The antimalarial effect of curcumin is mediated by the inhibition of glycogen synthase kinase-3β

Curcumin, a bioactive compound in Curcuma longa, exhibits various pharmacological activities, including antimalarial effects. In silico docking simulation studies suggest that curcumin possesses glycogen synthase kinase-3β (GSK3β)-inhibitory properties. The involvement of GSK3 in the antimalarial effects in vivo is yet to be demonstrated. In this study, we aimed to evaluate whether the antimalarial effects of curcumin involve phosphorylation of host GSK3β. Intraperitoneal administration of curcumin into Plasmodium berghei NK65-infected mice resulted in dose-dependent chemosuppression of parasitemia development. At the highest dose tested (30 mg/kg body weight), both therapeutic and prophylactic administrations of curcumin resulted in suppression exceeding 50% and improved median survival time of infected mice compared to control. Western analysis revealed a 5.5-fold (therapeutic group) and 1.8-fold (prophylactic group) increase in phosphorylation of Ser 9 GSK3β and 1.6-fold (therapeutic group) and 1.7-fold (prophylactic group) increase in Ser 473 Akt in liver of curcumin-treated infected animals. Following P. berghei infection, levels of pro- and anti-inflammatory cytokines, tumor necrosis factor (TNF)-α, interferon (IFN)-γ, interleukin (IL)-10, and IL-4 were elevated by 7.5-, 35.0-, 33.0-, and 2.2-fold, respectively. Curcumin treatment (therapeutic) caused a significant decrease (by 6.0- and 2.0-fold, respectively) in serum TNF-α and IFN-γ level, while IL-10 and IL-4 were elevated (by 1.4- and 1.8-fold). Findings from the present study demonstrate for the first time that the antimalarial action of curcumin involved inhibition of GSK3β

Discrimination of clinacanthus nutans extracts and correlation with antiplasmodial activity using ATR-FTIR fingerprinting

Clinacanthus nutans or Sabah Snake Grass is a small shrub indigenous to tropical Asia. It has been used in the treatment of skin rashes, insect and snake bites, cancer and diabetes. In this study, Fourier transform infrared spectroscopy was used to discriminate the effects of different extraction methods on the chemical composition of C. nutans freeze dried leaves and stems. The samples were extracted using different methods (soaking and sonication) followed by the measurement of its antiplasmodial activity. Based on the absorption peaks, C. nutans extracts comprise of compounds with hydroxyl, methyl, sulfoxide, sulfone, aromatic and carbonyl functionalities which indicate the presence of carbohydrates, terpenes, sulfurous glycosides and aromatic compounds in the extracts. Multivariate data analysis such as orthogonal partial least square (OPLS) was used to correlate the FTIR spectra of the extracts with antiplasmodial activity. The OPLS model exhibited R2Y and Q2Y values of 0.896 and 0.736, respectively. The RMSEE and RMSECV value were 22.41 and 32.36. The loading line plot of the OPLS model revealed that OH, C[dbnd]O, C[sbnd]H and C[sbnd]C functional group induced the activity, whereas, C[sbnd]N and S[dbnd]O reduced the bioactivity. These preliminary results demonstrated that FTIR spectroscopy can be used as a simple and rapid technique to discriminate C. nutans extracts obtained from different extraction methods which is useful in the quality control during processing of this plant

Taburan parasit anura dan indeks kualiti air di kawasan tasik dan Tanah Bencah Putrajaya

