Reza Zolfaghari Emameh

Gastrointestinal (GI) malignancies are leading causes of global cancer mortality, with advanced stages showing pronounced therapeutic resistance. A key driver of this aggression is the immunosuppressive and acidic tumour microenvironment (TME). This niche is critically regulated by hypoxia-inducible carbonic anhydrase (CA) isoforms IX and XII. These enzymes catalyse extracellular carbon dioxide hydration, acidifying the milieu to promote invasion, metastasis and immune evasion. Pharmacological CA IX/XII inhibition counteracts this by normalising pH, reducing invasiveness and reinvigorating anti-tumour immunity. Oncolytic viruses (OVs) represent a complementary immunotherapeutic modality. Engineered to selectively replicate in tumour cells, OVs induce direct cytolysis and immunogenic cell death, thereby stimulating systemic immunity. However, their efficacy is hindered by the very acidosis sustained by CA activity. This establishes a compelling synergy: CA inhibition alleviates the acidic barrier to enhance OV spread and potency. Conversely, OV-mediated lysis disrupts hypoxic tumour regions, subsequently downregulating CA IX/XII expression and mitigating acidification. This bidirectional, self-reinforcing cycle positions their combination as a rational strategy to dismantle the TME's metabolic and immunological defences. Preclinical evidence supports that this multimodal approach enhances tumour regression, suppresses metastasis and prolongs survival, offering a promising translational paradigm for GI cancers.

Cholera is a bacterial diarrheal disease caused by pathogen bacteria Vibrio cholerae, which produces the cholera toxin (CT). In addition to improving water sanitation, oral cholera vaccines have been developed to control infection. Besides, rehydration and antibiotic therapy are complementary treatment strategies for cholera. ToxT regulatory protein activates transcription of CT gene, which is enhanced by bicarbonate (HCO₃^-). This review delves into the genomic blueprint of V. cholerae, which encodes for α-, β-, and γ- carbonic anhydrases (CAs). We explore how the CAs contribute to the pathogenicity of V. cholerae and discuss the potential of CA inhibitors in mitigating the disease's impact. CA inhibitors can reduce the virulence of bacteria and control cholera. Here, we reviewed all reported CA inhibitors, noting that α-CA from V. cholerae (VchCAα) was the most effective inhibited enzyme compared to the β- and γ-CA families (VchCAβ and VchCAγ). Among the CA inhibitors, acyl selenobenzenesulfonamidenamides and simple/heteroaromatic sulfonamides were the best VchCA inhibitors in the nM range. It was noted that some antibacterial compounds show good inhibitory effects on all three bacterial CAs. CA inhibitors belonging to other classes may be synthesized and tested on VchCAs to harness cholera.

Carbonic anhydrase (CA) is one of the most vital enzymes in living cells. This study has been performed due to the significance of this metalloenzyme for life and the novelty of some CA families like ζ‐CA to evaluate evolutionary processes and quality check their sequences. In this study, bioinformatics methods revealed the presence of ζ‐CA in some eukaryotic and prokaryotic microorganisms. Notably, it has not been previously reported in prokaryotes. The coexistence of β‐ and ζ‐CAs in some microorganisms is also a novel finding as well. Also, our analysis identified several CA proteins with 6–14 amino acid intervals between histidine and cysteine in the second highly conserved motif, which can be classified as the novel ζ‐CA subfamily members that emerged under the Zn deficiency of aquatic ecosystems and selection pressure in these environments. There is also a possibility that the achieved results are rooted in the contamination of samples from the environmental microbiome genome with genomes of diatom species and the occurrence of errors was observed in the DNA sequencing outcomes. Combining of all results from evolutionary analysis to quality control of ζ‐CA DNA sequences is the incentive motivation to explore more the hidden aspects of ζ‐CAs.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is potentially pathogenic and causes severe symptoms; in addition to respiratory syndromes, patients might experience other severe conditions such as digestive complications and liver complications injury. The abnormality in the liver is manifested by hepatobiliary dysfunction and enzymatic elevation, which is associated with morbidity and mortality. The direct cytopathic effect, immune dysfunction, cytokine storm, and adverse effects of therapeutic regimens have a crucial role in the severity of liver injury. According to aging and immune system alterations, cytokine patterns may also change in the elderly. Moreover, hyperproduction of cytokines in the inflammatory response to SARS-CoV-2 can lead to multi-organ dysfunction. The mortality rate in elderly patients, particularly those with other comorbidities, is also higher than in adults. Although the pathogenic effect of SARS-CoV-2 on the liver has been widely studied, the impact of age and immune-mediated responses at different ages remain unclear. This review discusses the association between immune system responses in coronavirus disease 2019 (COVID-19) patients of different ages and liver injury, focusing on cytokine alterations.

