Noni enhances the anticancer activity of cyclophosphamide and suppresses myelotoxicity and hepatotoxicity in tumor-bearing mice.

BACKGROUND AND AIM: Morinda citrifolia fruit juice (noni) is an herbal remedy documented to have antioxidant properties. It has been suggested that prevention of carcinogen-DNA adduct formation and the antioxidant activity of NJ may contribute to the cancer preventive effect. In the present study, the antitumor activity of noni was investigated in the presence of cyclophosphamide (CYL) in vitro and in vivo. METHODS: In vitro breast cancer cells (MDA-MB-468) were used to measure the percentage of inhibition and the IC50. The in vivo antitumor activity of noni was studied by monitoring the mean survival time (MST), percentage increase in life span (%ILS), viable and non-viable cell count, tumor volume, body weight, and hematological and serum biochemical parameters in mice. Treatment with noni and CYL exhibited dose- and time-dependent cytotoxicity toward breast cancer cells. RESULTS: Individual treatment of noni and CYL exhibited dose- and time-dependent cytotoxicity on breast cancer cell lines, while in combination therapy of noni and CYL, noni enhances cytotoxic effect of CYL at 48 h than that at 24 h. Similar result was found in in vivo studies, the results of which revealed that alone treatment of CYL and noni suppressed tumor growth. However, combination treatment with CYL and noni presented better tumor inhibition than that of alone treatment of CYL and noni. On the contrary, CYL alone drastically attenuated hematological parameters, i.e., RBC, WBC, and Hb compared to normal and control groups, and this change was reversed and normalized by noni when given as combination therapy with CYL. Moreover, the levels of serum biochemical markers, i.e., AST, ALP, and ALT, were significantly increased in the control and CYL-treated groups than those in the normal group. In the combination treatment of noni and CYL, the above biochemical marker levels significantly decreased compared to CYL alone-treated group. CONCLUSIONS: The present study suggested that CYL treatment can cause serious myelotoxicity and hepatic injury in cancer patients. In conclusion, the combined use of noni with CYL potentially enhances the antitumor activity of CYL and suppresses myelotoxicity and hepatotoxicity induced by CYL in tumor-bearing mice.

Four Togolese plant species exhibiting cytotoxicity and antitumor activities lightning polytherapy approach in cancer treatment.

Background: Cancer is leading to premature deaths across the globe. Therapeutic approaches are still being developed to enhance the survival of cancer patients. In our previous study, extracts from four Togolese plants, namely, Cochlospermum planchonii (CP), Piliostigma thonningii (PT), Paullinia pinnata (PP), and Securidaca longipedunculata (SL), actually used in traditional medicine for cancer treatment, showed beneficial health effects against oxidative stress, inflammation, and angiogenesis. Purpose: In the present study, we aimed to investigate the cytotoxicity and antitumor activities of these four plant extracts. Material and methods: Breast, lung, cervical, and liver cancer cell lines were exposed to the extracts, and viability was assessed using the Sulforhodamine B method. P. pinnata and S. longipedunculata with significant cytotoxicity were selected for in vivo tests. The acute oral toxicity of these extracts was assessed using BALB/c mice. The antitumor activity was evaluated using the EAC tumor bearing mice model, wherein mice were orally treated with extracts at different concentrations for 14 days. The standard drug was cisplatin (3.5 mg/kg, i.p), single dose. Results: Cytotoxicity tests revealed that SL, PP, and CP extracts have more than 50% cytotoxicity at 150 µg/mL. The acute oral toxicity of PP and SL at 2000 mg/kg did not show any toxic signs. At therapeutic doses of 100 mg/kg, 200 mg/kg and 400 mg/kg of PP and 40 mg/kg, 80 mg/kg, and 160 mg/kg of SL, extracts showed beneficial health effects by modulating several biological parameters. SL extract significantly reduced tumor volume (P < 0.001), cell viability, and normalized hematological parameters. SL also demonstrated a strong anti-inflammatory activity similar to the standard drug. The SL extract also revealed a significant increase of the life span of treated mice. PP extract reduced the tumor volume and significantly improved the values of endogenous antioxidants. Both PP and SL extracts also exerted significant anti-angiogenic potency. Conclusion: The study indicated that polytherapy would be a panacea for the efficient use of medicinal plant extracts against cancer. This approach will make it possible to act simultaneously on several biological parameters. Molecular studies of both extracts targeting key cancer genes in several cancer cells are currently underway.

