Unveiling the chemical profiling and remarkable modulation of carbohydrate metabolism by costus root, Dolomiaea costus (Falc.) in streptozotocin (STZ)-induced diabetic rats.

ETHNOPHARMACOLOGICAL RELEVANCE: Dolomiaea costus (Falc.), formerly Saussurea costus (Falc.) Lipsch., an ayurvedic medicinal plant, has long been recognized and utilized in diverse indigenous systems of medicine for its multifaceted therapeutic properties, including anti-inflammatory, carminative, expectorant, antiarthritic, antiseptic, aphrodisiac, anodyne, and antidiabetic effects. AIM OF THE STUDY: The potential and underlying mechanisms of D. costus root as an antidiabetic agent were investigated in this study. Additionally, the quantification of phenolic and flavonoid compounds, which dominate the extracts, was of particular interest in order to elucidate their contribution to the observed effects. MATERIALS AND METHODS: High-performance liquid chromatography/electrospray ionization tandem mass spectrometry (HPLC-ESI-MS/MS) was employed to analyze the chemical constituents in D. costus root aqueous extract (DCA) and D. costus root ethanolic extract (DCE). Furthermore, the inhibitory potentials of DCE and its respective fractions as well as DCA against α-amylase, α-glucosidase, and lipase enzymes were assessed. Subsequently, the efficacy of DCA and DCE extracts was evaluated using an established streptozotocin (STZ)-induced diabetic animal model; this involved administering the extracts at doses of 200 and 400 mg/kg bwt. and comparing them with a positive control (glibenclamide (Glib.) at 0.6 mg/kg bwt.). After induction of diabetes (except for negative control), all animals received the treatments orally for 21 days consecutively, followed by the collection of rat serum to assess various parameters including, glycemic and lipid profiles, liver and kidney functions, antioxidant activity, glycolysis, and gluconeogenesis pathways. RESULTS: The results of HPLC-ESI-MS/MS revealed that isochlorogenic acid A (8393.64 µg/g) and chlorogenic acid (6532.65 µg/g) were the predominant compounds in DCE and DCA, respectively. Both extracts exhibited notable antidiabetic properties, as evidenced by their ability to regulate blood glycemic and lipid profiles (glucose, insulin, HBA1C; HDL, TC, TGs), liver enzymes (ALT, ALP, AST), kidney function (urea, creatinine, uric acid), oxidative stress biomarkers (MDA), antioxidant enzymes (CAT, GSH, SOD), as well as glycolysis (glucokinase) and gluconeogenesis (G-6-P, FBP1) pathways. CONCLUSIONS: Furthermore, the administration of D. costus extracts significantly mitigated STZ-induced diabetic hyperglycemia. These results can be attributed, at least partially, to the presence of several polyphenolic compounds with potent antioxidant and anti-inflammatory activities.

Identification of cyclooxygenase-II inhibitory saponins from fenugreek wastes: Insights from liquid chromatography-tandem mass spectrometry metabolomics, molecular networking, and molecular docking.

INTRODUCTION: This research explores sustainable applications for waste generated from fenugreek (Trigonella foenum-graecum), a plant with both nutritional and medicinal uses. The study specifically targets waste components as potential sources of nutrients and bioactive compounds. OBJECTIVES: The focus is to conduct detailed metabolic profiling of fenugreek waste, assess its anti-inflammatory properties by studying its cyclooxygenase (COX) inhibitory effect, and correlate this effect to the metabolite fingerprint. MATERIALS AND METHODS: Ethanolic extracts of fenugreek fruit pericarp and a combination of leaves and stems were subjected to untargeted metabolic profiling using liquid chromatography-mass spectrometry integrated with online database searches and molecular networking as an effective dereplication strategy. The study also scrutinized the COX inhibitory capabilities of these extracts and saponin-rich fractions prepared therefrom. Molecular docking was employed to investigate the specific interactions between the identified saponins and COX enzymes. RESULTS: The analysis led to the annotation of 81 metabolites, among which saponins were predominant. The saponin-rich fraction of the fruit pericarp extract displayed the strongest COX-II inhibitory activity in the in vitro inhibition assay (IC50 value of 81.64 ± 3.98 µg/mL). The molecular docking study supported the selectivity of the identified saponins towards COX-II. The two major identified saponins, namely, proto-yamogenin 3-O-[deoxyhexosyl (1 → 2)] [hexosyl (1 → 4)] hexoside 26-O-hexoside and trigofenoside A, were predicted to have the highest affinity to the COX-II receptor site. CONCLUSION: In the present study, we focused on the identification of COX-II inhibitory saponins in fenugreek waste through an integrated approach. The findings offer valuable insights into potential anti-inflammatory and cancer chemoprotective applications of fenugreek waste.