Populasi anura (katak) di sesuatu ekosistem boleh menjadi penunjuk biologi bagi tahap kebersihan. Populasi yang rendah atau kadar kematian anura yang tinggi di sesuatu persekitaran menunjukkan ekosistem kawasan tersebut adalah tidak stabil, contohnya akibat pencemaran air atau kadar jangkitan parasit yang tinggi. Objektif kajian ini adalah untuk menentukan kepelbagaian spesies anura, mengenal pasti taburan parasit yang menjangkiti anura di kawasan tasik dan Tanah Bencah Putrajaya dan menentukan hubungan antara indeks kualiti air dengan taburan parasit dan anura. Sebanyak 74 ekor katak telah ditangkap sepanjang tempoh persampelan yang tergolong daripada lima famili dan enam spesies yang berbeza. Indeks kepelbagaian Shannon menunjukkan stesen LE, UN, UW, P.7 dan P.10 mempunyai nilai indeks kepelbagaian iaitu 1˗3 bermaksud kepelbagaian spesies anura adalah sederhana. Sebanyak 2437 ekor parasit telah ditemui pada semua 74 ekor katak yang telah dibedah dalam kajian ini. Anggaran 86.5% katak di kawasan Putrajaya telah dijangkiti parasit. Status indeks kualiti air bagi kesemua stesen Putrajaya adalah bersih hingga sederhana bersih (kelas II hingga III). Ujian Kruskal-Wallis mendapati bahawa taburan parasit pada anura di setiap stesen UE, UW, UN, LE, CW, P.7, dan P.10 adalah tidak signifikan (X² =9.28; df=6; p>0.05). Ini bermaksud tiada perbezaan signifikan antara taburan parasit pada anura di setiap kawasan dan jangkitan parasit ini adalah tidak dipengaruhi oleh indeks kualiti air di sesuatu stesen kajian

Konsep penghibridan 4-aminokuinolina sebagai alternatif agen antiplasmodium

Kemunculan strain parasit yang rintang terhadap hampir semua ubatan antimalaria telah mendorong para saintis mengkaji penggantian mekanisme tindakan alternatif yang lebih berkesan. Keberkesanan rawatan semasa antimalaria adalah terhad dari segi bio ketersediaan ubat yang rendah, ketoksikan ubat yang tinggi dan kadar keterlarutan dalam air yang rendah. Penghibridan adalah satu strategi menarik bagi mengembangkan konsep penemuan ubat antimalaria. Kerangka 4-aminokuinolina telah disasarkan dalam kebanyakan proses reka bentuk agen antiplasmodium kerana kos sintesisnya yang murah, selamat dan kurang toksik sejak 20 tahun yang lalu. Penemuan hibrid antiplasmodium menggunakan kerangka 4-aminokuinolina dan pelbagai moieti seperti artemisinin, piperidin, indolin, pirimidin telah menunjukkan aktiviti antiplasmodium yang baik. Walau bagaimanapun, sehingga kini penemuan hibrid ini masih tidak dapat dibangunkan dan memasuki ujian percubaan klinikal. Ulasan ini meringkaskan penemuan hibrid antiplasmodium yang telah diterbitkan dalam tempoh sebelas tahun ke belakang (2011-2021). Kelebihan dan kelemahan konsep penghibridan sebagai pengganti agen antiplasmodium sedia ada dibincangkan. Analisis kajian menunjukkan hibrid 4-aminokuinolina mempunyai aktiviti antiplasmodium yang setanding atau lebih baik secara in vitro berbanding rawatan profilaksis klorokuina. Hibrid kuinolina kelas IV adalah yang paling kerap dikaji dan diperoleh dalam kajian ini sepanjang tempoh sebelas tahun ke belakang. Kekurangan data praklinikal terperinci mengenai hibrid yang disintesis telah menghalang kajian lanjut dalam ujian klinikal

Pencirian jangkitan Plasmodium berghei NK65 pada mencit ICR sebagai model jangkitan malaria teruk