Novel therapeutic targets to halt the progression of Parkinson's disease: an in-depth review on molecular signalling cascades.

Recent research has focused mostly on understanding and combating the neurodegenerative mechanisms and symptoms of Parkinson's disease (PD). Moreover, developing novel therapeutic targets to halt the progression of PD remains a key focus for researchers. As yet, no agents have been found to have unambiguous evidence of disease-modifying actions in PD. The primary objective of this review is to summarize the promising targets that have recently been uncovered which include histamine 4 receptors, beta2 adrenergic receptor, phosphodiesterase 4, sphingosine-1-phosphate receptor subtype 1, angiotensin receptors, high-mobility group box 1, rabphilin-3A, purinergic 2Y type 12 receptor, colony-stimulating factor-1 receptor, transient receptor potential vanilloid 4, alanine-serine-cysteine transporter 2, G protein-coupled oestrogen receptor, a mitochondrial antiviral signalling protein, glucocerebrosidase, indolamine-2,3-dioxygenase-1, soluble epoxy hydroxylase and dual specificity phosphatase 6. We have also reviewed the molecular signalling cascades of those novel targets which cause the initiation and progression of PD and gathered some emerging disease-modifying agents that could slow the progression of PD. These approaches will assist in the discovery of novel target molecules, for curing disease symptoms and may provide a glimmer of hope for the treatment of PD. As of now, there is no drug available that will completely prevent the progression of PD by inhibiting the pathogenesis involved in PD, and thus, the newer targets and their inhibitors or activators are the major focus for researchers to suppress PD symptomatology. And the major limitations of these targets are the lack of clinical data and less number pre-clinical data, as we have majorly discussed the different targets which all have well reported for other disease pathogenesis. Thus, finding the disease-drug interactions, the molecular mechanisms, and the major side effects will be major challenges for the researchers.

An insight into the cytotoxic, antimicrobial, antioxidant, and biocontrol perspective of novel Iron(III) complexes of substituted benzimidazoles: Inhibition kinetics and molecular simulations.

Mononuclear complexes [FeCl3L2(OH2)] (L = L1, L2) were designed and synthesized by combining FeCl3 with 2-(3'-Aminophenylbenzimidazole) (L1) and 2-[(3'-N-Salicylidinephenyl)benzimidazole] (L2) and were characterized by physico-analytical strategies. The redox properties of the complexes were disclosed by the cyclic voltammetric method. Further, the interactions of complexes with proteins were studied by performing molecular docking engaging protein models of common cancer therapeutic targets to foresee their affinity to bind to these proteins. The complexes evidenced better protein-ligand docking (-8.4 and -9.0 kcal mol-1) and higher binding energies than their ligands. However, the L1 complex displayed improved binding free energy (-33.576 ± 1.01 kcal mol-1) compared to the other complexes and individual ligands. These compounds were screened for in vitro cytotoxic assays against triple-negative breast cancer cell lines (MDA-MB-468 cells), anti-inflammatory, antimicrobial, and antioxidant properties. The in vitro study complemented the in silico assay; therefore, these compounds may be a viable choice for expanding anticancer therapy. Additionally, the L2 showed better biocontrol activity owing to the enhanced growth of Trichoderma and inhibited the growth of Fusarium oxysporum.Communicated by Ramaswamy H. Sarma.

In vivo anti-tumour activity of novel Quinazoline derivatives.