Natural angiotensin converting enzyme inhibitors: A safeguard against hypertension, respiratory distress syndrome, and chronic kidney diseases.

Hypertension is a serious concern as it is one of the causes of kideny failure and pulmonary fibrosis. An important therapeutic strategy for treating chronic hypertension is to inhibit the angiotensin converting enzyme (ACE). ACE inhibition reduces kidney damage, pulmonary artery pressure, and high blood pressure. Due to their high efficacy and low risk of side effects, natural renin-angiotensin system inhibitors have drawn increasing attention over the past decades. Alkaloids, amino acids, anthocyanidins, flavonoids, glucosinolates, isoflavonoids, phenolic acids, polyphenolics, and triterpenoids are among the bioactive metabolites pocessing an impressive ACE inhibitory activity. Many herbs including Rosmarinus officinalis, Hibiscus sabdariffa, Curcuma longa, Rauwolfia serpentina, Emblica officinalis, Cynara scolymus, Punica granatum, Mucuna pruriens, Capsicum annuum, and Moringa olifera were found having ACE inhibitory activities comparable to captopril and enalpril. These enticing natural ACE inhibitors deserve to be a safeguard medicine against hypertension, respiratory distress syndrome, and chronic kidney diseases. More clinical trials are required before new natural compounds and herbs can be used to treat chronic hypertension and its ramifications, such as respiratory distress syndrome and kidney failure.

Acovenoside A as a novel therapeutic approach to boost taxol and carboplatin apoptotic and antiproliferative activities in NSCLC: Interplay of miR-630/miR-181a and apoptosis genes.

The aim of the present study is to explore the potential anticancer effect of the cardenolide; acovenoside A against non-small cell lung cancer (NSCLC), understand its molecular mechanism in inducing apoptosis and show the effect of its combination with carboplatin and taxol. MTT assay showed that the combination of acovenoside A with taxol and carboplatin caused 78.9% cytotoxicity reflecting the synergistic effect. The triple combination showed the best growth inhibition efficiency where the number of cells at the G2/M phase was decreased and boosted up apoptotic and necrotic activity. The combination also showed the most remarkable increase in gene expression of Bax and p53 and the least level of Bcl2. The gene expression of miRNA181a and miRNA630 was significantly upregulated in cell lines treated with the combination. The present study has proven that the underlying mechanism of acovenoside A is partially attributed to the upregulation of miR-630 and miR-181a gene expressions which in turn targets the intrinsic apoptosis genes as p53, Bax and Bcl2 as well as caspase 3. The present study is the first to address the valuable effect of using acovenoside A together with carboplatin and taxol in the treatment of NSCLC via exerting apoptotic, antiproliferative, and cytotoxic effects..

Suppression of breast cancer: modulation of estrogen receptor and downregulation of gene expression using natural products.

The main cause of cancer death among women is breast cancer. The most common type of breast cancer is the estrogen receptor positive breast cancer. Discovery of estrogen receptor provided a highly effective target for treatment of hormone-dependent breast cancer. Selective estrogen receptor inhibitors are useful for halting the growth of breast cancer cells and inducing apoptosis. Tamoxifen, a popular selective estrogen receptor modulator, can treat breast cancer but also has unfavourable side effects due to its estrogenic activity in other tissues. Many herbal remedies and bioactive natural compounds, such as genistein, resveratrol, ursolic acid, betulinic acid, epigallocatechin-3-gallate, prenylated isoflavonoids, zearalenol, coumestrol, pelargonidin, delphinidin, and biochanin A, have the ability to specifically modulate the estrogen receptor alpha. Moreover, several of these compounds speed up cell death by supressing estrogen receptor gene expression. This opens wide avenue to introduce number of natural medicines with a revolutionary therapeutic impact and few side effects.