Malaria teruk atau ‘severe’ kebiasaannya disebabkan oleh jangkitan Plasmodium falciparum. Jangkitan Plasmodium falciparum pada manusia boleh menyebabkan kerosakan organ, anemia teruk, komplikasi serius, koma dan kematian. Bagi tujuan memahami patogenesis malaria teruk, model haiwan digunakan dalam kajian kali ini bagi mengenal pasti sama ada gabungan hos-parasit daripada mencit ICR dengan Plasmodium berghei NK65 boleh menyebabkan jangkitan malaria teruk pada hos. Pencirian jangkitan P. berghei ANKA pernah dilakukan sebelum ini terhadap mencit ICR; walau bagaimanapun, pencirian jangkitan P. berghei NK65 secara terperinci terhadap mencit ICR dalam kajian ini adalah pertama kali dilaporkan. Inokulasi sel darah merah (RBC) terjangkit-P. berghei NK65 (2 × 107 parasit RBC (pRBC)/ mL) dilakukan terhadap mencit ICR dengan suntikan secara intraperitoneum. Pemantauan perubahan ciri fizikal seperti berat, suhu mencit, kematian mencit, pos mortem, histologi dan aras sitokin inflamasi yang terhasil selepas jangkitan direkod untuk analisis. Strain P. berghei NK65 menghasilkan jangkitan tahap teruk terhadap mencit ICR iaitu paras parasitemia melebihi 50% pada hari ke-10 selepas jangkitan diikuti kematian. Analisis histopatologi menunjukkan jangkitan ini menyebabkan perubahan pada tisu serebrum, perlekatan leukosit pada endotelium dan pensekuesteran pRBC dalam salur darah serebrum serta pendarahan intravaskular. Selepas jangkitan, pensekuesteran pRBC dan pengumpulan pigmen malaria turut dilihat pada organ utama mencit. Tambahan lagi, edema pulmonari, pembentukan membran hialin pada peparu dan pendarahan kortikal pada ginjal dilihat pada mencit terjangkit. Sitokin proinflamasi (TNF-α, IFN-γ, dan IL-18) dan sitokin antiinflamasi (IL-10 dan IL-4) juga meningkat dalam serum mencit terjangkit. Secara rumusannya, model jangkitan mencit ICR-P. berghei NK65 yang digunakan dalam kajian ini menunjukkan ciri-ciri jangkitan malaria teruk. Hasil daripada kajian ini boleh digunakan sebagai asas untuk memahami patogenesis bagi malaria teruk pada manusia dan model jangkitan malaria haiwan pada masa akan datang

Sintesis, aktiviti antiplasmodium dan kesitotoksikan secara in vitro sebatian porfirin logam ke atas strain Plasmodium falciparum K1

Jangkitan malaria adalah penyakit berjangkit serius yang disebabkan oleh parasit plasmodium dan harus dirawat sebagai perubatan kecemasan. Sehingga kini, tiada vaksin yang sudah dikomersialkan untuk mencegah malaria. Enam sebatian porfirin logam nikel(II) dan zink(II) berasaskan porfirinmeso bebas bes 5,15-difenilporfirin (2), 5,15-diheksilporfirin (3) dan 5,10,15,20-tetrafenilporfirin (4) iaitu NiDDHP, NiDPP, NiTPP, ZnDHP, ZnDPP dan ZnTPP dihasilkan melalui penyejatan Lindsey sebelum dicirikan secara spektroskopi (resonans magnet nukleus, ultra lembayung boleh nampak, spektrometri jisim) dan fizikal (takat lebur). Aktiviti antiplasmodium dan kesitotoksikan secarain vitro terhadap strain rintang-klorokuina, P. falciparum K1 dinilai dan dibandingkan dengan aktiviti antiplasmodium dadah rujukan seperti klorokuina dan artemisinin. ZnDHP, ZnTPP dan NiDPP merencat pertumbuhan parasit dengan 50% kepekatan perencatan berkesan (EC50) dalam julat aktiviti antiplasmodium sederhana iaitu 21.4 sehingga 36.0 µM. Aktiviti kesitotoksikan terhadap sel mamalia Vero yang ditunjukkan oleh NiDPP, ZnDHP dan ZnTPP berada dalam julat tidak toksik iaitu 97 sehingga 587 µM. ZnDHP mempunyai nilai indeks pemilihan yang paling tinggi iaitu 27.2 µM, menunjukkan aktiviti antiplasmodium yang selektif terhadap perencatan plasmodium dan tidak toksik terhadap sel mamalia

