Medical toxicology experience: Poisoning consultations cases registry in Saudi Ministry of Health -2020 annual report.

INTRODUCTION: Saudi poison control centers provide surveillance data that should be used to determine the magnitude of poisoning exposures and the level of public awareness that is to evaluate control measures. This work aimed to review and assess the characteristics of toxic events received by toxicological information center's hotline all over Saudi Arabia during 2020. PATIENTS AND METHODS: Data were collected from the poison control centers in Saudi Arabia. Cases of poisonings were studied during the period from 1st January to 31st December 2020. RESULTS AND DISCUSSION: The poison control center received 20,513 calls in the year 2020. Most of calls were from Riyadh city (40.9 %) and from public places (92.9 %). Regarding the patients, most of the cases were less than 6 years old and more than half of them were males. The majority of toxic exposures were accidental oral poisoning. About 84 % of patients (84.3 %) called for help within one hour from poisons exposure. Household substances toxic exposure represented about one third of toxic cases. Chemicals and alcohol sanitizers' poisoning were the highest among house hold substances toxicities (39.3 % and 17.7 % respectively of all household substances toxicity). In addition, the most frequently ingested drugs were vitamins poisoning. CONCLUSION: Household chemicals represented the highest risk in exposures among children below 6 years. Finally, we recommended widespread awareness of the poisons risk and the importance of poison control that play a great role in time management and saving lives.

The sarcoplasmic-endoplasmic reticulum Ca(2+)-ATPase (SERCA) is the likely molecular target for the acute toxicity of the brominated flame retardant hexabromocyclododecane (HBCD).

Hexabromocyclododecane (HBCD) is a widely utilised brominated flame retardant (BFR). It has been shown to bio-accumulate within organisms, including man, and possibly cause neurological disorders. The acute neurotoxicity of HBCD, and six other unrelated BFRs, were assessed in SH-SY5Y human neuroblastoma cells by 24h viability assays and HBCD proved to be the most lethal (LC50, 3µM). In addition, the effects of these BFRs were also assessed for their potency at inhibiting the sarcoplasmic-endoplasmic reticulum Ca(2+) ATPase (SERCA) derived from the SH-SY5Y cells and again HBCD was the most potent (IC50, 2.7µM). The data for the other BFRs tested showed a direct correlation (coefficient 0.94) between the potencies of inducing cell death and inhibiting the Ca(2+) ATPase, indicating that SERCA is likely to be the molecular target for acute toxicity. Mechanistic studies of HBCD on the Ca(2+) ATPase suggest that it affects ATP binding, phosphorylation as well as the E2 to E1 transition step.

Some commonly used brominated flame retardants cause Ca2+-ATPase inhibition, beta-amyloid peptide release and apoptosis in SH-SY5Y neuronal cells.

Brominated flame retardants (BFRs) are chemicals commonly used to reduce the flammability of consumer products and are considered pollutants since they have become widely dispersed throughout the environment and have also been shown to bio-accumulate within animals and man. This study investigated the cytotoxicity of some of the most commonly used groups of BFRs on SH-SY5Y human neuroblastoma cells. The results showed that of the BFRs tested, hexabromocyclododecane (HBCD), tetrabromobisphenol-A (TBBPA) and decabromodiphenyl ether (DBPE), all are cytotoxic at low micromolar concentrations (LC(50) being 2.7 ± 0.7 µM, 15 ± 4 µM and 28 ± 7 µM, respectively). They induced cell death, at least in part, by apoptosis through activation of caspases. They also increased intracellular [Ca(2+)] levels and reactive-oxygen-species within these neuronal cells. Furthermore, these BFRs also caused rapid depolarization of the mitochondria and cytochrome c release in these neuronal cells. Elevated intracellular [Ca(2+)] levels appear to occur through a mechanism involving microsomal Ca(2+)-ATPase inhibition and this maybe responsible for Ca(2+)-induced mitochondrial dysfunction. In addition, µM levels of these BFRs caused ß-amyloid peptide (Aß-42) processing and release from these cells with a few hours of exposure. These results therefore shows that these pollutants are both neurotoxic and amyloidogenic in-vitro.

Alisol B, a novel inhibitor of the sarcoplasmic/endoplasmic reticulum Ca(2+) ATPase pump, induces autophagy, endoplasmic reticulum stress, and apoptosis.