Effect of adenoid size on the post-adenoidectomy hypernasality in children with a normal palate.

PURPOSE: Adenoidectomy, either alone or with tonsillectomy, is a common surgical procedure in the field of pediatric otorhinolaryngology. Resonance function may be altered postoperatively in the form of hypernasality, which is usually transient. This study aimed to investigate the effect of adenoid size on post-adenoidectomy hypernasality in children with a normal palate. METHODS: Seventy-one children with different degrees of adenoid hypertrophy were included in this prospective observational study. Endoscopic assessment of the adenoid size and preoperative and postoperative evaluation of speech (at 1 and 3 months) with auditory perceptual assessment (APA) and nasometry were performed. RESULTS: APA showed preoperative hyponasality in 59.1% of children and was found to be significantly related to the adenoid size, with more hyponasality in grades 3 and 4. One month postoperatively, hypernasality was detected in 26.7% of patients and was found to be related to the preoperative adenoid size with higher hypernasality in grades 3 and 4. Three months postoperatively, all patients had gained normal nasality except one (1.4%) who was subjected to a longer follow-up period. Nasometric assessment showed significant differences at the three visits (pre, 1, and 3 months postoperatively), with a negative correlation between the grade of adenoid size and nasalance scores preoperatively and a significant positive correlation between them at 1 month postoperatively. However, no significant correlation was detected at 3 months postoperatively. CONCLUSION: Transient hypernasality may develop in some patients after adenoidectomy, especially in children with a larger preoperative adenoid size. However, transient hypernasality generally resolves spontaneously within 3 months.

Dolomiaea costus: an untapped mine of sesquiterpene lactones with wide magnificent biological activities.

Dolomiaea costus (Falc.) Kasana & A.K. Pandey Family Asteraceae, formerly known as Saussurea costus (Falc.) Lipsch contains a rich treasury of diverse bioactive compounds such as monoterpenes, sesquiterpenes, triterpenes, sterols, cardenolides, flavonoids, coumarins, lignans, phenylpropanoids and alkaloids. The sesquiterpene lactones, costunolide and dehydrocostuslactone in D. costus, possess unique promising in vitro and in vivo biological activities for the prevention and cure of diverse ailments like Parkinson's disease, oxidative stress, hyperpigmentation, ulcerative colitis, breast cancer, hepatocellular carcinoma, colon cancer, prostate cancer, ovarian cancer, leukemia, stomach cancer, prostate cancer, lung cancer, osteosarcoma, neuroblastoma, allergy, type 2 diabetes, hepatotoxicity, bronchitis, pulmonary fibrosis, thrombosis and various microbial infections. Costunolide and dehydrocostuslactone are potential drug candidates that could lead to the development of new medications for a variety of difficult-to-treat diseases.

Herbal medicine: the magic way crouching microbial resistance.

Bacterial resistance to antibiotics poses a high level of danger worldwide. Bacterial resistance mechanisms are spreading globally, impeding our ability to treat common infectious diseases. Misuse and overuse of antibiotics accelerate microbial resistance to antibiotics. Despite the exerted efforts, none of the newly developed antibiotics are expected to be effective against the dangerous forms of antibiotic-resistant bacteria. Since many plants have been shown to contain powerful antimicrobial compounds that can act synergistically or alternatively to antibiotics, the demand for herbal medicines has recently increased to co-treat microbes that are resistant to antibiotics. Maximum benefit can be achieved when the pharmacokinetics and pharmacodynamics of natural products match the antibiotic. This review article refers to nine highly effective and key herbs to use alongside antibiotics to overcome crises of antibiotic resistance. Their unique molecular mechanisms of action have been highlighted.

Furlow Palatoplasty and Tonsillectomy for Treating Patients With Submucous Cleft Palate and Tonsillar Hypertrophy: A One-Stage Procedure.

