No evidence of hemoglobin damage by SARS-CoV-2 infection

SARS-CoV-2 disease (COVID-19) has affected over 22 million patients worldwide as of August 2020. As the medical community seeks better understanding of the underlying pathophysiology of COVID-19, several theories have been proposed. One widely shared theory suggests that SARS-CoV-2 proteins directly interact with human hemoglobin (Hb) and facilitate removal of iron from the heme prosthetic group, leading to the loss of functional hemoglobin and accumulation of iron. Herein, we refute this theory. We compared clinical data from 21 critically ill COVID-19 patients to 21 non-COVID-19 ARDS patient controls, generating hemoglobin-oxygen dissociation curves from venous blood gases. This curve generated from the COVID-19 cohort matched the idealized oxygen-hemoglobin dissociation curve well (Pearson correlation, R2 = 0.97, P<0.0001; CV(RMSD) = 7.3%). We further analyzed hemoglobin, total bilirubin, lactate dehydrogenase, iron, ferritin, and haptoglobin levels. For all analyzed parameters, patients with COVID-19 had similar levels compared to patients with ARDS without COVID-19. These results indicate that patients with COVID-19 do not exhibit any hemolytic anemia or a shift in the normal hemoglobin-oxygen dissociation curve. We therefore conclude that COVID-19 does not impact oxygen delivery through a mechanism involving red cell hemolysis and subsequent removal of iron from the heme prosthetic group in hemoglobin

Carbon disulfide. Just toxic or also bioregulatory and/or therapeutic?

The overview presented here has the goal of examining whether carbon disulfide (CS2) may play a role as an endogenously generated bioregulator and/or has therapeutic value. The neuro- and reproductive system toxicity of CS2 has been documented from its long-term use in the viscose rayon industry. CS2 is also used in the production of dithiocarbamates (DTCs), which are potent fungicides and pesticides, thus raising concern that CS2 may be an environmental toxin. However, DTCs also have recognized medicinal use in the treatment of heavy metal poisonings as well as having potency for reducing inflammation. Three known small molecule bioregulators (SMBs) nitric oxide, carbon monoxide, and hydrogen sulfide were initially viewed as environmental toxins. Yet each is now recognized as having intricate, though not fully elucidated, biological functions at concentration regimes far lower than the toxic doses. The literature also implies that the mammalian chemical biology of CS2 has broader implications from inflammatory states to the gut microbiome. On these bases, we suggest that the very nature of CS2 poisoning may be related to interrupting or overwhelming relevant regulatory or signaling process(es), much like other SMBs

Uncaging carbon disulfide. Delivery platforms for potential pharmacological applications: a mechanistic approach.

We describe the kinetics of the formation and decay of a series of dithiocarbamates under physiological conditions. The goal is to provide a toolbox of compounds that release CS2 by well-defined kinetics in such media. Carbon disulfide is a known environmental toxin, but there is fragmentary evidence suggesting that CS2 may have bioregulatory and/or therapeutic roles in mammalian biology. Further investigation of such roles will require methodologies for controlled delivery of this bioactive small molecule to specific targets. Reported here are mechanistic and computational studies of CS2 release from a series of dithiocarbamate anions (DTCs), where R2N represents several different secondary amido groups. The various DTCs under physiologically relevant conditions show a tremendous range of reactivities toward CS2 dissociation with decay lifetimes ranging from ∼2 s for imidazolidyldithiocarbamate (ImDTC-) to ∼300 s for diisopropyldithiocarbamate (DIDTC-) to &gt;24 h for pyrrolidinyldithiocarbamate (PDTC-) in pH 7.4 phosphate buffer solution at 37 °C. Thus, by making the correct choice of these tools, one can adjust the flux of CS2 in a biological experiment, while the least reactive DTCs could serve as controls for evaluating the potential effects of the dithiocarbamate functionality itself. Kinetics studies and density functional calculations are used to probe the mechanism of DTC- decay. In each case, the rate of CS2 dissociation is acid dependent; however, the DFT studies point to a mechanistic pathway for ImDTC- that is different than those for DIDTC-. The role of general acid catalysis is also briefly probed

