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Biomedical subjects

T Ohnuma

Publications and source records attributed to T Ohnuma.

At least 19 recordsLinked to original sources
PubMed2003

Height, weight, and alcohol consumption in relation to the risk of colorectal cancer in Japan: a prospective study.

Colorectal cancer incidence in relation to body size, smoking, and alcohol consumption was studied in a cohort of 29 051 city residents of Japan. In 1992, each participant completed a self-administered questionnaire on sociodemographic characteristics, drinking, cigarette smoking, diet, exercise, and reproductive and medical histories. The response rate was 92%. From 1993 to 2000, 161 men and 134 women were diagnosed with colorectal cancer at two major hospitals in the city. Relative risks and 95% confidence intervals were calculated by using Cox proportional hazard models. A positive relation between height and colorectal cancer was seen in both sexes, controlling for age, body mass index (BMI), smoking and drinking habits, and years of education. The findings were statistically significant only for men (relative risk 2.13 for the tallest compared with the shortest height tertile; 95% confidence interval=1.26-3.58). Body mass index was also associated positively with colon cancer risk for men, whereas the pattern for women was not clear. There was a positive association between pack-years of cigarette smoking and the risk of rectal cancer in men. A positive dose-response relation between alcohol consumption and colon cancer risk was observed for men and women.

Adult↗
PubMed2001

Diet and colorectal adenoma in Japanese males and females.

PURPOSE: The purpose of this study was to assess the relationship between risk of colorectal adenoma and dietary intake of nutrients and foods. METHODS: In 1992, diet was assessed by a semiquantitative food-frequency questionnaire in a cohort of the Takayama Study in Japan. Patients were 181 male and 98 female cohort members who were newly histologically proved to have colorectal adenoma at colonoscopic examination between January 1, 1993, and December 31, 1995. Controls were 12,607 males and 15,754 females who had no history of colorectal polyp, adenoma, and cancer at baseline (1992) and were not diagnosed to have these diseases during the follow-up period. RESULTS: In males, the risk of adenoma was significantly associated with intake of animal protein and vitamin A (relative risk, 1.42; 95 percent confidence interval, 1.00-2.04; and relative risk, 1.51; 95 percent confidence interval, 1.04-2.20, for the highest vs. lowest tertiles, respectively; P for trend = 0.048 and 0.03, respectively) after controlling for age, years of smoking, and alcohol intake. A significantly inverse association was observed for carbohydrate intake after controlling for the covariates (relative risk, 0.52; 95 percent confidence interval, 0.32-0.82, for the highest vs. lowest tertiles; P for trend = 0.02). Intakes of animal fat and cholesterol were marginally associated with risk of adenoma. CONCLUSION: Some dietary components such as animal protein and carbohydrate, which have been associated with risk of colorectal adenoma or cancer in western populations, were also associated with risk of colorectal adenoma in the Japanese population.

Adenoma↗
PubMed2000

Gene expression of metabotropic glutamate receptor 5 and excitatory amino acid transporter 2 in the schizophrenic hippocampus.

A disturbance in glutamatergic transmission has been suggested to contribute to the pathophysiology of schizophrenia and recent studies on ionotropic glutamate receptors are consistent with altered glutamatergic function in the hippocampus of schizophrenics. In order to investigate this hypothesis further, the expression of two 'glutamatergic' markers, the mRNAs of metabotropic glutamate receptor 5 (mGluR5) and human excitatory amino acid transporter (EAAT2) were compared in the hippocampus of control subjects and schizophrenics. We examined the regional/cellular mRNA expression of mGluR5 and EAAT2 in postmortem hippocampal sections from schizophrenics and control subjects, using in situ hybridization. Regions of interests were dentate gyrus, cornu ammonis 4, 3, 1 and parahippocampal gyrus. The regional/cellular mGluR5 mRNA content was not different between the two groups. The cellular EAAT2 mRNA content was significantly decreased in schizophrenic parahippocampal gyrus, but not in other hippocampal regions. Furthermore, only in the parahippocampal gyrus, schizophrenics had a significantly increased mGluR5/EAAT2 ratio at both the regional and cellular mRNA level. The results suggest that a disturbance of glutamatergic neurotransmission in schizophrenia was not apparent using these indices in the hippocampus, but 'hypo-glutamatergic' neurotransmission may be present in the schizophrenic parahippocampal gyrus.