BACKGROUND: Children with cleft palate are more liable to have obstructive sleep apnea than children with normal palate due to narrow airways. Tonsillar hypertrophy is a common cause of pediatric obstructive sleep apnea; hence, it is not surprising to be encountered during cleft palate repair. The aim of this study was to evaluate the feasibility of tonsillectomy and Furlow palatoplasty performed as a 1-stage operation in patients presenting with submucous cleft palate (SMCP) and tonsillar hypertrophy. MATERIALS AND METHODS: Eleven pediatric patients with SMCP and hypertrophied tonsils were included in this case series study. Furlow palatoplasty and tonsillectomy were performed for the patients in 1 sitting. The evaluation of velopharyngeal function was done preoperatively and postoperatively via auditory-perceptual-assessment, nasometry, and flexible nasopharyngoscopy. In addition, the Epworth sleepiness scale for children/adolescents was administered to the parents to assess daytime sleepiness of their children. RESULTS: The speech improved postoperatively. Auditory-perceptual-assessment showed significant reductions in hypernasal speech, nasal air escape, and weak pressure consonants. In addition, nasometry revealed significantly decreased nasalance scores for nasal and oral sentences. A postoperative increased velar movement was observed with a significant improvement in velopharyngeal closure. The preoperative Epworth sleepiness scale for children/adolescents assessment revealed excessive daytime sleepiness in 8 patients, with significant improvement of scores postoperatively. CONCLUSIONS: Removal of hypertrophied tonsils during the repair of SMCP with Furlow palatoplasty did not negatively affect speech outcome or velar movement postoperatively. It is logical to perform both procedures simultaneously in 1 sitting to avoid postoperative sleep-related breathing disorder, which may necessitate a second stage operation.

In-vivo and in-silico studies of Eucalyptus kino polyphenolics: outstanding activity in quenching solid liver tumors through inhibition of MMP-9 and TGF-ß gene expression.

As a result of our continuous research efforts to investigate the molecular mechanisms of Eucalyptus kino polyphenolics for healing liver solid tumors, in-vivo histopathological studies of the solid tumor tissues and in-silico molecular docking were carried out. Histopathology of female mice treated with a dose of 200 mg/kg Eucalyptus kino methanolic extract in combination with low level ionising γ-radiation (0.25 Gy) recovered a near-to-normal histological structure revealing a substantial number of cells with hyper-chromachia in nuclei, fibroblast lobules and necrotic cells. Analysis for matrix metalloproteinase-9 (MMP-9) by Western blot and also molecular docking study were conducted to evaluate and rank the potential of the individual components dominated in the extract to inhibit MMP-9 and TGF-ß. The current study presents new lead compounds for the design of novel MMP-9 and TGF-ß strong inhibitors of natural origin.

Intriguing diverse chemistry and unique molecular mechanisms: new medicines with diverse pharmacological activities from cephalopods ink.

The ink that cephalopods secrete to hide and frighten the enemies contains a treasury rich in bioactive diverse compounds like DOPA, melanin, melanin synthase, tyrosinase, angiotensin converting enzyme, catecholamines, oligopeptides, polyphenols, flavonoids, alkaloids, polysaccharides, fatty acids and minerals. These groups of the aforementioned compounds have promising unique in-vitro and in-vivo biological activities like antioxidant activity, anti-inflammatory, vasopressin, anti-Parkinson, anti-cancer, anti-coagulant, antimicrobial, anti-retroviral, anti-ulcerogenic and immune boosting activities. Cephalopods ink can be offered in its raw state or after separation and purification of its chemical constituents for use as natural medicine to treat many diverse diseases.

A new firewall in the fight against breast cancer: in-vitro and in-silico studies correlating chemistry to apoptotic activity of Otostegia fruticosa.

