The fruit itself is something of a botanical curiosity. It comes in two distinct forms: a bitter wild type loaded with cucurbitacins, triterpenoid compounds that are highly toxic in large quantities, and a non bitter cultivated form that has gained international acceptance and is now grown commercially in countries such as New Zealand and Australia. The non bitter variety is rich in saponins, oily glycosides that foam when shaken with water and carry a mixture of medicinal properties and potential toxicity. Traditional practitioners have used decoctions of the root to relieve postpartum pain and to treat gonorrhea, while the fruit has been investigated for antimicrobial activity against Salmonella Gallinarum. Yet despite this long history of use, the authors noted a striking gap: almost no toxicological data existed for the fruit in mice, the workhorse animal of modern pharmacology.

To fill that gap, the team collected ripe fruits at the National Veterinary Research Institute, had them authenticated by a plant taxonomist at the University of Jos, and processed them into a powder that was extracted with distilled water using cold maceration over 72 hours. The resulting crude aqueous extract was then tested in Swiss albino mice of both sexes under protocols approved by the institute’s Animal Use and Care Committee. The researchers ran two complementary investigations: an acute toxicity test following Lorke’s method, in which mice received single oral doses ranging from 10 to 5000 milligrams per kilogram of body weight, and a 28 day sub acute study modeled on OECD guideline 407, in which one hundred mice were divided into a control group receiving distilled water and three treatment groups receiving daily doses of 200, 400, or 600 milligrams per kilogram.

The acute results were reassuring. Not a single mouse died or showed abnormal behavior at any dose, from the lowest to the highest, meaning the median lethal dose exceeds 5000 milligrams per kilogram. By the classification standards of Clarke and Clarke, natural substances with lethal doses in the range of 5000 to 15000 milligrams per kilogram are considered only slightly toxic, and OECD guidelines place compounds with values at or above 5000 milligrams per kilogram in class 5, the lowest toxicity category. The finding also aligns with earlier work in rats and cockerels, which similarly reported lethal doses above 5000 milligrams per kilogram for both aqueous and methanol extracts of the fruit. In other words, a one time dose of the ripe fruit extract is, by every measure applied here, remarkably benign.

The 28 day study told a subtler story. Body weights remained unchanged across all groups, suggesting the extract did not suppress appetite, an effect the authors attribute to phytochemicals such as alkaloids, flavonoids, and phenols that are known to regulate feeding. But the blood work revealed significant shifts. Red blood cell counts and packed cell volume rose markedly, with the highest dose group reaching a red cell count of 11.10 million cells per liter on day 21, up from 8.15 at baseline, and packed cell volume climbing from 48.54 percent to 65.11 percent. The researchers suggest these changes may reflect the fruit’s abundant iron, riboflavin, niacin, and amino acids, nutrients known to support red cell synthesis, and they speculate the fruit could hold promise as an anti anemia agent. Total white blood cells, by contrast, fell significantly at the highest dose, dropping from 8.84 to 2.66 billion cells per liter by day 21, alongside reduced lymphocyte counts, a pattern the authors interpret as a possible immunosuppressive effect.

The serum biochemistry raised the loudest alarm bells. Levels of aspartate aminotransferase, alanine aminotransferase, and alkaline phosphatase, the classic trio of liver enzymes monitored in clinical practice, rose significantly across the treatment groups. Alanine aminotransferase is primarily liver specific and a reliable marker of liver disease, while aspartate aminotransferase, though found in many tissues, is sensitive to hepatic injury. Albumin and total protein declined, globulin climbed, and direct bilirubin fell at the highest dose. Taken together, these changes point toward liver damage or dysfunction, and the authors flag the presence of coumarins in the extract as a plausible culprit, since these compounds have been linked to hepatotoxicity despite their anticoagulant benefits.

Histopathology confirmed what the blood tests implied. Under the microscope, livers from treated mice showed congestion of hepatocytes at every dose tested, and at 400 milligrams per kilogram the tissue displayed slight necrosis, the death of liver cells. The kidneys and intestines, however, remained structurally normal at all doses. That renal resilience was echoed in the chemistry: urea and creatinine, the standard indicators of kidney function and protein metabolism, actually decreased significantly during treatment. The authors suggest that flavonoids and quinones in the fruit, which scavenge reactive oxygen species and promote diuresis, may exert a nephroprotective effect, consistent with earlier reports of kidney protection from methanol extracts of the fruit in cockerels.

The electrolyte data added one more layer of complexity. Serum sodium rose significantly at the highest dose, from 129.76 to 141.36 milliequivalents per liter by day 28, and chloride increased across all treatment groups. Elevated sodium and chloride can signal dehydration or kidney damage, but since the treated mice showed no dehydration and their kidney tissue appeared normal, the researchers point to another explanation: the fruit itself is rich in sodium, with previous analyses reporting roughly 8.9 to 16.7 milligrams of sodium per 100 grams of seed, so dietary intake from the extract may simply have raised circulating levels directly.