Actins↗
PubMed2000

Gene expression of PSD95 in prefrontal cortex and hippocampus in schizophrenia.

A number of studies have suggested that disturbance in glutamatergic transmission in the cerebral cortex may underlie, or contribute to the pathophysiology of schizophrenia. In this study we examined expression of the postsynaptic density protein 95 (PSD95) mRNA in the prefrontal cortex and hippocampus in postmortem material from neuroleptic-treated schizophrenics and normal controls. PSD95 is known to bind to NMDA receptor subunits and is known to be involved in synaptic plasticity. In situ hybridization analysis showed that the expression of PSD95 was significantly decreased in Brodmann area 9 of the prefrontal cortex but not in the hippocampus. These results further implicate the prefrontal cortex in the pathophysiology of schizophrenia and suggest dysfunction of NMDA receptors in the schizophrenic cortex.

Aged↗
PubMed2000

No genetic association between alpha-2 macroglobulin I1000V polymorphism and Japanese sporadic Alzheimer's disease.

Alpha-2 macroglobulin (A2M) is a serum pan-protease inhibitor that is related with the pathogenesis of Alzheimer's disease (AD) through its ability to mediate amyloid beta degradation. Recently, it has been reported that the I1000V polymorphism in A2M gene might increase the risk of AD. In the present study, we investigated this mutation in 95 healthy controls and in 111 sporadic AD cases by polymerase chain reaction-restriction fragment length polymorphism method in order to study this hypothesis in the Japanese AD population. Allelic frequencies with the I1000V polymorphism in the gene were 7.4 and 6.8% in the control and AD groups, respectively. Our results failed to demonstrate an association between this polymorphism and Japanese sporadic AD, and the A2M I1000V mutation does not seem to be a risk factor per se for sporadic AD.

Aged↗
PubMed2000

Lack of an association of estrogen receptor alpha gene polymorphisms and transcriptional activity with Alzheimer disease.

BACKGROUND: Long-term cognitive decline in postmenopausal women is associated with aging and Alzheimer disease (AD). Estrogen replacement therapy has been reported to reduce the risk of developing AD. The distribution of estrogen receptors (ERs) in neurons overlaps that of the brain neurons known to develop AD. Estrogen increases the secretion and metabolism of amyloid precursor protein, may help synapse formation, and is reported to protect neurons from toxins. Restriction fragment length polymorphisms (RFLPs) of the ERalpha gene at intron 1 and exon 2 were associated with a low bone mineral density in postmenopausal women and also with AD in a Japanese population. OBJECTIVE: To determine whether ERalpha gene polymorphisms are associated with transcriptional activity and AD. METHODS: A luciferase reporter assay analyzed enhancer activity of the ERalpha gene at intron 1 and exon 2. This activity was evaluated according to the RFLPs. The RFLPs of the ERalpha gene were determined in Japanese patients clinically diagnosed as having AD, white patients diagnosed as having AD at autopsy, and corresponding healthy control subjects. The RFLPs were also evaluated for the contribution of the ERalpha gene RFLPs to AD. RESULTS: We found weak (about 2-fold) enhancer activity of the ERalpha gene, which differed among RFLPs. Although there were racial differences in these polymorphisms, we could not confirm the previously reported association between ERalpha gene polymorphisms and AD. CONCLUSION: Regulatory element of the ERalpha gene was found in intron 1, but we found no association between ERalpha gene polymorphisms and AD.

Aged↗
PubMed2000

Marked inhibition of glioblastoma target cell tumorigenicity in vitro by retrovirus-mediated transfer of a hairpin ribozyme against deletion-mutant epidermal growth factor receptor messenger RNA.