Biological Thiols and Carbon Disulfide: The Formation and Decay of Trithiocarbonates under Physiologically Relevant Conditions

Carbon disulfide is an environmental toxin, but there are suggestions in the literature that it may also have regulatory and/or therapeutic roles in mammalian physiology. Thiols or thiolates would be likely biological targets for an electrophile, such as CS₂, and in this context, the present study examines the dynamics of CS₂ reactions with various thiols (RSH) in physiologically relevant near-neutral aqueous media to form the respective trithiocarbonate anions (TTC^–, also known as “thioxanthate anions”). The rates of TTC^– formation are markedly pH-dependent, indicating that the reactive form of RSH is the conjugate base RS^–. The rates of the reverse reaction, that is, decay of TTC^– anions to release CS₂, is pH-independent, with rates roughly antiparallel to the basicities of the RS^– conjugate base. These observations indicate that the rate-limiting step of decay is simple CS₂ dissociation from RS^–, and according to microscopic reversibility, the transition state of TTC^– formation would be simple addition of the RS^– nucleophile to the CS₂ electrophile. At pH 7.4 and 37 °C, cysteine and glutathione react with CS₂ at a similar rate but the trithiocarbonate product undergoes a slow cyclization to give 2-thiothiazolidine-4-carboxylic acid. The potential biological relevance of these observations is briefly discussed

Carbon disulfide. Just toxic or also bioregulatory and/or therapeutic?

The overview presented here has the goal of examining whether carbon disulfide (CS2) may play a role as an endogenously generated bioregulator and/or has therapeutic value. The neuro- and reproductive system toxicity of CS2 has been documented from its long-term use in the viscose rayon industry. CS2 is also used in the production of dithiocarbamates (DTCs), which are potent fungicides and pesticides, thus raising concern that CS2 may be an environmental toxin. However, DTCs also have recognized medicinal use in the treatment of heavy metal poisonings as well as having potency for reducing inflammation. Three known small molecule bioregulators (SMBs) nitric oxide, carbon monoxide, and hydrogen sulfide were initially viewed as environmental toxins. Yet each is now recognized as having intricate, though not fully elucidated, biological functions at concentration regimes far lower than the toxic doses. The literature also implies that the mammalian chemical biology of CS2 has broader implications from inflammatory states to the gut microbiome. On these bases, we suggest that the very nature of CS2 poisoning may be related to interrupting or overwhelming relevant regulatory or signaling process(es), much like other SMBs

Photocatalytic carbon disulfide production via charge transfer quenching of quantum dots.

Carbon disulfide, a potentially therapeutic small molecule, is generated via oxidative cleavage of 1,1-dithiooxalate (DTO) photosensitized by CdSe quantum dots (QDs). Irradiation of DTO-QD conjugates leads to λ(irr) independent photooxidation with a quantum yield of ~4% in aerated pH 9 buffer solution that drops sharply in deaerated solution. Excess DTO is similarly decomposed, indicating labile exchange at the QD surfaces and a photocatalytic cycle. Analogous photoreaction occurs with the O-tert-butyl ester (t)BuDTO in nonaqueous media. We propose that oxidation is initiated by hole transfer from photoexcited QD to surface DTO and that these substrates are a promising class of photocleavable ligands for modifying QD surface coordination

Photocatalytic carbon disulfide production via charge transfer quenching of quantum dots.

Carbon disulfide, a potentially therapeutic small molecule, is generated via oxidative cleavage of 1,1-dithiooxalate (DTO) photosensitized by CdSe quantum dots (QDs). Irradiation of DTO-QD conjugates leads to λ(irr) independent photooxidation with a quantum yield of ~4% in aerated pH 9 buffer solution that drops sharply in deaerated solution. Excess DTO is similarly decomposed, indicating labile exchange at the QD surfaces and a photocatalytic cycle. Analogous photoreaction occurs with the O-tert-butyl ester (t)BuDTO in nonaqueous media. We propose that oxidation is initiated by hole transfer from photoexcited QD to surface DTO and that these substrates are a promising class of photocleavable ligands for modifying QD surface coordination