Anti-malarial and cytokine-modulating effects of Andrographolide in a murine model of malaria infection

Malarial pathogenesis involves among others, uncontrolled or excessive cytokine production arising from dysregulated immune responses mounted by the host to eliminate the plasmodial parasite. The ubiquitous serine/threonine kinase, glycogen synthase kinase3β (GSK3β) is a crucial regulator of the balance between pro- and anti-inflammatory cytokine productions in the inflammatory response to pathogenic infections. Andrographolide, a bioactive compound in Andrographis paniculata, displays GSK3-inhibitory effects. A previous study elsewhere has shown that this compound has antimalarial activity but the molecular basis of its action is yet to be elucidated. Here we aimed to study the anti-malarial activity of andrographolide in a murine model of malarial infection to investigate whether its mechanism of action involves cytokine modulation and inhibition of GSK3β. Andrographolide showed strong and selective anti-plasmodial activity (IC50 = 13.70±0.71 µM; SI = 30.43) when tested against cultures of P. falciparum 3D7. Intraperitoneal administration of andrographolide (5 mg/kg body weight (bw)) into P. berghei NK65-infected ICR mice resulted in chemo-suppression of 60.17±2.12%, and significantly (P<0.05) improved median survival time of infected mice compared to nontreated control. In addition, andrographolide treatment significantly (P<0.05) decreased the level of serum pro-inflammatory cytokine, IFN-γ (1.4-fold) whilst the anti-inflammatory cytokines, IL-10 and IL-4 were increased 2.3- and 2.6-fold respectively. Western blot analyses revealed that andrographolide treatment of P. berghei NK65-infected mice resulted in an increased level of phosphorylated GSK3β (Ser9) in liver of infected mice. Andrographolide administration also decreased the levels of phosphorylated NF-κB p65 (Ser536) and phosphorylated Akt (Ser473) in liver of malaria- infected animals. Taken together, our findings demonstrate that the cytokine-modulating effect of andrographolide in experimental malarial infection involves at least in part inhibition of NF-κB activation as a consequence of GSK3β inhibition. Based on its cytokine-modulating effects, andrographolide is thus a plausible candidate for adjunctive therapy in malaria subject to clinical evaluations

Medicinal plants with antimalarial activities mediated via glycogen synthase kinase-3 beta (GSK3β) inhibition

Many of the therapeutic effects of plant extracts and bioactive compounds appear related to their immunomodulatory effects and impact on the host immune system. The immune response is desirable to mitigate established infections and, in the case of severe malaria, is a feasible approach to dealing with the overwhelming cytokine response. Glycogen synthase kinase-3 (GSK3), a Ser/Thr kinase that is a central regulator of the cytokine response, is a promising antimalarial drug target. In this review, we discussed our ongoing research projects, which include assessing the antimalarial activities of medicinal plants and their bioactive compounds, immunomodulatory activities mediated by GSK3, and the potential inflammatory pathway involved in malarial infection

Synthesis, antimalarial activities of secondary amine-substituted eugenol compounds against plasmodium falciparum and in silico molecular docking analysis