OBJECT: The goal of this study was to evaluate the activity of certain hairpin ribozymes against deletion-mutant epidermal growth factor receptor (deltaEGFR) messenger (m)RNA in glioblastomas multiforme (GBMs). A distinct 801-bp deletion mutation associated with amplification of the EGFR gene is present in a large subgroup of primary GBMs and confers enhanced tumorigenicity in vivo. As a result of the deletion mutation, the fusion junction of the gene is created directly upstream of a GTA triplet, which is subsequently transcribed into a ribozyme target codon (GUA). METHODS: In attempts to intercept deltaEGFR gene expression at the mRNA level, the authors designed three different hairpin ribozymes derived from the negative strands of satellite RNAs in tobacco ringspot virus, chicory yellow mottle virus (sCYMV1), and arabis mosaic virus against this target and evaluated their efficiency and specificity in a cell-free system. The sCYMV1, identified as the most active anti-deltaEGFR hairpin ribozyme motif, was cloned into the retroviral plasmid N2A+tRNAi(met). High-titer recombinant retrovirus-containing supernatants (> 10(5) colony-forming units/ml) derived from an amphotropic GP+envAM 12 packaging cell line transfected with the N2A+tRNAi(met)-anti-deltaEGFR-sCYMV1 construct were used to introduce the sCYMV1 hairpin ribozyme into U-87MG.deltaEGFR glioblastoma cells, which overexpress exogenous deltaEGFR. Using a virus/target cell ratio of 40:1 in the absence of drug selection, the ribozyme transfer resulted in a greater than 90% reduction of deltaEGFR mRNA levels, a 69% inhibition of deltaEGFR-mediated proliferation advantage, and a greater than 95% decrease of colony formation in soft agar under relative serum starvation conditions in vitro; transfer of a control mutant ribozyme that was rendered incapable of cleaving its target yielded none of these effects. CONCLUSIONS: These findings indicate that the anti-deltaEGFR-sCYMV1 hairpin ribozyme is capable of specifically inhibiting the expression of deltaEGFR and reversing the deltaEGFR-associated malignant phenotype of GBM cells. This strategy may constitute a promising gene therapy approach for a molecularly defined subgroup of GBMs.

Base Sequence↗
PubMed2000

[Electromyographic study of the striated urethral sphincter by using the bulbocavernosus reflex: study on change of sacral reflex activity caused by bladder filling].

PURPOSE: The change of sacral reflex activity of the striated urethral sphincter in the urine storage phase is investigated using evoked potential reaction of the bulbocavernosus reflex (BCR). METHODS: Eleven normal male subjects and 13 male patients with neurogenic bladder due to suprasacral (C3-C7) spinal cord injury (SCI patients) were investigated. Within the SCI patients, five were complete SCI and 8 were incomplete SCI. BCR was elicited by electrical stimulation of dorsal nerve of the penis, and the evoked potential of the BCR was recorded with a concentric needle electrode from the periurethral striated muscle. BCR was performed both at empty and at filled bladder respectively, and changes of the amplitudes (AMP) were examined. Moreover, the changes of AMP affected by bladder filling were compared between the normal subjects and the SCI patients. RESULTS: In both the normal subjects and the SCI patients, AMP increased at the filled bladder as compared with that of the empty bladder. In addition, the change of AMP was statistically bigger in the SCI patients (a ratio of amplitude at filled bladder/amplitude at empty bladder: 4.73 +/- 3.90) than in the normal subjects (the ratio: 1.32 +/- 0.44). CONCLUSION: Sacral reflex activity was accelerated by bladder filling in both the normal subjects and SCI patients. And the acceleration in the SCI patients was more remarkable than that in the normal subjects. In addition to the conventional evaluation of the integrity of sacral reflex arc by BCR examination, the observation of changes of BCR affected by bladder filling may provide the information for the continuity of sacral segment and supraspinal micturition center.

Adult↗
PubMed1999

Genetic association between alpha-2 macroglobulin and Japanese sporadic Alzheimer's disease.

Alpha-2 macroglobulin (encoded by the gene A2M) is a serum pan-protease inhibitor that may be related with the pathogenesis of Alzheimer's disease (AD) because of its ability to mediate amyloid beta degradation. Recently, several groups have reported that the five-nucleotides deletion in A2M gene at the 5' splice site of exon 18 might increase risk for AD. In the present study, therefore, this mutation was studied in 69 healthy controls and 55 sporadic AD cases by polymerase chain reaction- restriction fragment length polymorphism method. The allelic frequencies with the deletion (A2M-2) are 9.4 and 6.4% in the control and AD groups, respectively. There is no significant difference in the A2M-2 frequencies between the controls and sporadic AD cases. This is the first report to study the frequencies of A2M-2 in Japanese AD cases, suggesting its no genetic association with sporadic AD.