OBJECTIVE: The two scaffold Quinazoline analogues (Compound 21, NSC: 95112/753439 and Compound 12, NSC: D-104834/ 758270) in three different concentrations were evaluated for their anti-tumor activity against Ehrlich ascites carcinoma (EAC) and two different concentration were evaluated for their anti-tumor activity against Dalton's ascites lymphoma (DLA) bearing Swiss albino mice. MATERIALS AND METHODS: The in vivo anti-tumor potency of Quinazoline bases was assessed in EAC model by measuring the increase in mean survival time of the drug treated over untreated control mice and treated standard (Gefitinib) mice. Their toxicity was assessed in vivo in normal, standard, and EAC-bearing mice by measuring the drug-induced changes in haematological parameters. The in vivo anti-tumor potency of Quinazoline bases was assessed in DLA model by measuring solid tumor volume, solid tumor weight and % inhibition of the tumor weight of the drug treated over untreated control mice and treated standard (Gefitinib) mice. RESULTS AND CONCLUSIONS: Among the two quinazoline bases studied, 3-(2-chloro benzylideneamine)-2-(furan-2-yl) quinazoline-4(3h)-one (Compound 21) at an optimal dose of 20 mg/kg body weight was found to enhance the mean survival time of infected mice. Haematological parameters and mean survival time in tumor bearing mice were found to be significantly restored towards normal after treatment with Compound 21 at 20 mg/kg body weight of mice in EAC model. Tumor volume and tumor weight in tumor bearing mice were found to be significantly restored towards normal after treatment with Compound 12 at 20 mg/kg body weight of mice in DLA model. Compound 21 at a prime dose of 20 mg has shown promising anticancer activity in vivo against EAC and DLA models when compared to standard drug with minimum toxic effects.

Novel dual PPARα/γ agonists protect against liver steatosis and improve insulin sensitivity while avoiding side effects.

Insulin resistance is a feature of type 2 diabetes mellitus (T2D), and is strongly interconnected with non-alcoholic fatty liver disease (NAFLD). Peroxisome-proliferator activated receptor gamma (PPARγ) and peroxisome-proliferator activated receptor alpha (PPARα) are master regulators of insulin sensitivity and lipid metabolism, respectively. Thiazolidinediones (TZDs) such as pioglitazone, which target PPARα/γ, are highly effective at treating insulin resistance and NAFLD, but their clinical utility has been restricted by side effects such as weight gain, adipocyte hypertrophy and fluid retention. Therefore, there is urgent need for new safer and effective drugs. Thus, we aimed to develop novel dual PPARα/γ agonists to avoid their known side effects while preserving their overall therapeutic effects. Here, we show that our novel agonists G4 and G5 strongly stimulate glucose transporter 4 (GLUT4) translocation to the cell membrane in skeletal muscle cells, and manifest weaker lipogenic effect in adipocytes. Moreover, G4 and G5 improve systemic glucose metabolism, hyperinsulinemia, hyperlipidemia, and markers of liver injury in high fructose diet-induced insulin resistant rats. Mechanistic studies revealed that G4 and G5 enhance GLUT4, and AMPK in skeletal muscle and protect against liver steatosis by upregulating PPARα and improve whole-body insulin sensitivity by increasing PPARγ. Despite this increase in PPARγ activity, G4 and G5 inhibit the unwanted side effects such as weight gain due to adiposity, hypertrophy of adipocytes, and fluid retention unlike TZDs. These findings identify G4 and G5 as promising dual PPARα/γ agonists for the treatment of NAFLD and insulin resistance with improved safety.

Ethnopharmacological evaluation of antioxidant, anti-angiogenic, and anti-inflammatory activity of some traditional medicinal plants used for treatment of cancer in Togo/Africa.