Emerging evidence suggests that autophagic modulators have therapeutic potential. This study aims to identify novel autophagic inducers from traditional Chinese medicinal herbs as potential antitumor agents. Using an image-based screen and bioactivity-guided purification, we identified alisol B 23-acetate, alisol A 24-acetate, and alisol B from the rhizome of Alisma orientale as novel inducers of autophagy, with alisol B being the most potent natural product. Across several cancer cell lines, we showed that alisol B-treated cells displayed an increase of autophagic flux and formation of autophagosomes, leading to cell cycle arrest at the G(1) phase and cell death. Alisol B induced calcium mobilization from internal stores, leading to autophagy through the activation of the CaMKK-AMPK-mammalian target of rapamycin pathway. Moreover, the disruption of calcium homeostasis induces endoplasmic reticulum stress and unfolded protein responses in alisol B-treated cells, leading to apoptotic cell death. Finally, by computational virtual docking analysis and biochemical assays, we showed that the molecular target of alisol B is the sarcoplasmic/endoplasmic reticulum Ca(2+) ATPase. This study provides detailed insights into the cytotoxic mechanism of a novel antitumor compound.

Commonly used ryanodine receptor activator, 4-chloro-m-cresol (4CmC), is also an inhibitor of SERCA Ca2+ pumps.

4-Chloro-m-cresol (4CmC) is an extensively used activator of ryanodine receptors (RyRs). Studies have shown that 4CmC, at a concentration of 1 mM, is sufficient to cause Ca(2+) release through RyRs. Here, we show that mM concentrations of 4CmC also inhibit the sarcoplasmic-endoplasmic reticulum Ca(2+)-ATPase (SERCA), (IC(50) 2-3mM) and cause Ca(2+) release. 4CmC also causes increased intracellular [Ca(2+)] levels in COS-7 cells, which lack functional RyRs. Thus, any increase in [Ca(2+)] levels associated with use of 4CmC (>or= 1mM) could lead to non-specific Ca(2+) changes due to SERCA inhibition rather than RyR activation.

Dual mechanisms of sHA 14-1 in inducing cell death through endoplasmic reticulum and mitochondria.

HA 14-1 is a small-molecule Bcl-2 antagonist that promotes apoptosis in malignant cells, but its mechanism of action is not well defined. We recently reported that HA 14-1 has a half-life of only 15 min in vitro, which led us to develop a stable analog of HA 14-1 (sHA 14-1). The current study characterizes its mode of action. Because of the antiapoptotic function of Bcl-2 family proteins on the endoplasmic reticulum (ER) and mitochondria, the effect of sHA 14-1 on both organelles was evaluated. sHA 14-1 induced ER calcium release in human leukemic cells within 1 min, followed by induction of the ER stress-inducible transcription factor ATF4. Similar kinetics and stronger intensity of ER calcium release were induced by the sarcoendoplasmic reticulum Ca(2+)-ATPase (SERCA) inhibitor thapsigargin, accompanied by similar kinetics and intensity of ATF4 induction. sHA 14-1 directly inhibited SERCA enzymatic activity but had no effect on the inositol triphosphate receptor. Evaluation of the mitochondrial pathway showed that sHA 14-1 triggered a loss of mitochondrial transmembrane potential (Delta psi m) and weak caspase-9 activation, whereas thapsigargin had no effect. (R)-4-(3-Dimethylamino-1-phenylsulfanylmethyl-propylamino)-N-{4-[4-(4'-chloro-biphenyl-2-ylmethyl)-piperazin-1-yl]-benzoyl}-3-nitrobenzenesulfonamide (ABT-737), a well established small-molecule Bcl-2 antagonist, rapidly induced loss of Delta psi m and caspase-9 activation but had no effect on the ER. The pan-caspase inhibitor N-benzyloxycarbonyl-Val-Ala-Asp-fluoromethyl ketone had some protective effect on sHA 14-1-induced cell death. These collective results suggest a unique dual targeting mechanism of sHA 14-1 on the apoptotic resistance machinery of tumor cells that includes antiapoptotic Bcl-2 family proteins and SERCA proteins.

Endocrine disrupting alkylphenols: structural requirements for their adverse effects on Ca2+ pumps, Ca2+ homeostasis & Sertoli TM4 cell viability.

Alkylphenols such as nonylphenol are pollutants that are widely dispersed within our environment. They bio-accumulate within man, with levels in the muM concentration range reported in human tissues. These chemicals act as endocrine disruptors, having xenoestrogenic activity. More recently alkylphenols have also been shown to affect Ca2+ signalling pathways. Here we show that alkylphenols are potent inhibitors of sarcoplasmic-endoplasmic reticulum Ca2+-ATPase (SERCA) activity. For linear chain alkylphenols the potency of inhibition is related to chain length, with the IC50 values for inhibition ranging from 8 microM for 4-n-nonylphenol (C9) to 1.3 mM for 4-n-propylphenol (C3). Branched chain alkylphenols generally had lower potencies than their linear chain counterparts, however, good correlations for all alkylphenols were observed between their Ca2+ pump inhibition and hydrophobicity, molecular volume and flexibility, indicating that these parameters are all important factors. Alkylphenols cause abnormal elevations of intracellular [Ca2+] within TM4 Sertoli cells (cells involved in sperm maturation) depolarise their mitochondria and induce cell death in these cells, in an alkyl chain size-dependent manner.