Adult↗
PubMed1999

Retrovirus-mediated transfer of anti-MDR1 hammerhead ribozymes into multidrug-resistant human leukemia cells: screening for effective target sites.

One of the underlying mechanisms of multidrug resistance (MDR) is cellular over-production of P-glycoprotein (P-gp), which acts as a drug efflux pump. P-gp is encoded by a small group of related genes termed MDR; only MDR1 is known to confer drug resistance. To overcome P-gp-mediated drug resistance, we have developed two anti-MDR1 hammerhead ribozymes driven by the beta-actin promoter. Upon transduction of the ribozymes into MDR cells, vincristine resistance was decreased. These two ribozymes were constructed, which showed different cleavage activities. In this study, to determine suitable target sites for the anti-MDR1 ribozyme, the exon 1b-intron 1 boundary, the translation-initiation site, the intron 1-exon 2 boundary and the exon 2-intron 2 boundary, codons 179 and 196 of the MDR1 gene were selected as candidates. To improve the ribozyme activity, a retroviral vector containing RNA polymerase III promoter was used. Stable retrovirus producer cells were generated by transfecting the retroviral vector plasmids carrying the ribozyme into the packaging cell line. Retroviral vector transduction of human leukemia cell lines expressing MDR1 was accomplished by co-culturing these with virus producer cells. Stably transduced cells were selected by G418 and pooled to determine the efficacy of each ribozyme. These ribozyme-transduced cells became vincristine-sensitive concomitant with the decreases in MDR1 expression, P-gp amount and drug efflux pump function. Among the ribozymes tested, the anti-MDR1 ribozyme against the translation-initiation site exhibited the strongest efficacy. This retrovirus-mediated transfer of anti-MDR1 ribozyme may be applicable to the treatment of MDR cells as a specific means to reverse resistance.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1999

Retrovirus-mediated transfer of anti-MDR1 ribozymes fully restores chemosensitivity of P-glycoprotein-expressing human lymphoma cells.

Development of multidrug resistance (MDR) is the major obstacle to successful cancer chemotherapy. We have developed Daudi human lymphoma cells that are 20-fold more resistant than the parent cell line to vincristine (VCR) by infecting cells with pHaMDR1/A retroviral vector (Daudi/MDR20). Three DNA sequences of anti-MDR1 hammerhead ribozymes (Rzs), one cleaving codon 196 of MDR1 mRNA (196MDR1-Rz), the second a stem II base-modified (U9-->Gg, U13-->A13, G14-->A14, A18-->C18) Rz against codon 196 (196MDR1-sRz), and the third a stem II base-modified Rz directed against the -6 approximately -4 GUC sequence of the translation initiation site of the MDR1 mRNA (iMDR1-sRz), were synthesized and cloned into the retroviral vector N2A+tRNAiMet downstream of the RNA polymerase III promoter and adjacent to a tRNA gene sequence, forming the constructs N2A+tRNAiMet-196MDR1-Rz, N2A+tRNAiMet-196MDR1-sRz, and N2A+tRNAiMet-iMDR1-sRz. The three constructs were transfected into GP+envAM 12 cells for packaging the retroviral vectors. The supernatants containing the packaged retrovirus in high titers (1.1-2.5 X 10(5) CFU/ml as determined by infection of NIH 3T3 cells) were used to infect Daudi/MDR20 cells. The iMDR1-sRz- and 196MDR1-sRz-transduced Daudi/MDR20 cells completely restored chemosensitivity to VCR and doxorubicin, and were accompanied by blocked expression of MDR1 mRNA and P-glycoprotein as well as overexpression of anti-MDR1 Rz. In a cell-free system, the chimeric tRNA-sRz molecules were more stable and had more efficient catalytic activities than the corresponding naked Rz molecules. The stem II base-modified Rz were also more stable and efficient in catalytic activities than the unmodified Rz molecules. The base modification in the Rz stem II structure and the development of chimeric tRNA-Rz molecules were identified to enhance the cleavage efficacy. The combination of these two factors, together with the use of a retroviral vector, appear to have contributed to the complete reversal of MDR.

ATP Binding Cassette Transporter, Subfamily B↗
PubMed1999

Cigarette smoking, alcohol use, and colorectal adenoma in Japanese men and women.