Breast cancer is the most devastating disease for women. There is a great demand for new sources to treat this disease. Medicinal plants are an indispensable source of bioactive compounds with wide range of pharmacological activities. In-vitro cytotoxic activity of Otostegia fruticosa methanolic extract against human breast cancer was studied using MCF-7 cell line. The extract showed mildly potent activity (IC50 = 51 ± 9.836 µg/mL) in comparison to the standard anticancer doxorubicin (IC50 = 7.467 ± 1.05 µg/mL). Potential compounds responsible for activity have been identified using Molecular Operating Environment (MOE) module on the major compounds detected by HPLC-MS/MS technique against estrogen alpha receptor (ERα+: PDB ID 2JF9). 3,5-di-O-dicaffeoylquinic acid, hyperoside and rutin showed similar binding and antagonistic interaction with the estrogen alpha receptor as tamoxifen in several poses. The retrieved results confirm that we can add this plant to a powerful arsenal that combats this insidious disease.

A new arsenal of polyphenols to make Parkinson's disease extinct: HPLC-MS/MS profiling, very interesting MAO-B inhibitory activity and antioxidant activity of Otostegia fruticosa.

Fifteen compounds belong to phenolic acids, derivatives of phenolic acids, iridoids, xanthones and flavonoids were characterized in the methanolic extract of Otostegia fruticosa leaves using HPLC-MS/MS. Extract has been also investigated for its MAO-B inhibitory activity, antioxidant activity, total phenolic and total flavonoid content. The extract exhibited interesting MAO-B inhibitory activity (IC50; 2.24 ± 0.08) compared to the reference compound selegiline (0.55 ± 0.02 µg/mL). It also showed a potent antioxidant activity proven in both DPPH and ORAC assay methods. The extract showed an IC50 of 3.64 ± 1.22 µg/mL in the DPPH test which was significantly lower than that of the standard ascorbic acid which attained an IC50 of 18.3 ± 1.41 µg/mL. Moreover, in the oxygen radical absorbance capacity assay (ORAC) the extract showed a decline in the IC50 to 3.48 ± 1.16 µg/mL as compared to the standard Trolox which exhibited an IC50 of 27.0 ± 13.41.

Eucalyptus kino: a treasure trove of polyphenols eradicating tumors in-vivo by elevating caspase-3 level, inhibiting TGF-ß and NF-κb gene expression.

30 secondary polyphenolic metabolites were characterised in Eucalyptus kino methanol extract using HPLC-MS/MS. The antitumor activity of the extract in combination with low level ionising radiation in female mice with solid tumors from inoculated Ehrlich ascites carcinoma cells was investigated. Tumor cell-inoculated mice received daily extract doses (100 mg/kg, 200 mg/kgBW) with or without a single exposure to 0.25 Gy γ-rays, and cis-platin as a reference anticancer drug. Changes in the tumor volume, oxidative state, levels of caspase-3, TGF-ß and Nf-κB were assessed by q-PCR. Surprisingly, a dose of 200 mg/kg extract together with γ-radiation remarkably reduced the tumor volume, improved the oxidative and apoptotic biomarker levels. In conclusion, results showed that a combination of kino extract with low level γ-radiation synergistically reduced tumor progression due to the antioxidant and anti-proliferative activities of the polyphenolics in the extract.

Dismantling Parkinson's disease with herbs: MAO-B inhibitory activity and quantification of chemical constituents using HPLC-MS/MS of Egyptian local market plants.

Withania somnifera, Angelica sinensis, Glycyrrhiza glabra, and Simmondsia chinensis were acquired from the Egyptian market, profiled for their chemical constituents, screened for the in-vitro MAO-B inhibitory activity and evaluated for the total phenolic content. Thirty compounds were characterized in the selected herbs using HPLC-MS/MS. In-vitro MAO-B inhibitory activity and total phenolic content of the acquired herbs were compared with those of a prepared herbal formula consisting of a mixture of equal amounts of the four mentioned herbs. The most potent MAO-B inhibitory activity was exerted by the methanol extract of the prepared formula (IC50 of 712.19 ± 13.90 ng/mL) compared to selegiline (IC50 of 581.69 ± 11.35 ng/mL). The highest value of the total phenolic content was shown by Angelica sinensis methanolic extract (76.15 ± 0.1 mg/g) followed by Glycyrrhiza glabra methanolic extract (65.74 ± 0.1 mg/g), then the mixture's methanolic extract of the four herbs (37.04 ± 0.1 mg/g).

Antioxidant and Antiapoptotic Effects of a Turraea fischeri Leaf Extract on Cryopreserved Goat Sperm.