The overall verdict is a cautionary tale about the difference between a single dose and sustained use. The aqueous extract of Cucumis metuliferus appears safe within 24 hours, may support red blood cell production, and shows no signs of harming the kidneys, but prolonged administration risks liver injury, a conclusion consistent with earlier reports of hepatic and renal toxicity in cockerels and rats given extended courses of the extract. The authors emphasize that their findings apply to unrefined, crude extracts, whose chemical composition can vary widely, and they call for further research to identify the specific phytochemicals responsible for both the beneficial hematological effects and the hepatic damage. For the millions of people who turn to traditional plant remedies first, the spiky horned melon now comes with a clearer, and more nuanced, safety label: fine in a pinch, potentially harmful as a daily habit.

Subject of Research: Acute and sub-acute oral toxicity of the aqueous extract of ripe Cucumis metuliferus fruit in Swiss albino mice

Article Title: Toxicity assessment of the ripe fruit of Cucumis metuliferus in Swiss albino mice

Article References: Usman, J. G., Gadzama, U. N., Thliza, C. B., Elisha, I. L., Barde, I. J., Onakpa, M. M., Sanni, S., & Ajagbonna, O. P. (2025). Toxicity assessment of the ripe fruit of Cucumis metuliferus in Swiss albino mice. Discover Toxicology, 2(1), Article 5. https://doi.org/10.1007/s44339-025-00021-1

Image Credits: AI Generated

DOI: 10.1007/s44339-025-00021-1

Keywords: Cucumis metuliferus, horned melon, toxicity, hepatotoxicity, Swiss albino mice, acute toxicity, sub-acute toxicity, hematology, liver enzymes, nephroprotection, traditional medicine, aqueous extract

The research team, led by Kenedy Kiyimba of the University of Nairobi and Busitema University, together with colleagues in Pakistan and Kenya, harvested stem bark from trees growing in Mabira Forest in central Uganda in June 2023. A taxonomist verified the species, and a voucher specimen was deposited at the Makerere University Herbarium. The bark was shade-dried for twenty-eight days, ground into powder, and soaked in seventy percent ethanol for seventy-two hours to produce a crude extract that mirrors the decoctions traditional practitioners prepare. That extract was then separated into fractions using solvents of increasing polarity, beginning with n-hexane, followed by ethyl acetate and methanol, so that each chemical family could be studied in isolation.

Gas chromatography-mass spectrometry, the workhorse technique for identifying volatile organic compounds, revealed a rich chemical inventory. The ethanolic extract alone produced twenty-two chromatographic peaks, while the hexane fraction yielded an astonishing 121 peaks. Across all fractions, the researchers identified nineteen major phytocompounds, each selected when its mass spectral match in the National Institute of Standards and Technology library exceeded a fifty percent probability threshold. Fourier transform infrared spectroscopy then confirmed the presence of characteristic functional groups, including alkenes, carboxylic acids, quinones, and polyglycines, which are the molecular machinery behind much of the plant’s biological activity. Qualitative screening added further depth, detecting flavonoids, tannins, steroids, glycosides, alkaloids, phenolics, and anthraquinones.

Many of these compounds carry impressive pharmacological credentials. One constituent from the ethanolic extract has documented anti-inflammatory, anti-apoptotic, and anti-infective properties. Another from the ethyl acetate fraction has shown antioxidant, antiviral, and antineoplastic activity, while a compound in the methanolic fraction is closely related to molecules with demonstrated antitumor effects. Alkene-containing compounds are known to exhibit antioxidant, antibacterial, and antiproliferative actions, and carboxylic acids have shown antimicrobial and anticancer potential. These findings lend chemical credibility to the plant’s traditional uses, which range from treating venereal infections in Cameroon to managing diabetes among the Nandi community in Kenya and addressing malaria, fever, mental illness, and epilepsy in the eastern Democratic Republic of Congo.

But chemistry alone cannot establish safety, so the team turned to computational toxicology. Using six online prediction platforms, including ADMET Lab 3.0, SWISS ADME, admetSAR, pkCSM, PreADMET, and ProTox 3.0, the researchers assessed the nineteen most abundant compounds for nine categories of toxic risk: cardiotoxicity, hepatotoxicity, mutagenicity, carcinogenicity, rat oral acute toxicity, skin sensitization, eye irritation, eye corrosion, and respiratory toxicity. The predictions flagged skin sensitization for most compounds and identified a significant respiratory toxicity risk for five of them. Encouragingly, no meaningful concerns emerged for cardiotoxicity, liver injury, mutagenicity, or carcinogenicity, and only a single compound was predicted to pose oral toxicity risks in rats.