Multi-resistance cases with antimalarial drugs had been developed in over the years. One of the ways of developing antimalarial drugs is to focus on searching for the potential antifolate inhibitors against Plasmodium sp. from synthetic or natural products. The aims of this research was to synthesis secondary amine-substituted eugenol compounds through the Mannich reaction for antimalarial evaluation using Plasmodium falciparum 3D7. The compounds were also evaluated on Plasmodium falciparum dihydrofolate reductase-thymidylate synthase (PfDHFR-TS) as a protein target and the compounds’ drug-likeness properties were determined. Five secondary amine-substituted eugenol compounds (1a-e) were synthesized via substitution of the secondary amine i.e., pyrrolidine, piperidine, methyl piperidine, and morpholine in the eugenol structures. The plasmodium lactate dehydrogenase assay (pLDH) showed that 1a and 1c had good antimalarial effects against P. falciparum 3D7 with the IC50s values of 0.89 µM and 0.62 µM, respectively. The molecular docking analysis showed that 1a and 1c had perfect interaction with PfDHFR-TS (PDB ID: 1J3I) with strong hydrogen bond interactions occurring with PfDHFR-TS protein. The eugenol derivatives 1a and 1c exerted CDOCKER binding energies of -6.1407 and -6.6536 kcal/mol, respectively. Based on this research, it was found that PfDHFR-TS is a plausible protein target for the synthesized secondary amine-substituted eugenol in P. falciparum infection. The substitution of a secondary amine group for eugenol significantly enhanced the antimalarial properties of the compounds. Thus, eugenol derivatives are potential compounds to be pursued to combat folate resistance in malarial infection

Prevalence of simian malaria among macaques in Malaysia (2000–2021): A systematic review

Background The aim of Malaysia to eliminate malaria nationwide by 2020 seems need to be prolonged. Whilst Malaysia has successfully eliminated human malaria transmission, simian malaria parasites such as Plasmodium knowlesi, P. cynomolgi, P. inui and P. cynomolgi are the emerging cause of malaria in humans. The epidemiological study of simian malaria in primates provides useful information in identifying the risk of human-macaques Plasmodium infection. Methodology/Principal findings This study was performed to gather all available data in terms of simian malaria epidemiology study among macaques in Malaysia over the last two decades. This systematic review was conducted according to the PRISMA guidelines to select appropriate articles as references. Data searches were performed through international databases such as Google Scholar, PubMed, CrossRef, Scopus, Web of Science and Science Direct for original articles published from 2000 until 2021. The review identified seven simian malaria epidemiology studies in Malaysia over the 20-year study period. Most studies were conducted in Peninsular Malaysia (5/7; 71%) followed by East Malaysia (2/7; 29%). All studies showed positive detection of Plasmodium parasites in macaques. The most prevalent Plasmodium species in macaques was P. inui (49.27%) and the least prevalent was P. fieldi (4.76%). The prevalence of simian malaria was higher in East Malaysia compared to Peninsular Malaysia. The mono, dual and triple infection types were the most common among macaques. Conclusion/Significance The non-human primates like macaques are the reservoir of simian plasmodium in Malaysia. Hence, the study of host epidemiology is an important insight to public health management as there is a high occurrence of simian malaria in Malaysia. The right measurement can be taken as well to prevent the transmission of simian malaria from macaques to humans. Author summary Macaques are the most abundant primates in south east Asia including Malaysia. Due to deforestation, macaques came closer to human settlements searching for food. Macaques like the long-tailed and pig-tailed harbouring several Plasmodium species that can cause zoonotic malaria in humans. Close contact of human and macaques cause zoonotic transmission of simian malaria. The simian plasmodium such as P. knowlesi, P. inui and P. cynomolgi have been found infecting humans in Malaysia; mainly in East Malaysia (Borneo). Zoonotic malaria poses great risk to public health as prolonged in treatment often lead to fatal outcomes. Hence the knowledge of prevalence and diversity is important to access, this can therefore enlighten the authorities to plan a control strategy that will minimize the zoonotic transmission between non-human primate host to human. This systematic review has summarised all publish data of macaques-plasmodium infection from the year 2000–2021 by using PRISMA guidelines. Our result showed that P. inui (49.27%) is the most prevalent Plasmodium species found in macaques, followed by P. cynomolgi (33.05%) and P. knowlesi (26.86%). Simian plasmodium prevalent was also found higher in East Malaysia (97.0%) compared to Peninsular Malaysia (45.18%). The significant increase of simian malaria incidences in human have jeopardized the national malaria elimination programme. Hence, this study provides a compact insight into the plasmodium epidemiology of macaques in Malaysia