This study evaluated the efficacy of Turraea fischeri leaf extract for maintaining the viability of cryopreserved goat sperm. Ejaculated semen was collected from 5 mature Baladi bucks (50-60 kg, 2-4 years of age) and those samples with mass motility ≥ 70% and sperm concentration ≥ 2.5 × 109/mL were selected, pooled, and divided into 4 aliquots. Each aliquot was diluted in Tris-citric-soybean lecithin extender containing a different concentration of T. fischeri leaf extract (0, 125, 250, or 375 µg/mL). Treated semen samples were cooled to 5 °C, transferred to 0.25-mL French straws, and stored in liquid nitrogen (LN2) at -196 °C. After thawing, membrane integrity was examined by transmission electron microscopy, apoptotic activity by Annexin/propidium iodide staining and flow cytometry, and both enzyme activities and antioxidant capacity by spectroscopic assays. The leaf extract at 375 µg/mL significantly improved semen quality as indicated by enhanced total antioxidant capacity, reduced H2O2 concentration, a greater proportion of structurally intact motile sperm, and concomitant reductions in apoptosis and necrosis. The extract also significantly increased the proportion of sperm with a contiguous plasma membrane and intact acrosome (p < 0.05). Furthermore, LC-MS revealed numerous secondary metabolites in the extract that may contribute to sperm cryopreservation.

Genetic signature of CTLA-4, BTLA, TIM-3 and LAG-3 molecular expression in colorectal cancer patients: Implications in diagnosis and survival outcomes.

OBJECTIVE: Accumulating evidences suggest that immune checkpoints (ICs) inhibit immune response against cancerous cells and promote tumor cell survival. Up-regulation of ICs in tumor microenvironment is reported in patients with colorectal cancer (CRC). Thus, evaluating the peripheral blood expression of ICs may be used as non-invasive biomarkers for diagnosis and prognosis of CRC. METHODS: This study included 60 primary and treatment naïve CRC patients along with 15 age and sex matched healthy volunteers as a control group. Total RNA was extracted from peripheral blood samples and gene expression of cytotoxic T lymphocyte antigen-4 (CTLA-4), B and T lymphocyte attenuator (BTLA), T-cell immunoglobulin and mucin domain-containing protein 3 (TIM-3), and Lymphocyte activation gene-3 (LAG-3) was measured by quantitative real time polymerase chain reaction (qRT-PCR). All patients were followed for 12 months to correlate the measured ICs to patients' survival. RESULTS: The gene expression of CTLA-4, BTLA, TIM-3 and LAG-3 was significantly up-regulated in CRC patients compared to the control group (p < 0.001). Individually, CTLA-4 and BTLA showed 85% sensitivity in discriminating CRC patients from control group (p < 0.001). On the other hand, TIM-3 and LAG-3 expression showed higher sensitivity (93%) for diagnosis of CRC (p < 0.001). Conversely, CTLA-4 or BTLA strongly predicted CRC patients' survival (p < 0.001) compared to TIM-3 (p = 0.018) or LAG-3 (p = 0.035). CTLA-4, BTLA, TIM-3 and LAG-3 were independent prognostic factors of survival after adjustment for age and gender. CONCLUSION: The current study provided evidence that blood gene expression of ICs was up-regulated in CRC patients and associated with cancer stage and patients' survival, which highlights the diagnostic and prognostic values of ICs expression in CRC. Further investigations and validations in larger cohorts are required.

Salix tetrasperma Roxb. Extract Alleviates Neuropathic Pain in Rats via Modulation of the NF-κB/TNF-α/NOX/iNOS Pathway.

