and results in clinical signs of oleander poisoning. Thus, the dual pharmacological and toxicological role of oleander is a perplexing dichotomy in phytotherapy. The current investigative review, therefore, intended to analyze the intrinsic and extrinsic factors that likely contribute to this conundrum. Especially by focusing on gut microbial diversity, abundance, and metabolic functions, oleander-associated pharmacological and toxicological studies have been critically analyzed to define the dual effects of oleander. Electronic databases were extensively screened for relevant research articles (including pre-clinical and clinical) related to oleander bioactivities and toxicity. Taxonomic preference was given to the plant N. oleander L. and synonymous plants as per \'The World Flora Online\' database (WCSP record #135196). Discussion on yellow oleander (Cascabela thevetia (L.) Lippold) has intentionally been avoided since it is a different plant. The review indicates that the gut microbiota likely plays a key role in differentially modulating the pharmacological and toxicological effects of oleander. Other factors identified influencing the oleander bioactivities include dose and mode of treatment, cardiac glycoside pharmacokinetics, host-endogenous glycosides, plant material processing and phytochemical extraction methods, plant genotypic variations, environmental effects on the phytochemical quality and quantity, gene expression variations, host dietary patterns and co-morbidity, etc. The arguments proposed are also relevant to other medicinal plants containing toxic cardiac glycosides.

Antimony (Sb) is considered to be a toxic metalloid of increasing prevalence in the environment. Although several phytoremediation studies have been conducted, research regarding the mechanisms of Sb accumulation and translocation within plants remains limited. In this study, soil from a shooting range was collected and spiked with an initial Sb(III) concentration of 50 mg/kg. A pot experiment was conducted to investigate whether Nerium oleander could accumulate Sb in the root and further translocate it to the aboveground tissue. Biostimulation of the soil was performed by the addition of organic acids (OAs), consisting of citric, ascorbic, and oxalic acid at low (7 mmol/kg) or high (70 mmol/kg) concentrations. The impact of irrigation with water supplemented with oxygen nanobubbles (O2NBs) was also investigated. The results demonstrate that there was a loss in plant growth in all treatments and the presence of OAs and O2NBs assisted the plant to maintain the water content at the level close to the control. The plant was not affected with regards to chlorophyll content in all treatments, while the antioxidant enzyme activity of guaiacol peroxidase (GPOD) in the roots was found to be significantly higher in the presence of Sb. Results revealed that Sb accumulation was greater in the treatment with the highest OAs concentration, with a bioconcentration factor greater than 1.0. The translocation of Sb for every treatment was very low, confirming that N. oleander plant cannot transfer Sb from the root to the shoots. A higher amount of Sb was accumulated in the plants that were irrigated with the O2NBs, although the translocation of Sb was not increased. The present study provides evidence for the phytoremediation capacity of N. oleander to bioaccumulate Sb when assisted by biostimulation with OAs.

Nerium oleander is one of the most poisonous plants, and its accidental ingestion has frequently occurred in humans and livestock. It is vital to develop a rapid and accurate identification method for the timely rescue of oleander-poisoned patients and the investigation of poisoning cases. In this study, a specific and highly sensitive quantitative real-time PCR (qPCR)-based method was developed to identify oleander in mixture systems and simulated forensic specimens (SFS). First, a new pair of oleander-specific primers, JZT-BF/BR, was designed and validated. Then, a qPCR method was developed using the primers, and its detective sensitivity was examined. The results showed that JZT-BF/BR could specifically identify oleander in forage and food mixtures, and qPCR was capable of accurate authentication even at a low DNA concentration of 0.001 ng/μL. This method was further applied to the analysis of SFS containing different ratios of N. oleander. The method was confirmed to be applicable to digested samples, and the detection limit reached 0.1% (w/w) oleander in mixture systems. Thus, this study undoubtedly provides strong support for the detection of highly toxic oleander and the diagnosis of food poisoning in humans and animals.

Oleandrin, a cardiac glycoside isolated from the leaves of Nerium oleander, has known effects on the heart. Evidence from recent studies have highlighted its potential for anticancer properties. Therefore, we aimed to investigate the effects of oleandrin on cancer cell proliferation, viability and apoptosis in vitro and in vivo. We performed a systematic search in six electronic databases up to Jan 2022. We extracted information about the effects of oleandrin on cell proliferation, cell viability, apoptosis and/or cell cycle arrest in in vitro studies, and the effects on tumor size and volume in animal experimental models. We have retrieved 775 scientific studies. 14 studies met the inclusion criteria. They investigated the effects of oleandrin on breast, lung, pancreatic, colon, prostate, colorectal, oral, ovarian, glioma, melanoma, glioblastoma, osteosarcoma, and histiocytic lymphoma cancers. Overall, in vitro studies demonstrated that oleandrin was able to inhibit cell proliferation, decrease cell viability, and induce apoptosis and/or cell cycle arrest. In addition, oleandrin had an effect on reducing mean tumor size and volume in animal studies. Oleandrin, as a cytotoxic agent, demonstrated antitumor effects in different types of cancers, however important clinical limitations remain a concern. These results encourage future studies to verify the applicability of oleandrin in antineoplastic therapeutic protocols human and veterinary medicine, the investigation of antimetastatic properties, as well as the potential increase in patient survival and the decrease of tumor markers.