PURPOSE: The aim of this study was to examine the relationships between smoking and alcohol use and risk of colorectal adenoma. METHODS: Information about smoking, alcohol use, and other lifestyle variables were obtained prospectively from 14,427 male and 17,125 female residents in a city of Gifu Prefecture, Japan, by a self-administered questionnaire in September, 1992. Colorectal adenomas were newly diagnosed in 181 men and 78 women in this cohort between January, 1993 and December, 1995 by colonoscopic examination at two major hospitals of the city. Gender-specific and site-specific relative risks and 95 percent confidence intervals adjusted for age and for age plus other potential confounding factors were calculated by using logistic regression models. RESULTS: Thirty or more years of smoking was significantly associated with risk of adenoma in general compared with never having smoked in both men and women (relative risk, 1.60; 95 percent confidence interval, 1.02-2.62 and relative risk, 4.54; 95 percent confidence interval, 2.04-9.08, respectively). Effect of smoking was stronger in the proximal colon. After adjusting for age and carbohydrate intake, total alcohol intake was not associated with risk of adenoma in any site in the colon in men. Sake drinkers were at significantly increased risk of adenoma in general, but the dose-response relationship was not statistically significant. Risk of adenoma in the rectum was not significantly increased for those who consumed >30.3 g/day of ethanol (relative risk, 5.7). CONCLUSION: These data suggest that smoking is a risk factor of adenoma in Japanese men and women. The role of alcohol, however, is less clear.

Adenoma↗
PubMed1999

Measurement of GABAergic parameters in the prefrontal cortex in schizophrenia: focus on GABA content, GABA(A) receptor alpha-1 subunit messenger RNA and human GABA transporter-1 (HGAT-1) messenger RNA expression.

The hypothesis that the pathophysiology of schizophrenia may be associated with a dysfunction in GABA transmission in the human prefrontal cortex was investigated. Human post mortem brain tissue from 10 control cases and six cases of schizophrenia were processed for amino acid analysis and for radioactive in situ hybridization. Laminae III and V of three prefrontal cortical areas were examined in detail, namely Brodmann areas 9, 10 and 11. Of these three areas significant changes in GABAergic markers were found only in areas 9 and 10. Of note, a significant decrease in the tissue content of GABA was observed and this was accompanied by a marked increase in the cellular expression of the GABA(A) receptor alpha-1 subunit messenger RNA and a marked decrease in the expression of human GABA transporter-1, the messenger RNA encoding the neuronal GABA transporter protein. The amino acid analysis data provided in this study coupled with the detailed cellular study of several GABAergic markers in the human prefrontal cortex provide direct evidence in support of a disturbance in GABA transmission in the prefrontal cortex, which may be loosely termed "hypofrontality".

Aged↗
PubMed1999

Genetic association between cytochrome P-450 2D6 gene polymorphism and plasma concentration of haloperidol in Japanese schizophrenics.

Haloperidol is one of the major neuroleptics partly metabolized by cytochrome P-450 2D6 (CYP2D6), which has over 10 genetic polymorphisms. The purpose of this study was to investigate whether individual haloperidol plasma concentration was affected by CYP 2D6 gene polymorphisms. The genomic DNA of 56 subjects who have been taking haloperidol were analysed by restriction fragment length polymorphism (RFLP) method to detect the major Caucasian mutations, CYP 2D6A, 2D6B, and the major oriental population mutation, 2D6J. We found 10 cases of the CYP 2D6J mutation, only one case of the CYP 2D6B mutation, and no cases of the CYP 2D6A mutation in the present subjects. Contrary to expectations, haloperidol plasma concentration of the CYP 2D6B mutation case showed a lower haloperidol plasma concentration than the mean value of that of wild type homozygous cases. Haloperidol plasma concentration of 10 subjects who had the CYP 2D6J mutation cases showed no significant difference from that of the wild type homozygous group. These results suggest that the major genetic polymorphisms of CYP 2D6 do not seem to be one of the factors which affect individual haloperidol plasma concentration in Japanese schizophrenics.

Adult↗
PubMed1999

Inhibitory effect of telomere-mimic phosphorothioate oligodeoxy nucleotides (S-ODNS) on human tumor cell lines.