Patients with neuropathic pain experience chronic painful tingling, burning, and prickling sensations accompanied with hyperalgesia and/or allodynia. In this study, 38 secondary metabolites of a methanol extract from Salix tetrasperma flowers were identified by liquid chromatography-mass spectrometry (HPLC-MS/MS). The extract showed substantial anti-inflammatory, central and peripheral anti-nociceptive, antipyretic, and antioxidant activities in vitro and in different animal models. In the chronic constriction injury (CCI) rat model, the extract was able to attenuate and significantly relieve hyperalgesia and allodynia responses in a dose dependent manner and restore the myelin sheath integrity and Schwann cells average number in the sciatic nerve. The enzyme-linked immunosorbent assay (ELISA) showed that the extract significantly reduced the expression of various pro-inflammatory biomarkers including nuclear factor kabba B (NF-κB), tumor necrosis factor alpha (TNF-α), prostaglandin E2 (PGE2), 5-lipoxygenase (5-LOX), cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS), and the oxidative stress biomarker NADPH oxidase 1 (NOX1), in brain stem and sciatic nerve tissues. These findings were supported by in vitro enzyme inhibition assays (COX-1, COX-2 and 5-LOX). Moreover, the extract significantly reduced p53 expression in the brain stem tissue. These findings support the use of S. tetrasperma in folk medicine to alleviate pain. It could be a promising natural product for further clinical investigations to treat inflammation, nociceptive pain and chronic neuropathic pain.

A Novel Polyhalogenated Monoterpene Induces Cell Cycle Arrest and Apoptosis in Breast Cancer Cells.

Breast cancer is the most common cancer type and a primary cause of cancer mortality among females worldwide. Here, we analyzed the anticancer efficacy of a novel bromochlorinated monoterpene, PPM1, a synthetic analogue of polyhalogenated monoterpenes from Plocamium red algae and structurally similar non-brominated monoterpenes. PPM1, but not the non-brominated monoterpenes, decreased selectively the viability of several triple-negative as well as triple-positive breast cancer cells with different p53 status without significantly affecting normal breast epithelial cells. PPM1 induced accumulation of triple-negative MDA-MB-231 cells with 4N DNA content characterized by decreased histone H3-S10/T3 phosphorylation indicating cell cycle arrest in the G2 phase. Western immunoblot analysis revealed that PPM1 treatment triggered an initial rapid activation of Aurora kinases A/B/C and p21Waf1/Cip1 accumulation, which was followed by accumulation of polyploid >4N cells. Flow cytometric analysis showed mitochondrial potential disruption, caspase 3/7 activation, phosphatidylserine externalization, reduction of the amount polyploid cells, and DNA fragmentation consistent with induction of apoptosis. Cell viability was partially restored by the pan-caspase inhibitor Z-VAD-FMK indicating caspase contribution. In vivo, PPM1 inhibited growth, proliferation, and induced apoptosis in MDA-MB-231 xenografted onto the chick chorioallantoic membrane. Hence, Plocamium polyhalogenated monoterpenes and synthetic analogues deserve further exploration as promising anticancer lead compounds.

Albizia anthelmintica: HPLC-MS/MS profiling and in vivo anti-inflammatory, pain killing and antipyretic activities of its leaf extract.

In the current work, the phytochemical composition of a leaf methanol extract from Albizia anthelmintica was thoroughly investigated. The antioxidant, anti-inflammatory, analgesic, and antipyretic activities of the extract were investigated. In the carrageenan induced hind paw edema bioassay; the extract significantly reduced the edema thickness in rats and diminished the leukocyte migration to the peritoneal cavity in mice. The extract exhibited central and peripheral anti-nociceptive effects; it significantly decreased the number of acetic acid induced writhes and prolonged the latency time in the hot plate test. The extract showed a substantial antipyretic activity as it decreased significantly the elevated rectal temperature in mice after intraperitoneal injection of Brewer's yeast. Molecular docking of some major compounds in the extract to COX-1, COX-2 and 5-LOX, enzymes involved in the inflammation cascade, revealed appreciable interactions with the conserved amino acid residues in these target proteins. These findings were confirmed with in vitro enzyme inhibitory assays in which the extract showed IC50 values of 4.11, 0.054, and 1.74 µg/mL towards COX-1, COX-2 and 5-LOX, respectively. The extract displayed solid antioxidant properties as well with a TAC value of 35.13 U/L and EC50of 5.36 µg/mL in DPPH assay. These findings suggested that Albizia anthelmintica is a good antioxidant with potential therapeutic efficacy for treating inflammation, pain and related oxidative stress disorders.