ETHNOPHARMACOLOGICAL RELEVANCE: Cancer is a multistep disease and its management is exceedingly expensive. Nowadays medicinal plants are gaining more attention in drug discovery and approximately 70% of anticancer drugs were developed from natural products or plants. A strong candidate from medicinal plant with anticancer potential should have four major properties: antioxidant, anti-inflammatory, anti-angiogenic, and cytotoxic activities. AIM OF THE STUDY: In order to assess Togolese traditional healer's claims about the anticancer potential of medicinal plants and obtain candidate plants for anticancer drug discovery, some species were selected from surveys and evaluated for their antioxidant, anti-inflammatory, anti-angiogenic and cytotoxic activities. METHODS: Four species, Cochlospermum planchonii (CP), Piliostigma thonningii (PT), Paullinia pinnata (PP), and Securidaca longipedunculata (SL) were selected and analyzed to detect the phytochemical components. The mentioned bioactivities were evaluated using in vitro, ex vivo and in vivo assays. RESULTS: Relative to SL extract, CP and PT have shown significantly high polyphenols and flavonoids content. The DPPH, FRAP, and TAC of the extracts revealed that CP, PT, and PP have a potent antioxidant effect compared to SL. MDA analysis revealed the same antioxidant activity as CP, PT and PP showed a minor MDA level. The egg albumin denaturation assay showed that IC50 of CP and PP was significantly higher than control (P < 0.05). In contrast, the Bovine Serum Albumin (BSA) results showed a nonsignificant effect (P > 0.05). Notably, SL extract was nonsignificant to control in both Egg Albumin and BSA. Furthermore, angiogenesis assay showed that SL at 50 µg/ml and PP at 100 µg/ml effectively reduced the number of blood vessels than control and showed a potent anti-angiogenic effect (2.7-fold and 2.5-fold, respectively, P < 0.05). No cytotoxicity on PBMC was reported for CP, PP, and PT up to 1000 µg/ml, whereas SL at 1000 µg/ml exhibit benign cytotoxicity (P < 0.0001). CONCLUSION: This study provided in vitro evidence supporting further evaluation on cancer cell lines and tumors in vivo.

Mitochondria-lysosome crosstalk in GBA1-associated Parkinson's disease.

Organelle crosstalk is significant in regulating their respective functions and subsequent cell fate. Mitochondria and lysosomes are amongst the essential organelles in maintaining cellular homeostasis. Mitochondria-lysosome connections, which may develop dynamically in the human neurons, have been identified as sites of bidirectional communication. Aberrancies are often associated with neurodegenerative disorders like Parkinson's disease (PD), suggesting the physical and functional link between these two organelles. PD is often linked with genetic mutations of several mutations discovered in the familial forms of the disease; some are considered risk factors. Many of these genes are either associated with mitochondrial function or belong to endo-lysosomal pathways. The recent investigations have indicated that neurons with mutant glucosylceramidase beta (GBA1) exhibit extended mitochondria-lysosome connections in individuals with PD. This may be due to impaired control of the untethering protein, which aids in the hydrolysis of Rab7 GTP required for contact untethering. A GCase modulator may be used to augment the reduced GBA1 lysosomal enzyme activity in the neurons of PD patients. This review focuses on how GBA1 mutation in PD is interlinked with mitochondria-lysosome (ML) crosstalk, exploring the pathways governing these interactions and mechanistically comprehending the mitochondrial and lysosomal miscommunication in the pathophysiology of PD. This review is based on the limited literature available on the topic and hence may be subject to bias in its views. Our estimates may be conservative and limited due to the lack of studies under the said discipline due to its inherent complex nature. The current association of GBA1 to PD pathogenesis is based on the limited scope of study and further research is necessary to explore the risk factors further and identify the relationship with more detail.

Free radical scavenging and radioprotective activity of dehydrozingerone against whole body gamma irradiation in Swiss albino mice.

Dehydrozingerone (DZ) was explored for in vitro-in vivo antioxidant potential and in vivo radioprotective activity against whole body gamma irradiation in Swiss albino mice. DZ scavenged the ABTS (2, 2'-azinobis (3-ethylbenzothiazoline-6-sulfonic acid) and DPPH (1, 1-dipehnyl-2-picrylhydrazyl) free radicals at room temp. DZ reduced Fe (III) to Fe (II) at pH 7.4 and scavenged the NADH/phenazine methosulfate generated superoxide radical in cell free system. DZ also scavenged the nitric oxide radical generated by sodium nitroprusside. To evaluate the radioprotective activity, mice were exposed to whole body gamma irradiation 30 min after the drug treatment at a dose rate of 1.66 Gy/min. Pretreatment with DZ 75, 100 and 125 mg/kg, i.p. reduced the radiation induced mortality and increased the mean survival times (MSTs). An i.p. dose of DZ 100 mg/kg was found the most effective dose in preventing radiation sickness and increasing the MST. Pretreatment DZ100 mg/kg maintained the spleen index (spleen weight/body weight x 100) and stimulates the endogenous spleen colony forming units (CFU). Pretreatment with DZ100 mg/kg maintained the villus height close to normal, prevents mucosal erosion and basement membrane damage in irradiated mice jejunum. However, no significant reductions in dead, inflammatory and mitotic cells were observed in DZ pretreated mice, but there was an increased in crypt cells proliferation and regeneration. Pretreatment with DZ100 mg/kg significantly elevated the endogenous antioxidant enzymes (GSH, GST and SOD) in mice at 2, 4 and 8 h post sham irradiation. Radiation induced fall in endogenous antioxidant enzymes was significantly prevented by DZ pretreatment. Pretreatment with DZ 75 and 100 mg/kg reduced the radiation induced micronucleated polychromatic erythrocytes (MPCE) and normochromatic erythrocytes (MNCE) in mice bone marrow. DZ also maintained the polychromatic erythrocytes (PCE) and normochromatic erythrocytes (NCE) ratio (P/N ratio) in irradiated mice. Dose modifying factor (DMF) was calculated by using the graded radiation dose (8.0, 9.0, 9.5 and 10 Gy). DZ 100 mg/kg elevated radiation LD(50) from 9.1 to 10.0 Gy, indicating the DMF of 1.09.