To clarify the inhibitory effect of telomere-mimic oligonucleotides on human cancer cell lines, we synthesized 18-mers (18T; n = 3), 24-mers (24T; n = 4) and 30-mers (30T; n = 5) of telomere-mimic phosphorothioate oligodeoxy nucleotides [5'-d(TTA GGG)n-3'] and examined their effects on the proliferation of human tumor cells by XTT assay. After 7 days of continuous exposure to 24T and 30T at concentrations ranging from 0.1 to 10 microM, concentration-dependent cell growth inhibition was observed in MCF-7 clone E3, ZR-75-1, MDA-MB 231, Colo 201 and WiDr. All of these cell lines highly expressed telomerase using the telomeric repeat amplification protocol. None of these tumor cell lines were affected by 18T. In MCF-7, ZR-75-1 and Colo 201 cell lines, a more than 50% growth inhibition was obtained by 3 microM of 24T and 30T whereas, in MDA-MB 231 and WiDr cell lines, cell growth inhibition was less than 50%. 30T was more effective than 24T. Estrogen-dependent growth of both MCF-7 and ZR-75-1 was inhibited by 3 microM of 24T and 30T, however, in the absence of estrogen, no growth inhibition was seen. The MCF-10A cell line, which was developed from normal human breast tissue and expressed telomerase only weakly, was inhibited by 10 microM of 18T. In conclusion, these observations indicate that S-ODNs inhibit tumor growth in cell lines expressing telomerase in a concentration-dependent manner and that cell growth inhibition is dependent on the length of S-ODNs. In addition, the short-length S-ODNs may inhibit growth of cells weakly expressing telomerase, but not of cells with high telomerase expression.

Breast Neoplasms↗
PubMed1999

[Screening of prostate cancer with PSA and transperineal six sextant biopsy].

OBJECT: The objectives of this study are to examine how many cancer patients we can detect among the outpatients whose PSA values are above 4.0 ng/ml, and to compare the usefulness of transperineal six sextant biopsy (ss-biopsy) with that of transrectal one. METHODS: All the male outpatients (above 50 years old) were inspected Tandem-R PSA levels and digital rectal examination (DRE). Among them, 129 patients showed more than 4.0 ng/ml of PSA values and/or positive finding of DRE, and underwent subsequent transperineal ss-biopsy. RESULTS: Cancers were detected in 52 patients (40.3%) without major complications. Among 64 gray zone (PSA 4.1-10.0 ng/ml) patients, 17 (26.6%) were found to be cancer by ss-biopsy, meanwhile only 2 cancer patients (8.9%) were detected from 23 gray zone ones by traditional directed biopsy. Application of PSA density could not be found practicable to eliminate unnecessary biopsies in the gray zone group. CONCLUSION: Prostate cancer could be found nearly a fourth in the gray zone group of the outpatients. To enhance the detection rate, obtaining at least 6 core samples are recommended from either perineal or rectal root.

Aged↗
PubMed1998

Vincristine saturation of cellular binding sites and its cytotoxic activity in human lymphoblastic leukemia cells: mechanism of inoculum effect.

Vincristine (VCR) is an active agent in the treatment of acute lymphoblastic leukemia (ALL). We evaluated the relationship between the cytotoxic activity of VCR and the degree of VCR saturation of cellular drug binding sites, using the MOLT-3 ALL cell line. When MOLT-3 cells at a density of 1 x 10(6) or 1 x 10(8) cells/mL of pH-controlled medium were exposed to VCR for 1 hr, its cytotoxic activity on cells at high density was 10-fold less than on cells at low density (inoculum effect). The number of VCR binding sites measured by Scatchard analysis was 9.25 x 10(6)/cell. At high cell density, the saturation of VCR binding sites was one log order less than that at low density. Irrespective of cell density, curves of cell-kill versus the degree of VCR saturation of the cellular binding sites overlapped each other. Minimal cytotoxic activity was observed at 0.3% VCR saturation, and nearly maximal cytotoxic activity occurred at about 25% saturation, with the Ic50 at about 4% saturation. These data show that the VCR-induced cell-kill effect is dependent on the degree of saturation of VCR binding sites rather than on the extracellular VCR concentration. The lesser cell-kill on cells at high density can be explained by the lack of drug molecules to sufficiently saturate cellular binding sites. This phenomenon may be responsible, at least in part, for the poor chemotherapeutic outcome of ALL patients with high leukocyte counts at presentation.

Antineoplastic Agents, Phytogenic↗