Carbonic anhydrases (CAs) are metalloenzymes that can help organisms survive in hydrothermal vents by hydrating carbon dioxide (CO₂). In this study, we focus on alpha (α), beta (β), and gamma (γ) CAs, which are present in the thermophilic microbiome of marine hydrothermal vents. The coding genes of these enzymes can be transferred between hydrothermal-vent organisms via horizontal gene transfer (HGT), which is an important tool in natural biodiversity. We performed big data mining and bioinformatics studies on α-, β-, and γ-CA coding genes from the thermophilic microbiome of marine hydrothermal vents. The results showed a reasonable association between thermostable α-, β-, and γ-CAs in the microbial population of the hydrothermal vents. This relationship could be due to HGT. We found evidence of HGT of α- and β-CAs between Cycloclasticus sp., a symbiont of Bathymodiolus heckerae, and an endosymbiont of Riftia pachyptila via Integrons. Conversely, HGT of β-CA genes from the endosymbiont Tevnia jerichonana to the endosymbiont Riftia pachyptila was detected. In addition, Hydrogenovibrio crunogenus SP-41 contains a β-CA gene on genomic islands (GIs). This gene can be transferred by HGT to Hydrogenovibrio sp. MA2-6, a methanotrophic endosymbiont of Bathymodiolus azoricus, and a methanotrophic endosymbiont of Bathymodiolus puteoserpentis. The endosymbiont of R. pachyptila has a γ-CA gene in the genome. If α- and β-CA coding genes have been derived from other microorganisms, such as endosymbionts of T. jerichonana and Cycloclasticus sp. as the endosymbiont of B. heckerae, through HGT, the theory of the necessity of thermostable CA enzymes for survival in the extreme ecosystem of hydrothermal vents is suggested and helps the conservation of microbiome natural diversity in hydrothermal vents. These harsh ecosystems, with their integral players, such as HGT and endosymbionts, significantly impact the enrichment of life on Earth and the carbon cycle in the ocean.

Background: Coronavirus disease 2019 was spread worldwide, as a pandemic, from December 2019. Venous thromboembolism events can inflict patients with coronavirus disease 2019 during the hospitalization or convalescent period. Therefore, monitoring of these patients, in terms of venous thromboembolism events signs and symptoms, and timely management of antithrombotic agents are of great importance. Case report: A 45-year-old Iranian man, who is the first author of this case report, was infected by severe acute respiratory syndrome coronavirus 2 and displayed the typical signs and symptoms of coronavirus disease 2019. Although reverse transcription polymerase chain reaction for coronavirus disease 2019, and specific immunoglobulin M and immunoglobulin G against severe acute respiratory syndrome coronavirus 2, were negative at first, chest computed tomography scan showed the characteristic pattern of lung involvement of a coronavirus disease 2019 infection including bilateral and multilobar ground-glass opacities. At that time, there were no signs or symptoms of deep-vein thrombosis or pulmonary thromboembolism, so these were not investigated. About 30 hours after hospital discharge, the patient presented back to the hospital with acute-onset chest pain. We instantly tested his blood for D-dimer, and sent him to take a Doppler sonography of his lower legs and a chest computed tomography angiography in search of pulmonary thromboembolism and deep-vein thrombosis. Although we could confirm pulmonary thromboembolism with computed tomography angiography in our patient, there were no signs or symptoms of venous thromboembolism in his lower legs, and color Doppler sonography of lower limbs was normal. So, the patient was treated with rivaroxaban as an antithrombotic agent. After some days, he was discharged in good condition. About 1 month later, he was referred to our hospital because of left lower limb edema. Although he was under antithrombotic therapy, color Doppler sonography of lower limbs revealed acute deep-vein thrombosis of the left leg. Hence, we decided to shift antithrombotic therapy from rivaroxaban to warfarin, as it is more potent than rivaroxaban in recurrent venous thromboembolism and when taking new oral anticoagulants. Unlike rivaroxaban, which needs no blood test to monitor its efficacy but has a warning for signs and symptoms of bleeding, warfarin therapy must be monitored carefully by regular blood tests for prothrombin time and international normalized ratio to maintain them in the therapeutic range. The patient was informed about the bleeding cautions, and required regular check of prothrombin time and international normalized ratio to maintain them in the proper and advised range of treatment (international normalized ratio therapeutic range 2–3). Conclusion: In the case of unexpected recurrent venous thromboembolism in coronavirus disease 2019, especially when patients are taking rivaroxaban or other new oral anticoagulants, such drugs should be substituted by warfarin, with routine follow-up, to maintain the value of prothrombin time and international normalized ratio within the therapeutic range.

Schistosoma mansoni is an intestinal parasite with one β-class carbonic anhydrase, SmaBCA. We report the sequence enhancing, production, catalytic activity, and inhibition results of the recombinant SmaBCA. It showed significant catalytic activity on CO₂ hydration in vitro with k_cat 1.38 × 10⁵ s⁻¹ and k_cat/K_m 2.33 × 10⁷ M⁻¹ s⁻¹. Several sulphonamide inhibitors, from which many are clinically used, showed submicromolar or nanomolar inhibitory effects on SmaBCA. The most efficient inhibitor with a K_I of 43.8 nM was 4-(2-amino-pyrimidine-4-yl)-benzenesulfonamide. Other effective inhibitors with K_Is in the range of 79.4–95.9 nM were benzolamide, brinzolamide, topiramate, dorzolamide, saccharin, epacadostat, celecoxib, and famotidine. The other tested compounds showed at least micromolar range inhibition against SmaBCA. Our results introduce SmaBCA as a novel target for drug development against schistosomiasis, a highly prevalent parasitic disease.