Preliminary evaluation of in vitro cytotoxicity and in vivo antitumor activity of Premna herbacea Roxb. in Ehrlich ascites carcinoma model and Dalton's lymphoma ascites model.

In the present study, the root nodules of Premna herbacea Roxb. (PH) was investigated for its in vitro cytotoxicity and in vivo antitumor activity. Two extracts, aqueous and alcoholic; two fractions of alcoholic extract, ethyl acetate and butanol fractions were screened for their in vitro cytotoxicity by brine shrimp lethality (BSL) assay, trypan blue exclusion assay and MTT assay. Alcoholic extract and its ethyl acetate fraction were found to be the most effective in BSL assay, trypan blue exclusion assay. In vivo antitumor activity was screened in the Ehrlich ascites carcinoma (EAC) model and the Dalton lymphoma ascites (DLA) model. The extracts and the fractions were tested at two dosages (250 and 500 mg/kg) by intraperitoneally (i.p.) route on every alternate day upto 13th day. Cisplatin was used as positive control in both studies in single dose (day 1) 3.5 mg/kg by i.p. route. In EAC model, ascites tumor was induced by inoculating 2.5 million of EAC cells i.p. alcoholic extract at 500 mg/kg was the most effective in elevating MST, reduction in body weight in EAC induced tumor. Only the effective extract i.e., alcoholic extract were studied for hematological and antioxidant parameter. It showed a restoring effect on altered hematological parameters and a significant improvement in biochemical parameters at 250 mg/kg dose of alcoholic extract. These results explain the toxicity of 500 mg/kg might be high. In the Dalton lymphoma ascites (DLA) model, solid tumor was developed by i.m. injection of 1 million DLA cells. Both the extracts and the fractions possessed potent antitumor activity against solid tumor models by significantly reducing the solid tumor weight and volume.

Synthesis and antitumor activity of optically active thiourea and their 2-aminobenzothiazole derivatives: a novel class of anticancer agents.

A novel series of optically active 2-aminobenzothiazole derivatives were synthesized by reaction of optically active amine (I) with thiophosgene to obtain optically active isothiocyanates (IIa-h) which on condensation with 4-fluoro-3-chloro aniline (III) yielded various optically active thioureas (IVa-h). Further oxidative cyclisation in the presence of bromine and chloroform yielded title compounds (Va-h). The structures of these compounds were established by IR, (1)H NMR, (13)C NMR, Mass and HRMS. The compounds (IVa-h and Va-h) were evaluated for in vitro cytotoxicity against mouse Ehrlich Ascites Carcinoma (EAC) and two human cancer cell lines (MCF-7 and HeLa). In preliminary MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] cytotoxicity studies the optically active thiourea derivatives (IVe, IVf and IVh) were found most effective. In EAC cells the IC(50) values for IVe, IVf, IVh and Vg were found in the range of 10-24 microM, whereas in MCF-7 and HeLa cells the IC(50) values were observed in the range of 15-30 microM and 33-48 microM, respectively. In alkaline comet assay the compounds (IVe and IVf) showed dose-dependent DNA damaging activity.