The in vivo phase of the study followed internationally recognized protocols. For acute toxicity testing, female Wistar rats received a single oral dose of the ethanolic extract at either 2000 or 5000 milligrams per kilogram of body weight. Within thirty minutes, the animals showed decreased activity, lethargy, piloerection, and unusual vocalizations, effects that persisted for roughly twelve hours. More than half of the rats had recovered by twenty-four hours, and all animals returned to normal within forty-eight hours. Crucially, no deaths occurred during the fourteen-day observation period, meaning the lethal dose for fifty percent of the animals, the LD50, exceeds 5000 milligrams per kilogram, a threshold that classifies the extract as essentially non-toxic in acute terms.

The sub-acute study was more demanding. Forty young adult rats of both sexes received daily oral doses of 200, 400, or 800 milligrams per kilogram for twenty-eight days, corresponding to one-tenth, one-fifth, and two-fifths of the maximum tolerated acute dose, while a control group received distilled water. Blood samples collected on day twenty-nine underwent full hematological and biochemical analysis, covering red and white blood cell counts, hemoglobin, hematocrit, platelets, liver enzymes, kidney markers, lipids, and electrolytes. The results were largely reassuring: no significant toxic changes appeared in any biochemical or hematological parameter compared with controls, and the weights of the liver, kidneys, pancreas, lungs, heart, stomach, uterus, and testes remained unaltered.

Two subtle signals did emerge, however. Rats receiving the highest dose lost body weight in a dose-dependent pattern, and food consumption differed significantly between treated and control animals, hinting that the extract may influence appetite and metabolism, an observation that aligns with the plant’s traditional reputation for regulating appetite and supporting digestive health. Hemoglobin and hematocrit levels rose with dose, suggesting possible stimulation of blood cell production that could support the plant’s folk use as a blood tonic. The most consequential finding, though, came from the microscope. Histopathological examination of lung tissue revealed dose-dependent inflammation: the two lower doses produced mild bronchitis with mononuclear cell infiltration, while the highest dose caused marked accumulation of lymphoid cells around the bronchioles and blood vessels. No comparable lesions appeared in the liver, kidneys, or heart.

The lung findings dovetail strikingly with the computational predictions, which had flagged five compounds for potential respiratory toxicity. The authors suggest the damage may stem either from direct accumulation of phytocompounds in lung tissue or from immune-mediated reactions, though pinpointing the responsible chemicals will require further work. There is also an important caveat regarding the chemistry itself: gas chromatography primarily detects volatile and thermally stable compounds, so large non-volatile molecules such as polyphenols, alkaloids, and glycosides may have escaped detection. The researchers recommend follow-up analysis with liquid chromatography-mass spectrometry and nuclear magnetic resonance spectroscopy to build a more complete chemical picture, alongside mechanistic and clinical studies to bridge the gap between rats and humans.

For the millions of people across tropical Africa who brew Parasol Tree bark as medicine, the study delivers a nuanced verdict. The plant’s acute safety profile is genuinely strong, its effects on blood chemistry and organ function appear benign at traditional dose ranges, and its phytochemical arsenal plausibly underpins the anticancer, antibacterial, and hypoglycemic activities documented in earlier research. Yet the same analysis shows the plant is not entirely innocent: prolonged exposure may inflame the lungs, and several of its constituents are predicted to irritate skin and eyes. As modern science continues to validate traditional remedies, Polyscias fulva emerges as a valuable resource that merits both further investigation and careful conservation, used with respect for its power rather than blind faith in its safety.

Subject of Research: Phytochemical profiling and acute and sub-acute toxicity evaluation of Polyscias fulva stem bark extract

Article Title: Phytochemical analysis and toxicity evaluation of Polyscias fulva stem bark extract using gas chromatography-mass spectrometry, fourier transform infrared spectroscopy, in silico, and in vivo studies in wistar rats

Article References: Kiyimba, K., Ahmed, A., Choudhary, M. I., Obakiro, S. B., Gavamukulya, Y., Guantai, E. M., & Munyendo, W. L. (2025). Phytochemical analysis and toxicity evaluation of Polyscias fulva stem bark extract using gas chromatography-mass spectrometry, fourier transform infrared spectroscopy, in silico, and in vivo studies in wistar rats. Discover Toxicology, 2(1), Article 11. https://doi.org/10.1007/s44339-025-00031-z

Image Credits: AI Generated

DOI: 10.1007/s44339-025-00031-z

Keywords: Polyscias fulva, phytochemistry, GC-MS, FTIR, acute toxicity, sub-acute toxicity, Wistar rats, in silico toxicity prediction, traditional medicine, lung histopathology, medicinal plants, toxicology